CN116323672A - 包含il-12和抗fap抗体的融合蛋白及其应用 - Google Patents
包含il-12和抗fap抗体的融合蛋白及其应用 Download PDFInfo
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Abstract
本发明提供了一种双特异性抗体，其包含特异性结合FAP的抗原结合位点和IL‑12或其变体。所述双特异性抗体通过IL‑12表现出抗癌作用。特别是，如果在一种抗体中形成抗FAP，则可以通过特异性定位到肿瘤部位来有效地治疗癌症。IL‑12通过FAP表达，其在肿瘤中的表达特别高。因此，双特异性抗体可用作抗癌治疗的药物组合物，因而具有较高的工业适用性。
Description
技术领域
本发明涉及包含IL-12或其变体和抗FAP抗体的新型融合蛋白，以及包含所述融合蛋白的抗癌药物组合物。
背景技术
白细胞介素-12(IL-12)是一种具有代表性的炎性细胞因子，在有效诱导细胞免疫应答中起着至关重要的作用。IL-12是一种异二聚体蛋白，其包含通过二硫键连接的40kDa(p40)和35kDa(p35)亚基，由活化的巨噬细胞、单核细胞、树突状细胞和活化的B淋巴细胞产生。IL-12可增强辅助性T细胞1(T-helper 1cell)的免疫，增加细胞T淋巴细胞的细胞毒性，并抑制血管生成。一般来说，IL-12激活T细胞和NK细胞中IFN-γ的产生。
IL-12的局部表达使肿瘤细胞对T细胞介导的细胞毒性敏感，导致肿瘤生长抑制和体液免疫的建立。然而，IL-12临床应用的缺点是，给药后可能发生全身性的细胞因子相关的毒性。这些临床结果表明，IL-12作为治疗癌症的单一药物的局限性。
另一方面，成纤维细胞活化蛋白α(FAP)是一种在活化的成纤维细胞上表达的明胶酶。已知FAP在各种人类癌症(包括前列腺癌和胰腺癌)的癌症相关成纤维细胞中的表达超过90％。因此，最近开发针对FAP表达细胞的免疫疗法的兴趣正在迅速增加(Fang J等人，Mol.Ther.Oncolytics，3:16007，2016)。
发明内容
技术问题
因此，本发明人已经研究开发出一种具有抗癌作用的新型融合蛋白。结果，本发明人发现包含IL-12和抗FAP抗体的融合蛋白提高了抗癌活性，同时降低全身毒性，从而完成了本发明。
问题的解决方案
在本发明的一个方面，提供了一种融合蛋白，其包括包含IL-12或其变体的第一单体；和包含特异性结合FAP的抗原结合位点的第二单体。
在本发明的另一方面，提供了一种用于预防或治疗癌症的药物组合物，其包含所述融合蛋白作为活性成分。
在本发明的另一方面，提供了一种编码所述第一单体的多核苷酸。
在本发明的另一方面，提供了一种编码所述第二单体的多核苷酸。
在本发明的另一方面，提供了一种包含所述多核苷酸的载体。
在本发明的另一方面，提供了一种已将所述载体引入其中的转化细胞。
在本发明的另一方面，提供了一种产生融合蛋白的方法，其包括i)培养所述转化细胞；和ii)回收包含所述第一单体和所述第二单体的融合蛋白。
在本发明的另一方面，提供了一种治疗或预防癌症的方法，其包括向受试者施用一种融合蛋白，其包含含有IL-12或其变体的第一单体，和包含特异性结合FAP的抗原结合位点的第二单体。
在本发明的另一方面，提供了一种融合蛋白，其包含含有IL-12或其变体的第一单体和包含特异性结合FAP的抗原结合位点的第二单体在治疗癌症中的应用。
在本发明的另一方面，提供了一种融合蛋白，其包含含有IL-12或其变体的第一单体和包含特异性结合FAP的抗原结合位点的第二单体在制备用于治疗癌症的药物中的应用。
发明效果
包含IL-12和特异性结合FAP的抗原结合位点的融合蛋白可能通过IL-12表现出抗癌作用。此外，还发现，当抗FAP抗体在一种抗体中实施时，IL-12在具有高FAP表达的肿瘤中特异性积累，从而降低全身性毒性并表现出肿瘤特异性抗癌效果。也就是说，通过特异性靶向肿瘤中高表达的FAP，并将IL-12特异性定位到肿瘤部位，可以有效地治疗癌症。
附图说明
图1示出了根据实施方案，通过SDS-PAGE鉴定T1.01、T1.02、T1.03、T1.04、T1.05、T1.06和T1.07获得的结果。
图2示出了根据实施方案，通过SDS-PAGE鉴定T1.08、T1.09、T1.10、T1.11、T1.12、T1.13、T1.14和T1.15获得的结果。
图3示出了根据实施方案，通过SDS-PAGE鉴定T1.16、T1.17、T1.18、T1.19和T1.21获得的结果。
图4示出了根据实施方案，通过SDS-PAGE鉴定T1.01m、T1.02m、T1.03m、T1.04m、T1.05m、T1.06m和T1.07m获得的结果。
图5示出了根据实施方案，通过SDS-PAGE鉴定T1.08m、T1.09m、T1.10m、T1.11m、T1.12m、T1.13m和T1.15m获得的结果。
图6示出了根据实施方案，通过SDS-PAGE鉴定T1.16m、T1.17m、T1.18m、T1.19m、T1.20m、T1.21m和T1.22m获得的结果。
图7示出了通过表面等离子体共振分析方法显示T1.01和T1.02与人重组FAP(rhFAP)的结合亲和力的图。
图8示出了通过表面等离子体共振分析方法显示T1.03与人重组FAP的结合亲和力的图。
图9示出了通过表面等离子体共振分析方法显示T1.04和T1.05与人重组FAP的结合亲和力的图。
图10示出了通过表面等离子体共振分析方法显示T1.06和T1.07与人重组FAP的结合亲和力的图。
图11示出了通过表面等离子体共振分析方法显示T1.08和T1.09与人重组FAP的结合亲和力的图。
图12示出了通过表面等离子体共振分析方法显示T1.10和T1.11与人重组FAP的结合亲和力的图。
图13示出了通过表面等离子体共振分析方法显示T1.01m和T1.02m与小鼠重组FAP的结合亲和力的图。
图14示出了通过表面等离子体共振分析方法显示T1.03m与小鼠重组FAP的结合亲和力的图。
图15示出了通过流式细胞术显示T1.12、T1.01、T1.02和T1.03与HEK293-hFAP细胞和HEK293细胞的结合亲和力的图。
图16示出了通过流式细胞术显示T1.12m、T1.01m、T1.02m和T1.03m与B16F10-mFAP细胞和B16F10细胞的结合亲和力的图。
图17示出了通过酶联免疫吸附测定显示T1.01、T1.02、T1.03和T1.12与IL-12受体β1的结合亲和力的图。
图18示出了通过HEKblue报告细胞中的吸光度检测T1.01m、T1.02m、T1.03m和T1.12m的IL-12活性得到的结果的图。
图19示出了通过人T细胞的信号传导能力显示T1.01、T1.02、T1.03和T1.12的IL-12活性的图。
图20示出了在低分子量肝素(LMWH)存在下通过人T细胞信号传导能力显示T1.01、T1.02和T1.03的IL-12活性的图。
图21示出了通过T1.12、T1.01、T1.02和T1.03测量人T细胞分泌细胞因子IFN-γ的能力的结果的图。
图22示出了通过T1.12、T1.01、T1.02和T1.03测量人NK细胞分泌细胞因子IFN-γ的能力的结果的图。
图23示出了通过测量小鼠FAP过表达成纤维细胞NIH-3T3和结直肠癌细胞系CT26共注射的小鼠肿瘤模型的肿瘤大小变化，显示T1.01m和T1.02m的肿瘤生长抑制能力的图。
图24示出了通过测量每个受试者的肿瘤大小而获得的结果，以在与小鼠FAP过表达成纤维细胞NIH-3T3和结直肠癌细胞系CT26共注射的小鼠肿瘤模型中鉴定T1.01m和T1.02m的肿瘤生长抑制能力。
图25示出了通过测量在小鼠肿瘤模型中植入小鼠FAP过表达结直肠癌细胞系CT26的肿瘤大小的变化，显示施用每种浓度T1.01m和T1.02m的肿瘤抑制能力的图。
图26示出了通过CT26细胞和4T1细胞移植到小鼠中构建肿瘤再激发模型后CT26肿瘤大小变化的图，其中通过T1.01m治疗在与小鼠FAP过表达成纤维细胞NIH-3T3和结直肠癌细胞系CT26共注射的小鼠肿瘤模型中实现了完全应答。
图27示出了通过CT26细胞和4T1细胞移植到小鼠中构建肿瘤再激发模型后4T1肿瘤大小变化的图，其中通过T1.01m治疗在与小鼠FAP过表达成纤维细胞NIH-3T3和结直肠癌细胞系CT26共注射的小鼠肿瘤模型中实现了完全应答。
图28示出了通过在植入小鼠FAP过表达CT26细胞的小鼠模型中测量每个受试者的肿瘤大小，显示通过给每个受试者施用T1.01m、T1.02m和T1.03m的肿瘤生长抑制能力的图。
图29示出了通过在植入小鼠FAP过表达CT26细胞的小鼠模型中测量每个受试者的肿瘤大小变化，显示通过给每个受试者施用每种浓度的T1.03m的肿瘤生长抑制能力的图。
图30示出了通过在植入小鼠FAP过表达B16F10细胞的小鼠模型中测量每个受试者的肿瘤大小变化，显示施用每种浓度的T1.03m的肿瘤生长抑制能力的图。
图31示出了在与小鼠FAP过表达成纤维细胞NIH-3T3和肺癌细胞系LLC1共注射的小鼠模型中测量每个受试者的肿瘤大小变化，显示施用每种浓度的T1.03m的肿瘤生长抑制能力的图。
图32示出了在与小鼠FAP过表达成纤维细胞NIH-3T3和肺癌细胞系LLC1共注射的小鼠模型中，在给予T1.16m、T1.17m、T1.03m或T1.16m和T1.17m的组合后10天的时间点测量肿瘤大小获得的结果的图。
图33示出了抗FAP/IL-12融合蛋白的示意图(左起第一个；图中左侧为抗FAP单体，右侧为包含IL-12的单体)、具有双可变结构域的抗FAP/IL-12融合蛋白(第二个)、与FAP特异性单链可变片段(scFv)结合的抗FAP/IL-12双抗(第三个和第四个)，以及抗FAP/IL-12融合蛋白，其中IL-12与Fc的C末端结合(第五个)。
图34示出了FAP特异性Fab/FAP特异性单链可变片段(scFv)和IL-12融合蛋白(左)、包含FAP特异性Fab和IL-12的融合蛋白二聚体(中)以及包含FAP特异性单链可变片段(scFv)和IL-12(右)的融合蛋白二聚体的示意图。
实施本发明的方式
包含IL-12和抗FAP抗体的融合蛋白
在本发明的一个方面，提供了一种融合蛋白，其包含IL-12或其变体和特异性结合FAP(成纤维细胞活化蛋白α)的抗原结合位点。具体地，融合蛋白可包含免疫球蛋白Fc区。然后，IL-12或其变体可以是具有低肝素结合能力的变体。
在一个实施方案中，提供了一种融合蛋白，其包括包含IL-12或其变体的第一单体，和包含特异性结合FAP的抗原结合位点的第二单体。
在另一个实施方案中，提供了一种融合蛋白二聚体，其包含IL-12或其变体和特异性结合FAP的抗原结合位点。
IL-12或其变体
如本文所用，术语“IL-12”是由分别由两个独立基因IL-12A和IL-12B编码的p35和p40亚基组成的异二聚体细胞因子。IL-12由抗原呈递细胞(如巨噬细胞)产生，并与活化的T细胞和NK细胞的细胞表面上的受体结合。IL-12促进T细胞和NK细胞的增殖，增强T细胞、NK细胞和巨噬细胞的细胞毒性作用。此外，IL-12诱导IFN-γ、TNF-α和GM-CSF的产生，并诱导Th1细胞的活化。另一方面，IL-12与IL-12受体结合，IL-2受体是由IL-12Rβ1和IL-12Rβ2形成的异二聚体受体。
如本文所用，术语IL-12的“变体”包括具有与野生型IL-12蛋白相似或相同功能的氨基酸序列。具体地，构成IL-12的p35和p40亚基的氨基酸序列与野生型相比可以具有取代、插入或删除。
IL-12或其变体可包括IL-12A(p35)或其变体，以及IL-12B(p40)或其变体。
此外，IL-12或其变体可包括一种结构，其中IL-12A或其变体、IL-12B或其变体由肽接头结合。
在一个实施方案中，IL-12或其变体可以是包含以下结构式(I)或(II)的融合蛋白：
N′-Y-[接头(1)]o-Z-C′(I)
N′-Z-[接头(1)]o-Y-C′(II)
在结构式(I)和(II)中，
N′可以是融合蛋白的N末端，
C′可以是融合蛋白的C末端，
Y可以是IL-12A或其变体，
Z可以是IL-12B或其变体，
接头(1)可以是肽接头，并且
o可以是0或1。
IL-12或其变体的一个实施方案可以是IL-12B或其变体、肽接头和IL-12A或其变体在N末端依次连接的结构。此外，IL-12或其变体的一个实施方案可以是IL-12A或其变体、肽接头、IL-12B或其变体在N末端依次连接的结构。
如本文所用，术语“IL-12A”是IL-12的35kDa亚基(p35)，其通过二硫键与IL-12的40kDa亚基(p40)结合以产生活性细胞因子。
IL-12A的氨基酸序列可以是GenBank索引号AAK84425(关于小鼠p35的氨基酸序列，参见GenBank索引号AAA39292)中描述的序列。此外，IL-12A(p35)基因是编码IL-12A亚基的序列，并且可以是与GenBank索引号AF404773(关于小鼠序列，参见GenBank索引号M86672)描述的序列中的编码序列(CDS)相对应的核苷酸序列。
如本文所用，术语IL-12A的“变体”包括具有与野生型IL-12A蛋白相似或相同功能的氨基酸序列。具体地，这意味着与野生型相比，IL-12A的氨基酸序列具有取代、插入或删除。具体地，IL-12A变体可以是IL-12A的片段，并且可以是删除SEQ ID NO:122的第1至第22个氨基酸的氨基酸序列。更具体地，IL-12A的变体可以具有SEQ ID NO:75的氨基酸序列。
此外，在本发明的一个实施方案中使用的IL-12A可以是作为人IL-12A的SEQ IDNO:75的氨基酸序列。在一个实施方案中，小鼠IL-12A可以是SEQ ID NO:87的氨基酸序列。
如本文所用，术语“IL-12B”是指IL-12的40kDa亚基(p40)，其通过二硫键与IL-12的35kDa亚基(p35)结合形成IL-12，并且还与IL-23的亚基p19结合形成IL-23。另一方面，IL-12B也被称为自然杀伤细胞刺激因子2。
“IL-12B”的氨基酸序列可以是GenBank索引号AAD56386(关于小鼠p40的氨基酸序列，参见GenBank索引号AAA39296)中描述的氨基酸序列。此外，IL-12B(p40)基因是编码IL-12B亚基的序列，并且可以是与GenBank索引号AF180563(关于小鼠序列，参见GenBank索引号M86671)中描述的序列的编码序列(CDS)相对应的核苷酸序列。
此外，在本发明的一个实施方案中使用的IL-12B可以是人IL-12B，并且具体地，IL-12B可以是SEQ ID NO:74的氨基酸序列。在一个实施方案中，小鼠IL-12B可以具有SEQID NO:86的氨基酸序列。
如本文所用，术语IL-12B的“变体”包括具有与野生型IL-12B蛋白相似或相同功能的氨基酸序列。具体地，这意味着与野生型相比，IL-12B的氨基酸序列具有取代、插入或删除。
具体地，IL-12B变体可以是删除SEQ ID NO:121的第1至第22个氨基酸的变体。更具体地，IL-12B变体可以是在SEQ ID NO:74的序列中1至8个氨基酸被取代的变体。此外，IL-12B变体可以是删除SEQ ID NO:123的第1至第22个氨基酸的变体。更具体地，IL-12B变体可以是在SEQ ID NO：86的序列中最多1至8个氨基酸被取代的变体。
IL-12B(p40)的变体可以是参与肝素结合IL-12的氨基酸被取代的变体。
在一个实施方案中，IL-12B(p40)的变体可以是IL-12B中与肝素结合的赖氨酸(K)被另一种氨基酸取代的形式。具体地，它可以是SEQ ID NO:74的第258、260、263和264位的赖氨酸被其他氨基酸取代的形式。具体地，IL-12B(p40)的变体可以包括对SEQ ID NO：74的氨基酸序列中选自由K258A、K260A、K263A和K264A组成的组中的至少一个进行取代获得的氨基酸序列。具体地，IL-12B(p40)的变体可以包括对SEQ ID NO:74的氨基酸序列中的K258A和K263A取代而获得的氨基酸序列，或者还可以包括在SEQ ID NO:74的氨基酸序列中K260A和/或K264A的突变。
在一个实施方案中，IL-12B(p40)的变体可以是IL-12B中与肝素结合的精氨酸(R)或赖氨酸(K)被另一种氨基酸取代的形式。具体地，它可以是SEQ ID NO:86的第254个精氨酸和/或第255、256和260个赖氨酸被其他氨基酸取代的形式。具体地，IL-12B(p40)的变体可以包括对SEQ ID NO:86的氨基酸序列中选自由R254A、K255A、K256A和K260A组成的组中的至少一个进行取代而获得的氨基酸序列。具体地，IL-12B(p40)的变体可以包括对SEQ IDNO:86的氨基酸序列中的R254A和K260A取代而获得的氨基酸序列，或者还可以包括SEQ IDNO：86序列中的K255A和/或K256A的突变。
在一个实施方案中，IL-12B(p40)的变体可包括SEQ ID NO:77、SEQ ID NO:79、SEQID NO:89或SEQ ID NO:91的氨基酸序列。
在一个实施方案中，人IL-12B变体可由以下结构式A组成：
[结构式A]
X1-L-X2
其中，X1为SEQ ID NO:125的氨基酸序列，
X2为SEQ ID NO:126的氨基酸序列，并且
L是由V-A1-A2-Q-A3-K*-A4-A5-A6-A7-K*-A8组成的氨基酸序列。
A1为R或Q，A2为V、A或I，A3为G或R*，A4为S、N或K*，A5为K*、N或E，A6为R或K，A7为E、M或T，A8为K*或E。
至少一个标有“*”的氨基酸残基可以被选自A、G、I、L、M、F、P和V组成的组中的非极性氨基酸残基取代，但不限于此。
在一个实施方案中，IL-12B(p40)的变体可以包括参与肝素结合的氨基酸的取代，以降低IL-12的细胞因子相关毒性，同时保持对癌细胞的杀伤效果。
与FAP特异性结合的FAP和抗原结合位点
本文所用的术语“FAP(fibroblast activation protein)”是指成纤维细胞活化蛋白，它是在细胞表面表达并呈现在各种肿瘤类型的肿瘤细胞的环境中或各种肿瘤类型的肿瘤细胞中的蛋白质。已知FAP在肿瘤微环境中的癌相关成纤维细胞(CAF)表面选择性地过表达。
此外，FAP为一种含有两个N-糖基化亚基的同源二聚体，在其C端的胞外结构域上有酶催化结构域，并且FAP的糖基化形式同时具有脯氨酰二肽基肽酶和明胶酶活性。
另一方面，FAP为一种脯氨酰内肽酶，其约为170kDa膜结合明胶酶。脯氨酰内肽酶FAP可以识别并切割特定的氨基酸序列。因此，FAP也被称为FAPα、分离酶或循环抗血浆切割酶。
FAP的氨基酸序列可以是GenBank索引号AAC51668中描述的氨基酸序列，并且人FAP首先通过使用单克隆抗体(mAb)F19在培养的成纤维细胞中鉴定(参见国际专利申请公开号WO 93/05804)。FAP在许多癌症中表达，由于其在正常组织中的表达有限，因此被用作成像、诊断和治疗各种癌症的有前途的抗原靶标。
FAP包括人FAP的任何变体、同种型和物种同源物，其由细胞自然表达或在用FAP基因转染的细胞上表达。本发明的抗体可以与存在于癌细胞(肿瘤细胞或肿瘤基质的细胞)膜或细胞表面的FAP结合并可能引起ADCC或其他效应器介导的癌细胞的杀伤。此外，它可用于阻断FAP的酶活性(例如丝氨酸肽酶、明胶酶、胶原酶活性)、FAP介导的ECM降解和FAP介导的细胞浸袭或迁移。
如本文所用，术语“特异性结合”是指可测量地不同于非特异性相互作用的结合。特异性结合可以通过与类似于不具有结合活性的靶标的对照分子竞争来确定。
如本文所用，术语“抗原结合位点(表位)”是指与抗体可变区中的特定抗原结合位点相互作用的决定簇。抗原结合位点是一组分子，例如氨基酸或糖侧链，其通常具有特定的结构特征以及特定的电荷特性。特异性结合FAP的抗原结合位点可以是能够特异性结合FAP的抗原抗体的分子的通用术语。
此外，抗体或其片段可以以任何形式使用，只要其含有能够特异性结合FAP的抗原结合结构域。
抗原结合位点可以包括不直接参与结合的其他氨基酸，或其作用被抗原结合位点的氨基酸残基阻断的氨基酸。
具体地，抗原结合位点可以是特异性结合FAP或其片段的抗体。
如本文所用，术语“抗体”是指含有抗原结合位点的分子，以及含有抗原结合位点的免疫球蛋白分子的免疫活性片段。所述免疫球蛋白分子可以是IgG、IgE、IgM、IgD、IgA、IgY或其亚类的免疫球蛋白分子。抗体包括合成抗体、单克隆抗体、单域抗体、单链抗体、重组产生的抗体、多特异性抗体(包括双特异性抗体)、人抗体、人源化抗体、嵌合抗体、体内抗体、scFv(包括例如单特异性和双特异性等)、Fab片段、F(ab′)片段、二硫键连接的Fv(sdFv)、抗独特型(抗-Id)抗体和抗体的抗原结合片段，但不限于此。
如本文所用，术语“抗体片段”可以是抗体的一部分，例如F(ab′)2、F(ab)2、Fab′、Fab、Fv、scFv。无论结构如何，抗体片段都与完整抗体识别的相同抗原结合。
在一个实施方案中，特异性结合FAP的抗原结合位点可包括包含如SEQ ID NO：96所示的HCDR1、如SEQ ID NO：97所示的HCDR2和如SEQ ID NO：98所示的HCDR3的重链可变区；以及包含如SEQ ID NO:99所示的LCDR1，如SEQ ID NO:100所示的LCDR2和如SEQ ID NO:101所示的LCDR3的轻链可变区。然后，在一个实施方案中，特异性结合FAP的抗原结合位点可以具有如SEQ ID NO:102所示的重链可变区和如SEQ ID NO:103所示的轻链可变区。
此外，在一个实施方案中，特异性结合FAP的抗原结合位点可包括如SEQ ID NO:104所示的HCDR1，如SEQ ID NO:105所示的HCDR2和如SEQ ID NO:106所示的HCDR3的重链可变区；以及包含如SEQ ID NO:107所示的LCDR1，如SEQ ID NO:108所示的LCDR2和如SEQ IDNO:109所示的LCDR3的轻链可变区。然后，在一个实施方案中，特异性结合FAP的抗原结合位点可以具有如SEQ ID NO:110所示的重链可变区和如SEQ ID NO:111所示的轻链可变区。
在一个实施方案中，特异性结合FAP的抗原结合位点可以是scFv。然后，scFv可以包含上述重链和轻链CDR。在一个实施方案中，特异性结合FAP的scFv可以具有SEQ ID NO:72或SEQ ID NO:84的氨基酸序列。
此外，特异性结合FAP的抗原结合位点可包括已知的抗FAP抗体或其片段。所述抗FAP抗体或其片段可以指本领域技术人员已知的抗体，但不限于此。
抗FAP抗体或其片段可以包括选自由NG-641、AMG-506/MP-0310、RG-7827的28H1、RG-7827的4B9、OMTX-705、3F2、4G8、3D9、4B3、19G1、20G8、5B8、5F1、14B3、16F1、16F8、O3C9、29B11、O2D7和23C10组成的组中的至少一个可变区。
在另一个实施例中，作为抗体，可以使用公开于韩国专利申请公开号KR20200037826A、美国专利申请公开号US 2020-0385488 A1、美国专利号US 3,924,445 B2、美国专利号US 9,011,847 B2或美国专利申请公开号US 2017-007716 A1中的抗FAP抗体或其片段。
在一个实施方案中，抗FAP抗体可包含NG-641的可变区。具体地，抗体可包括包含如SEQ ID NO：127所示的HCDR1，如SEQ ID NO:128所示的HCDR2和如SEQ ID NO:129所示的HCDR3的重链可变区，以及包含如SEQ ID NO：130所示的LCDR1，如SEQ ID NO:131所示的LCDR2和如SEQ ID NO:132所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:248所示的重链可变区和如SEQ ID NO:249所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含28H1的可变区。具体地，抗体可包括包含如SEQ ID NO:133所示的HCDR1，如SEQ ID NO:134所示的HCDR2和如SEQ ID NO:135所示的HCDR3的重链可变区，以及包含如SEQ ID NO:136所示的LCDR1，如SEQ ID NO:137所示的LCDR2和如SEQ ID NO:138所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:250所示的重链可变区和如SEQ ID NO:251所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含4B9的可变区。具体地，抗体可包括包含如SEQ ID NO：139所示的HCDR1，如SEQ ID NO:140所示的HCDR2和如SEQ ID NO:141所示的HCDR3的重链可变区，以及包含如SEQ ID NO:142所示的LCDR1，如SEQ ID NO:143所示的LCDR2和如SEQ ID NO：144所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:252所示的重链可变区和如SEQ ID NO:253所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含OMTX-705的可变区。具体地，抗体可包括包含如SEQ ID NO:145所示的HCDR1、如SEQ ID NO:146所示的HCDR2和如SEQ ID NO:147所示的HCDR3的重链可变区，以及包含如SEQ ID NO：148所示的LCDR1、如SEQ ID NO:149所示的LCDR2和如SEQ ID NO:150所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:254所示的重链可变区和如SEQ ID NO:255所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含3F2的可变区。具体地，抗体可包括包含如SEQ ID NO:151所示的HCDR1，如SEQ ID NO:152所示的HCDR2和如SEQ ID NO:153所示的HCDR3的重链可变区，以及包含如SEQ ID NO:154所示的LCDR1，如SEQ ID NO:155所示的LCDR2和如SEQ ID NO:156所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:256所示的重链可变区和如SEQ ID NO:257所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含4G8的可变区。具体地，抗体可包括包含如SEQ ID NO:157所示的HCDR1，如SEQ ID NO:158所示的HCDR2和如SEQ ID NO:159所示的HCDR3的重链可变区，以及包含如SEQ ID NO:160所示的LCDR1，如SEQ ID NO:161所示的LCDR2和如SEQ ID NO:162所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:258所示的重链可变区和如SEQ ID NO:259所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含3D9的可变区。具体地，抗体可包括包含如SEQ ID NO:163所示的HCDR1，如SEQ ID NO:164所示的HCDR2和如SEQ ID NO：165所示的HCDR3的重链可变区，以及包含如SEQ ID NO:166所示的LCDR1，如SEQ ID NO：167所示的LCDR2和如SEQ ID NO:168所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:260所示的重链可变区和如SEQ ID NO:261所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含4B3的可变区。具体地，抗体可包括包含如SEQ ID NO:169所示的HCDR1，如SEQ ID NO:170所示的HCDR2和如SEQ ID NO：171所示的HCDR3的重链可变区，以及包含如SEQ ID NO：172所示的LCDR1，如SEQ ID NO:173所示的LCDR2和如SEQ ID NO:174所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:262所示的重链可变区和如SEQ ID NO:263所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含19G1的可变区。具体地，抗体可包括包含如SEQ ID NO:175所示的HCDR1，如SEQ ID NO:176所示的HCDR2和如SEQ ID NO:177所示的HCDR3的重链可变区，以及包含如SEQ ID NO:178所示的LCDR1，如SEQ ID NO:179所示的LCDR2和如SEQ ID NO：180所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:264所示的重链可变区和如SEQ ID NO:265所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含20G8的可变区。具体地，抗体可包括包含如SEQ ID NO:181所示的HCDR1，如SEQ ID NO:182所示的HCDR2和如SEQ ID NO:183所示的HCDR3的重链可变区，以及包含如SEQ ID NO:184所示的LCDR1，如SEQ ID NO：185所示的LCDR2和如SEQ ID NO:186所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO：266所示的重链可变区和如SEQ ID NO:267所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含5B8的可变区。具体地，抗体可包括包含如SEQ ID NO:187所示的HCDR1，如SEQ ID NO:188所示的HCDR2和如SEQ ID NO：189所示的HCDR3的重链可变区，以及包含如SEQ ID NO：190所示的LCDR1，如SEQ ID NO:191所示的LCDR2和如SEQ ID NO:192所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:268所示的重链可变区和如SEQ ID NO:269所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含5F1的可变区。具体地，抗体可包括包含如SEQ ID NO:193所示的HCDR1，如SEQ ID NO：194所示的HCDR2和如SEQ ID NO:195所示的HCDR3的重链可变区，以及包含如SEQ ID NO:196的所示LCDR1，如SEQ ID NO:197所示的LCDR2和如SEQ ID NO:198所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:270所示的重链可变区和如SEQ ID NO：271所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含14B3的可变区。具体地，抗体可包括包含如SEQ ID NO:199所示的HCDR1，如SEQ ID NO:200所示的HCDR2和如SEQ ID NO:201所示的HCDR3的重链可变区，以及包含如SEQ ID NO:202所示的LCDR1，如SEQ ID NO:203所示的LCDR2和如SEQ ID NO：204所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:272所示的重链可变区和如SEQ ID NO:273所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含16F1的可变区。具体地，抗体可包括包含如SEQ ID NO:205所示的HCDR1，如SEQ ID NO:206所示的HCDR2和如SEQ ID NO：207所示的HCDR3的重链可变区，以及包含如SEQ ID NO：208所示的LCDR1，如SEQ ID NO:209所示的LCDR2和如SEQ ID NO:210所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:274所示的重链可变区和如SEQ ID NO:275所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含16F8的可变区。具体地，抗体可包括包含如SEQ ID NO:211所示的HCDR1，如SEQ ID NO:212所示的HCDR2和如SEQ ID NO:213所示的HCDR3的重链可变区，以及包含如SEQ ID NO:214所示的LCDR1，如SEQ ID NO:215所示的LCDR2和如SEQ ID NO:216所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:276所示的重链可变区和如SEQ ID NO：277所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含O3C9的可变区。具体地，抗体可包括包含如SEQ ID NO:217所示的HCDR1，如SEQ ID NO:218所示的HCDR2和如SEQ ID NO:219所示的HCDR3的重链可变区，以及包含如SEQ ID NO:220所示的LCDR1，如SEQ ID NO:221所示的LCDR2和如SEQ ID NO:222所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:278所示的重链可变区和如SEQ ID NO:279所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含22A3的可变区。具体地，抗体可包括包含如SEQ ID NO:223所示的HCDR1，如SEQ ID NO:224所示的HCDR2和如SEQ ID NO：225所示的HCDR3的重链可变区，以及包含如SEQ ID NO：226所示的LCDR1，如SEQ ID NO:227所示的LCDR2和如SEQ ID NO:228所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:280所示的重链可变区和如SEQ ID NO:281所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含29B11的可变区。具体地，抗体可包括包含如SEQ ID NO:229所示的HCDR1，如SEQ ID NO:230所示的HCDR2和如SEQ ID NO：231所示的HCDR3的重链可变区，以及包含如SEQ ID NO：232所示的LCDR1，如SEQ ID NO:233所示的LCDR2和如SEQ ID NO:234所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:282所示的重链可变区和如SEQ ID NO:283所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含O2D7的可变区。具体地，抗体可包括包含如SEQ ID NO:235所示的HCDR1，如SEQ ID NO:236所示的HCDR2和如SEQ ID NO:237所示的HCDR3的重链可变区，以及包含如SEQ ID NO:238所示的LCDR1，如SEQ ID NO:239所示的LCDR2和如SEQ ID NO:240所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO:284所示的重链可变区和如SEQ ID NO:285所示的轻链可变区。
在一个实施方案中，抗FAP抗体可包含23C10的可变区。具体地，抗体可包括包含如SEQ ID NO:241所示的HCDR1，如SEQ ID NO:242所示的HCDR2和如SEQ ID NO:243所示的HCDR3的重链可变区，以及包含如SEQ ID NO:244所示的LCDR1，如SEQ ID NO：245所示的LCDR2和如SEQ ID NO:246所示的LCDR3的轻链可变区。此外，抗FAP抗体可包含如SEQ IDNO：286所示的重链可变区和如SEQ ID NO:287所示的轻链可变区。
在一个实施方案中，抗FAP抗体可以是AMG-506/MP-0310。具体地，抗体可以包括如SEQ ID NO:247所示的氨基酸序列。
抗FAP抗体特异性结合癌细胞上存在的FAP，并且可以使用任何抗体，只要其可以诱导癌细胞死亡。
第一单体的结构
第一单体包含IL-12或其变体。
第一单体还可以包含特异性结合FAP的抗原结合位点。
在一个实施方案中，第一单体可包含IL-12或其变体；和Fc区片段或其变体。
在一个实施方案中，第一单体可包含IL-12或其变体、Fc区片段或其变体，以及特异性结合FAP的抗原结合位点。
第一单体可包括以下结构式(III)或(IV)：
N′-X-[接头(2)]p-Fc区片段或其变体-[接头(3)]q-(T)r-C′(III)
N′-(T)r-[接头(2)]q-Fc区片段或其变体-[接头(3)]p-X-C′(IV)
在结构式(III)和(IV)中，
N′可以是融合蛋白的N末端，
C′可以是融合蛋白的C末端，
X可以是结构式(I)或(II)，
T可以是特异性结合FAP的抗原结合位点，
接头(2)和(3)可以是肽接头，并且
p、q和r各自独立地为0或1。
在一个实施方案中，当r为0时，第一单体可以是融合蛋白的形式，其中IL-12或其变体和Fc区片段或其变体通过肽接头连接。
然后，第一单体可以包括如SEQ ID NO:3所示、如SEQ ID NO：4所示、如SEQ ID NO:5所示、如SEQ ID NO:15所示、如SEQ ID NO:20所示、如SEQ ID NO:21所示、如SEQ ID NO:22所示或如SEQ ID NO:32所示的氨基酸序列。
然后，在结构式(III)中，当r为1时，第一单体可以是抗FAP抗体的单体与IL-12或其变体结合的形式。
然后，在结构式(III)中，当r为1时，第一单体可以包括如SEQ ID NO:292所示、如SEQ ID NO:293所示、如SEQ ID NO:296所示、如SEQ ID NO:297所示、如SEQ ID NO:298所示、如SEQ ID NO：299所示、如SEQ ID NO:302所示或如SEQ ID NO:303所示的氨基酸序列。
然后，在结构式(IV)中，当r为1时，第一单体可以包括如SEQ ID NO:294所示、如SEQ ID NO:295所示、如SEQ ID NO:300所示或如SEQ ID NO:301所示的氨基酸序列。
在一个实施方案中，当r为1时，结构式(III)可以包括以下结构式(III′)和(III”)：
N′-X-[接头(2)]p-Fc区片段或其变体-[接头(3)]q-(T′)-C′(III′)
N′-(T”)-C′(III”)
在结构式(III′)和(III”)中，
T′为特异性结合FAP的抗体的重链区，其包含可变区和CH1区，或抗体的轻链区；
T”为特异性结合FAP的抗体的轻链区，或抗体的重链区，其包含可变区和CH1区；
其中，T′和T”相互结合形成抗体的可变区，其中所述可变区特异性结合FAP；
接头(2)至(3)为肽接头，
p和q各自独立地为0或1，并且
N′、X和C′的定义如上所述。
在一个实施方案中，当r为1时，结构式(IV)可以包括以下结构式(IV′)和(IV”)：
N′-(T′)-[接头(2)]q-Fc区片段或其变体-[接头(3)]p-X-C′(IV′)；和
N′-(T”)-C′(IV”)
在结构式(IV′)和(IV”)中，
T′为特异性结合FAP的抗体的重链区，其包含可变区和CH1区，或抗体的轻链区；
T”为特异性结合FAP的抗体的轻链区，或抗体的重链区，其包含可变区和CH1区；
其中，T′和T”相互结合形成抗体的可变区，其中所述可变区特异性结合FAP；
接头(2)至(3)为肽接头，
p和q各自独立地为0或1，并且
N′、X和C′的定义如上所述。
然后，第一单体可以包括如SEQ ID NO：10和SEQ ID NO:2所示；如SEQ ID NO：11和SEQ ID NO:2所示；如SEQ ID NO:27和SEQ ID NO:19所示；如SEQ ID NO:28和SEQ ID NO:19所示；如SEQ ID NO:294和SEQ ID NO：2所示；如SEQ ID NO:295和SEQ ID NO：2所示；如SEQID NO：300和SEQ ID NO:19所示；或如SEQ ID NO：301和SEQ ID NO：19所示的氨基酸序列。
第二单体的结构
第二单体还可以包含特异性结合FAP的抗原结合位点。
在一个实施方案中，第二单体可包含第一FAP结合位点和第二FAP结合位点。
特异性结合FAP的抗原结合位点可以是Fab、scFv、Fv或其片段。然后，第一FAP结合位点可以是Fab，第二FAP结合位点可以是Fv或scFv。
第二FAP结合位点可以与第二单体的N末端或C末端结合。具体地，第二FAP结合位点可以另外结合到重链的C末端、轻链的C末端或可变区的N末端。
第二单体可包括以下结构式(V)：
N′-(R)s-[接头(4)]t-Q-[接头(5)]u-Fc区片段或其变体-[接头(6)]v-(W)a-C′(V)
在结构式(V)中，
N′可以是融合蛋白的N末端，
C′可以是融合蛋白的C末端，
R和Q可以是特异性结合FAP的抗原结合位点，
W可以是特异性结合FAP的scFv；或结构式(I)或(II)的IL-12或其变体，接头(4)、(5)和(6)可以各自为肽接头，并且
s、t、u、v和a可以各自独立地为0或1。
在一个实施方案中，结构式(V)可以包括选自由如SEQ ID NO:1、SEQ ID NO:2、SEQID NO:6、SEQ ID NO：7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:14、SEQ ID NO：18、SEQ IDNO:19、SEQ ID NO:23、SEQ ID NO：24、SEQ ID NO:25、SEQ ID NO：26、SEQ ID NO：31、SEQ IDNO:294、SEQ ID NO：295、SEQ ID NO:300和SEQ ID NO:301所示的氨基酸序列组成的组中的至少一个。
在一个实施方案中，结构式(V)可包括以下结构式(V′)和(V”)：
N′-(R′)s-[接头(4)]t-Q′-[接头(5)]u-Fc区片段或其变体-[接头(6)]p-(W)a-C′(V′)
N′-(R”)s-[接头(4)]t-Q”-[接头(7)]x-(W)b-C′(V”)
在结构式(V′)和(V”)中，
R′可以是特异性结合FAP的抗体的重链区，其包含可变区和CH1区，或抗体的轻链区；
R”可以是特异性结合FAP的抗体的轻链区，或抗体的重链区，其包含可变区和CH1区；
其中，R′和R”可以相互结合形成抗体的可变区，其中可变区特异性结合FAP；
Q′可以是特异性结合FAP的抗体的重链区，其包含可变区和CH1区，或抗体的轻链区；
Q”可以是特异性结合FAP的抗体的轻链区，或抗体的重链区，其包含可变区和CH1区；
其中，Q′和Q”可以相互结合形成一个抗体的可变区，其中可变区特异性结合FAP，W可以是特异性结合FAP的scFv；或结构式(I)或(II)的IL-12或其变体，接头(4)、(5)、(6)和(7)可以各自为肽接头，并且
s、t、u、x、a和b可以各自独立地为0或1。
在一个实施方案中，结构式(V′)可以是SEQ ID NO:1、SEQ ID NO：6、SEQ ID NO:8、SEQ ID NO:14、SEQ ID NO:18、SEQ ID NO：23、SEQ ID NO：25、SEQ ID NO：31、SEQ ID NO:294、SEQ ID NO:295、SEQ ID NO:300或SEQ ID NO:301。
在一个实施方案中，结构式(V”)可以是SEQ ID NO:2、SEQ ID NO:7、SEQ ID NO:9、SEQ ID NO:19、SEQ ID NO:24或SEQ ID NO:26。
在一个实施方案中，第二单体可以包括由SEQ ID NO:102的氨基酸序列组成的重链和由SEQ ID NO:103的氨基酸序列组成的轻链；或由SEQ ID NO:110的氨基酸序列组成的重链和由SEQ ID NO:111的氨基酸序列组成的轻链。
此外，当W为scFv时，W可以具有SEQ ID NO:72或SEQ ID NO:84的氨基酸序列。
肽接头
如本文所用，术语“肽接头”是指用于提供物理化学距离或连接融合蛋白结构域之间的肽。接头可包含免疫球蛋白的铰链区。
肽接头(1)至(7)是指由氨基酸组成的肽接头。具体地，肽接头(2)或(5)可由5至80个连续氨基酸、7至70个连续氨基酸或10至60个连续氨基酸或12至50个氨基酸组成。肽接头可以包括(G4S)n(其中，n为1至10的整数)。然后，在(G4S)n中，n可以分别为1、2、3、4、5、6、7、8、9或10。
在一个实施方案中，肽接头(1)可以是由如SEQ ID NO:93、SEQ ID NO:94或SEQ IDNO:95所示的氨基酸序列组成的肽接头。
肽接头(2)或(5)可由5至80个连续氨基酸、7至70个连续氨基酸、10至60个连续氨基酸或12至50个氨基酸组成。在一个实施方案中，肽接头(2)可由30个氨基酸组成。此外，肽接头(2)可包含至少一个半胱氨酸。具体地，可以包含一个、两个或三个半胱氨酸。此外，肽接头(2)可以衍生自免疫球蛋白的铰链，并且还可以包括(G4S)n(其中，n为1至10的整数)。具体地，肽接头(2)可包含由以下任意一种氨基酸序列组成的铰链区：SEQ ID NO:112、SEQID NO:113、SEQ ID NO:114、SEQ ID NO:115、SEQ ID NO:116、SEQ ID NO:117、SEQ ID NO：118、SEQ ID NO:119和SEQ ID NO:120。
此外，肽接头(3)、(4)、(6)和(7)可由1至30个连续氨基酸、5至20个连续氨基酸或10至15个连续氨基酸组成。肽接头可以包括(G4S)n(其中，n为1至10的整数)。然后，在(G4S)n中，n可以分别为1、2、3、4、5、6、7、8、9或10。
此外，具体地，肽接头(2)、(3)或(5)可包括SEQ ID NO:93或SEQ ID NO:94。
在本发明的一个实施方案中，肽接头(2)或(5)可以是包含如SEQ ID NO:118或SEQID NO:120所示的氨基酸序列的肽接头。
Fc区及其片段
然后，上述免疫球蛋白片段可以是一个免疫球蛋白的Fc区。免疫球蛋白的Fc区可以是野生型Fc结构域以及
Fc结构域变体。然后，Fc区可以是IgG、IgA、IgE、IgD或IgM的Fc区域。具体地，它可能来源于IgG1或IgG2a。
如本文所用，术语“Fc结构域变体”可以指其在糖基化模式方面不同于野生型Fc结构域的形式，与野生型Fc结构域相比具有高糖基化，与野生型Fc结构域相比具有低糖基化或具有去糖基化的形式。此外，其中还包括糖基化的Fc结构域。Fc结构域或其变体可以通过培养条件或宿主的基因操作而适于具有调整数量的唾液酸、岩藻糖基化或糖基化。
此外，免疫球蛋白的Fc结构域的糖基化可以通过常规方法进行修饰，例如化学方法、酶方法和使用微生物的基因工程方法。此外，Fc结构域变体可以是免疫球蛋白IgG、IgA、IgE、IgD或IgM的各自Fc区的混合形式。此外，Fc结构域变体可以是Fc结构域的某些氨基酸被其他氨基酸取代的形式。
通过取代和/或添加引入的“氨基酸”可以是选自由赖氨酸(K)、丙氨酸(A)、精氨酸(R)、天冬酰胺(N)、天冬氨酸(D)、半胱氨酸(C)、谷氨酰胺(Q)、谷氨酸(E)、甘氨酸(G)、组氨酸(H)、异亮氨酸(I)、亮氨酸(L)、蛋氨酸(M)、苯丙氨酸(F)、脯氨酸(P)、丝氨酸(S)、苏氨酸(T)、色氨酸(W)，酪氨酸(Y)和缬氨酸(V)组成的组中的任意一种。
此外，所述Fc区域可包含旋钮结构或孔结构。
如本文所用，术语“旋钮入孔”是用于制造特异性结合不同区域的抗体的设计策略，例如双特异性抗体、多特异性抗体或异二聚体抗体。通常，该技术涉及在第一多肽(例如第一抗体重链的第一CH3结构域)的界面处引入旋钮，并在第二多肽(例如第二抗体重链的第二CH3结构域)的界面处引入一个相应的孔，使得旋钮可以定位于孔内以促进异二聚体的形成并阻碍同二聚体的形成。
“旋钮”是通过用较大的侧链(例如精氨酸、苯丙氨酸、酪氨酸或色氨酸)替换第一多肽(例如第一抗体重链的第一CH3结构域)界面的小氨基酸侧链来构建的。通过将第二多肽(例如第二抗体重链的第二CH3结构域)界面的大氨基酸侧链替换为较小的侧链(例如丙氨酸、丝氨酸、缬氨酸或苏氨酸)，在旋钮中产生相同或相似大小的互补“孔”。旋钮和孔可以通过改变编码多肽的核酸来产生，例如通过位点特异性突变或通过肽合成。
在一个实施方案中，IgG1的旋钮结构可以是SEQ ID NO:13或SEQ ID NO:288，以及孔结构可以是SEQ ID NO:12或SEQ ID NO：289。旋钮结构或孔结构可以是其中SEQ ID NO：304的氨基酸序列的第146、148和187位氨基酸被其他氨基酸取代的形式。具体地，在本发明的一个实施方案中，旋钮结构或孔结构可以是其中SEQ ID NO:304的氨基酸序列被T146W、T146S、L148A和Y187A取代的形式。具体地，旋钮结构可以是用T146W取代的形式，孔结构可以是用T146S、L148A和Y148V取代的形式。
另一方面，在本发明的一个实施方案中，IgG2a的旋钮结构可以是SEQ ID NO:30或SEQ ID NO:290，以及孔结构可以是SEQ ID NO:29或SEQ ID NO:291。旋钮结构或孔结构可以是SEQ ID NO:305的氨基酸序列的第152、154和193位氨基酸被其他氨基酸取代的形式。具体地，在本发明的一个实施方案中，旋钮结构或孔结构可以是其中SEQ ID NO：305的氨基酸序列被T152W或T152S、M154A和Y193V取代的形式。具体地，旋钮结构可以是用T152W取代的形式，以及孔结构可以是用T152S、M154A和Y193V取代的形式。
在一个实施方案中，Fc结构域变体可以包括DANG突变或NG突变。然后，“DANG突变”是指用于去除人IgG1或小鼠IgG2a中的效应器功能的D265A/N297G突变。
由IgG分子中的Fc区介导的效应器功能包括C1q结合、补体依赖性细胞毒性、Fc受体结合、抗体依赖性细胞介导的细胞毒性(ADCC)、吞噬作用、细胞表面受体(例如B细胞受体、BCR)的下调等。通常，这些效应器功能需要Fc区与结合结构域(例如抗体可变结构域)结合。
效应器功能可以通过取代非突变Fc区的氨基酸序列而改变，并且可以例如通过修饰C1q结合和/或FcR结合来设计改变效应器功能的Fc区，从而改变CDC活性和/或ADCC活性。也就是说，“DANG突变”意味着由Fc区介导的效应器功能从IgG分子中去除，从而在抗体产生过程中不会发生不需要的效应器功能。
在一个实施方案中，DANG突变可以是SEQ ID NO:289的人IgG1中的氨基酸被D45A/N77G取代的形式。此外，其可以是SEQ ID NO：291的小鼠IgG2a中的氨基酸被D51A/N83G取代的形式。
融合蛋白的结构
融合蛋白可以是抗体。具体地，所述抗体可以是包括旋钮入孔结构的异二聚体抗体。
所述融合蛋白可包括结构式(III)和结构式(V)；或结构式(IV)和结构式(V)。
更具体地，融合蛋白的一个实施方案可包含以下(i)或(ii)的第一单体；以及下文(iii)、(iv)、(v)或(vi)的第二单体：
第一单体的实例：
(i)当r为0时，结构式(III)
(ii)当r为1时，结构式(IV)
第二单体的实例：
(iii)当s、a和b为0时，结构式(V′)和结构式(V”)
(iv)当s为1且a和b为0时，结构式(V′)和结构式(V”)
(v)当s和b为0且a为1时，结构式(V′)和结构式(V”)
(vi)当b为1且s和a为0时，结构式(V′)和结构式(V”)。
在一个实施方案中，融合蛋白可包括包含上述(i)的第一单体；和包含上述(iii)的第二单体(图33中左起第一个)。然后，所述融合蛋白可以包括至少一个选自以下组的氨基酸序列：SEQ ID NO:1、SEQ ID NO：2、SEQ ID NO：3、SEQ ID NO:4、SEQ ID NO:5、SEQ IDNO:18、SEQ ID NO：19、SEQ ID NO：20、SEQ ID NO:21和SEQ ID NO:22。具体地，所述融合蛋白可包括SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3；SEQ ID NO:1、SEQ ID NO:2和SEQ IDNO:4；SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:5；SEQ ID NO:18、SEQ ID NO:19和SEQ IDNO:20；SEQ ID NO:18、SEQ ID NO：19和SEQ ID NO：21；或SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:22。
在一个实施方案中，融合蛋白可包括包含上述(i)的第一单体；和包含上述(iv)的第二单体(图33左起第二个)。然后，所述融合蛋白可以包括至少一个选自以下组的氨基酸序列：SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:20、SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24。具体地，所述融合蛋白可包括SEQ ID NO:3、SEQ ID NO:6和SEQ ID NO:7；SEQ ID NO：5、SEQ ID NO:6和SEQ ID NO:7；SEQ ID NO:20、SEQ ID NO:23和SEQ ID NO:24；或SEQ ID NO:22、SEQ ID NO:23和SEQ ID NO:24。
在一个实施方案中，融合蛋白可包括包含上述(i)的第一单体；和包含上述(v)的第二单体(图33左起第三个)。然后，所述融合蛋白可以包括至少一个选自以下组的氨基酸序列：SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:8、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:22和SEQ ID NO：25。具体地，所述融合蛋白可包括SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO：8；SEQ ID NO:2、SEQ ID NO:5和SEQ ID NO：8；SEQ ID NO:19、SEQ ID NO：20和SEQ ID NO：25；或SEQ ID NO:19、SEQ ID NO:22和SEQ ID NO:25。
在一个实施方案中，融合蛋白可包括包含上述(i)的第一单体；和包含上述(vi)的第二单体(图33左起第四个)。然后，所述融合蛋白可以包括至少一个选自以下组的氨基酸序列：SEQ ID NO:1、SEQ ID NO:3、SEQ ID NO:5、SEQ ID NO:9、SEQ ID NO:18、SEQ ID NO:20、SEQ ID NO：22和SEQ ID NO:26。具体地，所述融合蛋白可包括SEQ ID NO:1、SEQ ID NO：3和SEQ ID NO:9；SEQ ID NO:1、SEQ ID NO：5和SEQ ID NO：9；SEQ ID NO:18、SEQ ID NO:20和SEQ ID NO:26；或SEQ ID NO：18、SEQ ID NO:22和SEQ ID NO：26。
在一个实施方案中，融合蛋白可包括包含上述(ii)的第一单体；和包含上述(iii)的第二单体(图33左起第五个)。然后，所述融合蛋白可以包括至少一个选自以下组的氨基酸序列：SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO：10、SEQ ID NO:11、SEQ ID NO:18、SEQ IDNO:19、SEQ ID NO:27和SEQ ID NO:28。具体地，所述融合蛋白可包括SEQ ID NO：1、SEQ IDNO：2和SEQ ID NO:10；SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO：11；SEQ ID NO:18、SEQ IDNO:19和SEQ ID NO:27；或SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO：28。
此外，在一个实施方案中，包含IL-12或其变体和特异性结合FAP的抗原结合位点的融合蛋白二聚体可以是包含结构式(III)的单体和结构式(V)的单体的融合蛋白二聚体(图34左)。然后，在结构式(III)中，r为1，在结构式(V)中，s、a和t为0。然后，结构式(V)可以包括(V′)和(V”)。然后，在(V′)和(V”)中，s、a、t和b为0。此外，二聚体的Fc区具有旋钮入孔结构，通过该结构不同的融合蛋白可以相互结合。
具体地，所述融合蛋白可以包括至少一个选自以下组的氨基酸序列：SEQ ID NO：1、SEQ ID NO:2、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:292、SEQ ID NO:293、SEQ IDNO:298和SEQ ID NO:299。具体地，所述融合蛋白可以包括SEQ ID NO:1、SEQ ID NO：2和SEQID NO：292；SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:293；SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO：298；或SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:299。
此外，包含IL-12或其变体和特异性结合FAP的抗原结合位点的融合蛋白二聚体可以是包括结构式(V)的融合蛋白二聚体(图34中的中间)。然后，所述融合蛋白二聚体可以包括(V′)和(V”)。然后，在结构式(V)中，s和t为0，a为1。此外，在(V′)和(V”)中，s、t和b为0，a为1。此外，融合蛋白二聚体可以是包括结构式(IV)的融合蛋白二聚体。然后，在结构式(IV)中，r为1。
具体地，所述融合蛋白可以包括至少一个选自以下组的氨基酸序列：SEQ ID NO:2、SEQ ID NO：19、SEQ ID NO:294、SEQ ID NO：295、SEQ ID NO:300和SEQ ID NO:301。具体地，所述融合蛋白可包括SEQ ID NO：2和SEQ ID NO:294；SEQ ID NO:2和SEQ ID NO:295；SEQ ID NO:19和SEQ ID NO：300；或SEQ ID NO:19和SEQ ID NO:301。
在一个实施方案中，包含IL-12或其变体和特异性结合FAP的抗原结合位点的融合蛋白二聚体可以是包括结构式(III)的融合蛋白二聚体(图34中的右侧)。然后，在结构式(III)中，r为1。
具体地，所述融合蛋白可包括SEQ ID NO：296、SEQ ID NO:297、SEQ ID NO:302或SEQ ID NO:303。
本文中的多特异性融合蛋白可以是化学修饰的形式。在一个实施方案中，融合蛋白可以通过糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、与已知保护/阻断基团的衍生化、蛋白水解切割和/或与细胞配体或其他蛋白质结合进行化学修饰。许多这些化学修饰可以通过已知技术进行。
编码融合蛋白的多核苷酸
在本发明的另一方面，提供了编码第一单体的多核苷酸或编码第二单体的多核苷酸。
在一个实施方案中，第一单体的多肽可包含与SEQ ID NO：3、SEQ ID NO:4、SEQ IDNO：5、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO：15、SEQ ID NO：20、SEQ ID NO：21、SEQ IDNO：22、SEQ ID NO：27、SEQ ID NO：28、SEQ ID NO:32、SEQ ID NO:292、SEQ ID NO:293、SEQID NO:294、SEQ ID NO:295、SEQ ID NO:296、SEQ ID NO:297、SEQ ID NO:298、SEQ ID NO:299、SEQ ID NO:300、SEQ ID NO:301、SEQ ID NO:302或SEQ ID NO:303具有至少约70％、至少约75％、至少约80％、至少约85％、至少约86％、至少约87％、至少约88％、至少约89％、至少约90％、至少约91％、至少约92％、至少约93％、至少约94％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％、或至少约100％同一性的氨基酸序列。
在一个实施方案中，编码第一单体的多核苷酸可以与SEQ ID NO：38、SEQ ID NO：39、SEQ ID NO：40、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:50、SEQ ID NO:55、SEQ IDNO:56、SEQ ID NO:57、SEQ ID NO:62、SEQ ID NO:63或SEQ ID NO:67具有至少约70％、至少约75％、至少约80％、至少约85％、至少约86％、至少约87％、至少约88％、至少约89％、至少约90％、至少约91％、至少约92％、至少约93％、至少约94％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％、或至少约100％的同一性。
在一个实施方案中，第二单体的多肽可包含与SEQ ID NO:1、SEQ ID NO:2、SEQ IDNO:6、SEQ ID NO:7、SEQ ID NO：8、SEQ ID NO:9、SEQ ID NO:14、SEQ ID NO:18、SEQ ID NO：19、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、SEQ ID NO:31、SEQ IDNO：294、SEQ ID NO:295、SEQ ID NO:300或SEQ ID NO:301具有约70％、至少约75％、至少约80％、至少约85％、至少约86％、至少约87％、至少约88％、至少约89％、至少约90％、至少约91％、至少约92％、至少约93％、至少约94％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％、或至少约100％同一性的氨基酸序列。
在一个实施方案中，编码第二单体的多核苷酸可以与SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO：41、SEQ ID NO：42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO：49、SEQ IDNO:53、SEQ ID NO:54、SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60、SEQ ID NO:61或SEQID NO:66具有至少约70％、至少约75％、至少约80％、至少约85％、至少约86％、至少约87％、至少约88％、至少约89％、至少约90％、至少约91％、至少约92％、至少约93％、至少约94％、至少约95％、至少约96％、至少约97％、至少约98％、至少约99％、或至少约100％的同一性。
所述多核苷酸还可以包含编码信号序列或前导序列的核酸。如本文所用，术语“信号序列”是指指导靶蛋白分泌的信号肽。信号肽被翻译，然后在宿主细胞中切割。具体地，信号序列是启动蛋白质通过内质网(ER)膜转运的氨基酸序列。
信号序列因其特性而在本领域是众所周知的。这种信号序列通常含有16至30个氨基酸残基，并且可以含有比这种氨基酸残基更多或更少的氨基酸残基。典型的信号肽由三个区域组成，即碱性N末端区域、中心疏水区域和极性更强的C末端区域。中央疏水区域包含4至12个疏水残基，这些疏水残基导致信号序列在未成熟多肽通过膜脂双层运输过程中被固定。
启动后，信号序列在ER的腔内被细胞酶(通常称为信号肽酶)切割。然后，信号序列可以是tPa(组织纤溶酶原激活剂)，HSV gDs(单纯疱疹病毒糖蛋白D的信号序列)或生长激素的分泌信号序列。优选地，可以使用用于包括哺乳动物等在内的高等真核细胞的分泌信号序列。此外，可以使用野生型信号序列，或者可以使用在宿主细胞中被具有高表达频率的密码子取代的信号序列。
含有多核苷酸的载体
在本发明的另一方面，提供了包含多核苷酸的载体。
载体可以被引入宿主细胞中，与宿主细胞的基因组重组并插入其中。或者，载体被理解为包括多核苷酸序列的核酸手段，该多核苷酸序列可作为附加体自主复制。所述载体包括线性核酸、质粒、噬菌体、粘粒(cosmid)、RNA载体、病毒载体及其类似物。病毒载体的实例包括但不限于逆转录病毒、腺病毒和腺相关病毒。
具体地，载体可以包括质粒DNA、噬菌体DNA等；以及商业开发的质粒(pUC18、pBAD、pIDTSAMRT-AMP等)、大肠杆菌衍生质粒(pYG601BR322、pBR325、pUC118、pUC119等)、枯草芽孢杆菌衍生质粒(pUB110、pTP5等)、酵母衍生质粒(YEp13、YEp24、YCp50等)、噬菌体DNA(Charon4A、Charon21A、EMBL3、EMBL4、λgt10、λgt11、λZAP等)、动物病毒载体(逆转录病毒、腺病毒、牛痘病毒等)，昆虫病毒载体(杆状病毒等)。由于载体根据宿主细胞表现出不同的表达水平和蛋白质修饰，因此优选选择和使用最适合该目的的宿主细胞。
如本文所用，术语目标蛋白的“基因表达”或“表达”被理解为DNA序列的转录、mRNA转录本的翻译以及融合蛋白产物或其片段的分泌。有用的表达载体可以是RcCMV(Invitrogen，Carlsbad)或其变体。表达载体可以含有用于促进哺乳动物细胞中靶基因连续转录的人巨细胞病毒(CMV)启动子，以及用于提高转录后RNA稳定性水平的牛生长激素聚腺苷酸化信号序列。
表达融合蛋白的转化细胞
在本发明的另一方面，提供了一种已将载体引入其中的转化细胞。
转化细胞的宿主细胞可以包括但不限于原核细胞、真核细胞和哺乳动物、植物、昆虫、真菌或细菌来源的细胞。作为原核细胞的一个例子，可以使用大肠杆菌。此外，作为真核细胞的一个例子，可以使用酵母。此外，对于哺乳动物细胞，可以使用CHO细胞、F2N细胞、CSO细胞、BHK细胞、Bowes黑色素瘤细胞、HeLa细胞、911细胞、AT1080细胞、A549细胞、HEK293细胞、HEK293T细胞等。然而，哺乳动物细胞不限于此，任何本领域技术人员已知的可用作哺乳动物宿主细胞的细胞都可以使用。
此外，为了将表达载体引入宿主细胞，CaCl2沉淀，Hanahan方法通过在CaCl2沉淀中使用还原剂(例如二甲基亚砜(DMSO))来提高效率，电穿孔、磷酸钙沉淀、原生质体融合、使用碳化硅纤维搅拌、农杆菌介导的转化，使用PEG、硫酸葡聚糖、脂质体或干/抑制介导的转化，或可以使用类似物。
如上所述，为了优化融合蛋白作为治疗剂的性质或用于任何其他目的，融合蛋白的糖基化模式(例如，唾液酸、岩藻糖基化、糖基化)可以通过本领域技术人员已知的方法操纵宿主细胞所具有的糖基化相关基因来调节。
产生融合蛋白的方法
在本发明的另一方面，提供了一种产生融合蛋白的方法，包括i)培养转化细胞；ii)回收包含第一单体和第二单体的融合蛋白。
培养转化细胞的方法可以使用本领域公知的方法进行。具体地，所述培养可以在分批进料过程中进行，或者在补料分批或重复补料分批过程中连续进行。
融合蛋白的使用
在本发明的另一方面，提供了一种用于预防或治疗癌症的药物组合物，其包含融合蛋白作为活性成分。
然后，所述癌症可以是选自由胃癌、肝癌、肺癌、结直肠癌、乳腺癌、前列腺癌、皮肤癌、骨癌、多发性骨髓瘤、神经胶质瘤、卵巢癌、胰腺癌、宫颈癌、甲状腺癌、喉癌、急性髓系白血病、慢性髓系白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、脑肿瘤、神经母细胞瘤、视网膜母细胞瘤、头颈癌、唾液腺癌和淋巴瘤组成的组中的任一种。
药物组合物的优选剂量根据患者的病情和体重、疾病的严重程度、药物形式、给药途径和持续时间而变化，并且可以由本领域技术人员适当地选择。在本发明用于治疗或预防肿瘤的药物组合物中，活性成分可以根据应用、剂型、混合目的等以任意量(有效量)含有，只要活性成分可以表现出治疗肿瘤的活性或特别是对癌症的治疗效果。其常规有效量将基于组合物的总重量在0.001％至20.0％重量的范围内确定。然后，术语“有效量”是指活性成分的量，其能够诱导改善或治疗疾病状况的效果，特别是诱导改善或治疗癌症状况的效果。这种有效量可以在本领域技术人员的公知范围内通过实验确定。
如本文所用，术语“治疗”可用于表示治疗性和预防性治疗。然后，预防可用于表示缓解或减轻受试者的病理状况或疾病。在一个实施方案中，术语“治疗”既包括应用或任何形式的给药，也包括用于治疗哺乳动物(包括人)的疾病。此外，该术语包括抑制或减缓疾病的进展；并且包括恢复或修复受损或丧失的功能，以部分或完全缓解疾病的含义；刺激低效流程；或缓解严重疾病。
药代动力学参数(例如生物利用度)和基础参数(例如清除率)也可能影响疗效。因此，“增强功效”(例如功效的改善)可以是由于增强的药代动力学参数和增强的功效，这可以通过比较试验动物或人类受试者的肿瘤，诸如清除率和治疗或改善等参数来测量。
如本文所用，术语“治疗有效量”或“药学有效量”是指有效预防或治疗所讨论疾病的化合物或组合物的量，其足以以适用于医学治疗的合理益处/风险比治疗该疾病并且不引起副作用。有效量的水平可以取决于包括患者的健康状况、疾病的类型和严重程度、药物的活性、患者对药物的敏感性、给药方式、给药时间、给药途径和排泄率、治疗持续时间、配方或同时使用的药物，以及医学领域公知的其他因素等因素来确定。在一个实施方案中，治疗有效量是指有效治疗癌症的药物的量。
然后，所述药物组合物可进一步包含药学上可接受的载体。药学上可接受的载体可以是任何载体，只要该载体是适合递送给患者的无毒物质。可以含有蒸馏水、酒精、脂肪、蜡和惰性固体作为载体。药学上可接受的佐剂(缓冲剂、分散剂)也可以包含在药物组合物中。
具体地，通过包括除活性成分之外的药学上可接受的载体，可以使用本领域已知的常规方法根据给药途径将药物组合物制备成肠胃外制剂。然后，术语“药学上可接受的”是指载体不具有比要施用(规定)的受试者可以适应的毒性更大的毒性，同时不抑制活性成分的活性。
当将药物组合物制备成肠胃外制剂时，可以根据本领域已知的方法将其制成具有合适载体的注射剂、透皮贴剂、鼻吸入剂或栓剂形式的制剂。在被制成注射剂的情况下，可以使用无菌水、乙醇、多元醇如甘油或丙二醇，或其混合物可用作合适的载体；可以优选使用等渗溶液，例如林格氏溶液、含有三乙醇胺或无菌注射用水的磷酸盐缓冲盐水(PBS)，和5％葡萄糖等。药物组合物的配方是本领域已知的，并且可以具体参考雷明顿的《药物科学》(第19版，1995)等。本文档被视为本规范的一部分。
药物组合物的优选剂量范围可以是每天0.01μg/kg至10g/kg，或0.01mg/kg至1g/kg，这取决于患者的状况、体重、性别、年龄、患者的严重程度和给药途径。剂量可以每天施用一次，也可以每天分成几次。这样的剂量不应被解释为在任何方面限制本发明的范围。
可以应用(规定)药物组合物的受试者为哺乳动物和人，特别优选人。除了活性成分之外，本申请的药物组合物还可以含有任何化合物或天然提取物，其已知对肿瘤具有治疗作用。
在本发明的另一方面，提供了融合蛋白的用途，其包括包含IL-12或其变体的第一单体；以及包含用于治疗癌症的特异性结合FAP的抗原结合位点的第二单体，用于治疗癌症。
在本发明的另一方面，提供了融合蛋白的用途，其包含含有IL-12或其变体的第一单体；以及包含特异性结合FAP的抗原结合位点的第二单体，用于制造治疗癌症的药物。
在本发明的又一方面，提供了一种治疗或预防癌症的方法，包括向受试者施用融合蛋白，所述融合蛋白包含含有IL-12或其变体的第一单体；以及包含特异性结合FAP的抗原结合位点的第二单体。
那么，受试者可以是患有癌症的受试者。此外，受试者可以是哺乳动物，优选人。
融合蛋白或融合蛋白二聚体的给药途径、剂量和给药频率可以根据患者的病情和是否存在副作用而变化，因此融合蛋白或融合蛋白二聚体可以以各种方式和量施用于受试者。最佳给药方法、剂量和给药频率可由本领域技术人员在适当范围内选择。此外，融合蛋白或融合蛋白二聚体可以与其他药物或生理活性物质组合施用，其治疗效果相对于待治疗的疾病是已知的，或者可以配制成与其他药物的组合制剂的形式。
在下文中，将通过以下实施例对本发明进行更详细的描述。但是，以下实施例仅用于说明本发明，本发明的保护范围并不限于此。
制备实施例1.人融合蛋白抗FAP/IL-12 IgG1 DANG的概述
[表1]
[seq1]由人抗FAP重链可变区序列和人IgG1 Fc组成，其中通过DANG突变(D265A，N297G)去除效应器功能，并通过T366W突变形成旋钮结构。
[seq2]由人抗FAP轻链序列组成。
[seq3]由人IL-12 p40(β)区序列和接头GGGGSGGGGSGGGGS、人白细胞介素12p35(α)区序列、接头GGGGSGGGGS和人IgG1 Fc组成，其中通过DANG突变(D265A，N297G)去除效应器功能，并通过T366S、L368A和Y407V突变形成孔结构。
[seq4]由一个序列组成，其中人IL-12 p40(β)区中与肝素结合的第280和第285位氨基酸的赖氨酸(K)突变为丙氨酸(A)、接头GGGGSGGGGSGGGGS、人IL-12 p35(α)区序列、接头GGGGSGGGGS和人IgG1 Fc孔DANG。
[seq5]由一个序列组成，其中人IL-12 p40(β)区中与肝素结合的第280、282、285和286位氨基酸的赖氨酸(K)突变为丙氨酸(A)、接头GGGGSGGGGSGGGGS、人IL-12 p35(α)区序列、接头GGGGSGGGGS和人IgG1 Fc孔DANG。
[seq6]由人抗FAP重链可变区序列、接头GGGGSGGGGSGGGGS、人抗FAP重链可变区序列和人IgG1 Fc旋钮DANG组成。
[seq7]由人抗FAP轻链可变区序列、接头GGGGSGGGGSGGGGS和人抗FAP轻链序列组成。
[seq8]由人抗FAP重链可变区序列、人IgG1 Fc旋钮DANG、接头GGGGSGGGGSGGGGS、人抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和人抗FAP轻链可变区序列组成。
[seq9]由人抗FAP轻链序列、接头GGGGSGGGGSGGGGS、人抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和人抗FAP轻链可变区序列组成。
[seq10]由人抗FAP重链序列、人IgG1 Fc孔DANG、接头GGGGSGGGGSGGGGS、人IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和人IL-12 p35(α)区序列组成。
[seq11]由人抗FAP重链序列、人IgG1 Fc孔DANG、接头GGGGSGGGGSGGGGS、包含参与肝素结合的氨基酸突变(四个)的人IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和人IL-12 p35(α)区序列组成。
[seq12]仅由人IgG1 Fc孔DANG组成。
[seq13]仅由人IgG1 Fc旋钮DANG组成。
[seq14]由人抗FAP重链可变区序列和人IgG1 Fc DANG组成。
[seq15]由包含参与肝素结合的氨基酸突变(四个)的人IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS、人IL-12 p35(α)区序列、接头GGGGSGGGGS和人IgG1Fc DANG组成。
[seq16]由人抗CD20抗体和人IgG1 Fc旋钮DANG的重链序列组成。
[seq17]为人抗CD20抗体的轻链序列。
[seq292]由人IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、人IL-12 p35(α)区序列、接头GGGGSGGGGS和人IgG1 Fc孔DANG、接头GGGGSGGGGSGGGGS、人抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和人抗FAP轻链可变区序列组成。
[seq293]由包含参与肝素结合的氨基酸突变(四个)的人IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、人IL-12 p35(α)区序列、接头GGGGSGGGGS和人IgG1Fc孔DANG、接头GGGGSGGGGSGGGGS、人抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和人抗FAP轻链可变区序列组成。
[seq294]由人抗FAP重链序列、人IgG1 Fc DANG、接头GGGGSGGGGSGGGGS、人IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和人IL-12 p35(α)区序列组成。
[seq295]由人抗FAP重链序列、人IgG1 Fc DANG、接头GGGGSGGGGSGGGGS、包含参与肝素结合的氨基酸突变(四个)的人IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和人IL-12 p35(α)区序列组成。
[seq296]由人IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、人IL-12 p35(α)区序列、接头GGGGSGGGGS和人IgG1 Fc DANG、接头GGGGSGGGGSGGGGS、人抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和人抗FAP轻链可变区序列组成。
[seq297]由包含参与肝素结合的氨基酸突变(四个)的人IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、人IL-12 p35(α)区序列、接头GGGGSGGGGS和人IgG1Fc DANG、接头GGGGSGGGGSGGGGS、人抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和人抗FAP轻链可变区序列组成。
T1.01(seq1，seq2，seq3)为一种双特异性抗体，其中靶向人FAP的人抗FAP序列和人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.02(seq1，seq2，seq4)为一种双特异性抗体，其中靶向人FAP的人抗FAP序列和含有参与肝素结合的氨基酸突变(两个)的人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.03(seq1，seq2，seq5)为一种双特异性抗体，其中靶向人FAP的人抗FAP序列和含有参与肝素结合的氨基酸突变(四个)的人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.04(seq3，seq6，seq7)为一种双特异性抗体，其中双可变结构域免疫球蛋白(DVD-Ig)形式的人抗FAP序列和人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.05(seq5，seq6，seq7)为一种双特异性抗体，其中DVD-Ig形式的人抗FAP序列和含有参与肝素结合的氨基酸突变(四个)的人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.06(seq2，seq3，seq8)为一种双特异性抗体，其中人抗FAP序列中的单链可变片段(靶向人FAP的人抗FAP序列的scFv)与重链的C末端连接，人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.07(seq2，seq5，seq8)为一种双特异性抗体，其中人抗FAP序列中的靶向人FAP的人抗FAP序列的scFv与重链的C末端连接，并且含有参与肝素结合的氨基酸突变(四个)的人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.08(seq1，seq3，seq9)为一种双特异性抗体，其中人抗FAP序列中的靶向人FAP的人抗FAP序列的scFv与轻链的C末端连接，并且人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.09(seq1，seq5，seq9)为一种双特异性抗体，其中人抗FAP序列中的靶向人FAP的人抗FAP序列的scFv与轻链的C末端连接，并且含有参与肝素结合的氨基酸突变(四个)的人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.10(seq1，seq2，seq10)为一种抗体，其中靶向人FAP的人抗FAP序列和其中人IL-12序列与重链的C末端连接的人抗FAP序列形成旋钮入孔结构。
T1.11(seq1，seq2，seq11)为一种抗体，其中靶向人FAP的人抗FAP序列和其中含有参与肝素结合的氨基酸突变(四个)的人IL-12序列与重链的C末端连接的人抗FAP序列形成旋钮入孔结构。
T1.12(seq1，seq2，seq12)为一种抗体，其中仅具有靶向人FAP的人抗FAP序列的旋钮入孔结构的效应器功能被去除。
T1.13(seq3，seq13)为一种抗体，其中仅具有人IL-12序列的旋钮入孔结构的效应器功能被去除。
T1.14(seq4，seq13)为一种抗体，其中仅具有含有参与肝素结合的氨基酸突变(两个)的人IL-12序列的旋钮入孔结构的效应器功能被去除。
T1.15(seq5，seq13)为一种抗体，其中仅具有含有参与肝素结合的氨基酸突变(四个)的人IL-12序列的旋钮入孔结构的效应器功能被去除。
T1.16(seq2，seq14)为一种靶向人FAP的人抗FAP抗体。
T1.17(seq15)为一种Fc融合蛋白，其仅具有含有参与肝素结合的氨基酸突变(四个)的人IL-12序列。
T1.18(seq3，seq16，seq17)为一种双特异性抗体，其中靶向人CD20的人抗CD20序列和人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.19(seq4，seq16，seq17)为一种双特异性抗体，其中靶向人CD20的人抗CD20序列和含有参与肝素结合的氨基酸突变(两个)的人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.20(seq5，seq16，seq17)为一种双特异性抗体，其中靶向人CD20的人抗CD20序列和含有参与肝素结合的氨基酸突变(四个)的人IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.21(seq12，seq16，seq17)为一种抗体，其中仅具有靶向人CD20的人抗CD20序列的旋钮入孔结构的效应器功能被去除。
T1.23(seq1，seq2，seq292)为一种双特异性抗体，其中人抗FAP序列和人IL-12序列，其中人抗FAP序列的scFv与C末端连接形成旋钮入孔结构，并去除效应器功能。
T1.24(seq1，seq2，seq293)为一种双特异性抗体，其中人抗FAP重链序列和含有参与肝素结合的氨基酸突变(四个)的人IL-12序列，其，其中人抗FAP序列的scFv与C末端连接形成旋钮入孔结构，并去除效应器功能。
T1.25(seq2，seq294)为一种含有人抗FAP序列的Fc融合蛋白二聚体，，其中人IL-12序列与重链的C末端连接。
T1.26(seq2，seq295)为一种含有人抗FAP序列的Fc融合蛋白二聚体，其中含有参与肝素结合的氨基酸突变(四个)的人IL-12序列与重链的C末端连接。
T1.27(seq296)为一种含有人IL-12序列的Fc融合蛋白二聚体，其中人抗FAP序列的scFv与C末端连接。
T1.28(seq297)为一种Fc融合蛋白二聚体，其由含有参与肝素结合的氨基酸突变(四个)的人IL-12序列组成，其中人抗FAP序列的scFv与C末端连接。
[seq1]抗-hu FAP HC hu IgG1 Fc旋钮DANG
[seq2]抗-hu FAP LC
[seq3]hu scIL-12-hu IgG1 Fc孔DANG
[seq4]hu scIL-12 mut1-hu IgG1 Fc孔DANG
[seq5]hu scIL-12 mut2-hu IgG1 Fc孔DANG
[seq6](抗-hu FAP VH)2-hu IgG1 Fc旋钮DANG
[seq7](抗-hu FAP VL)2
[seq8]抗-hu FAP HC hu IgG1 Fc旋钮DANG-抗-hu FAP scFv
[seq9]抗-hu FAP LC-抗-hu FAP scFv
[seq10]抗-hu FAP HC hu IgG1 Fc孔DANG-hu scIL-12
[seq11]抗-hu FAP HC hu IgG1 Fc孔DANG-hu scIL-12 mut2
[seq12]hu IgG1 Fc孔DANG
[seq13]hu IgG1 Fc旋钮DANG
[seq14]抗-hu FAP HC hu IgG1 Fc DANG
[seq15]hu scIL-12 mut2-hu IgG1 Fc DANG
[seq16]抗-hu CD20 HC hu IgG1 Fc旋钮DANG
[seq17]抗-hu CD20 LC
[seq292]hu scIL-12-hu IgG1 Fc孔DANG-抗-hu FAP scFv
[seq293]hu scIL-12 mut2-hu IgG1 Fc孔DANG-抗-hu FAP scFv
[seq294]抗-hu FAP HC hu IgG1 Fc DANG-hu scIL-12
[seq295]抗-hu FAP HC hu IgG1 Fc DANG-hu scIL-12 mut2
[seq296]hu scIL-12-hu IgG1 Fc DANG-抗-hu FAP scFv
[seq297]hu scIL-12 mut2-hu IgG1 Fc DANG-抗-hu FAP scFv
制备实施例2.小鼠融合蛋白抗FAP/IL-12 IgG2a DANG的概述
[表2]
[seq18]由小鼠抗FAP重链可变区序列和小鼠IgG2a Fc组成，其中通过DANG突变(D265A，N297G)去除效应器功能，并通过T321W突变形成旋钮结构。
[seq19]由小鼠抗FAP轻链序列组成。
[seq20]由小鼠IL-12 p40(β)区域序列，接头GGGGSGGGGSGGGGS，小鼠IL-12p35(α)区序列，接头GGGGSGGGGS和小鼠IgG2a Fc组成，其中通过DANG突变去除效应器功能，并由T321S、M323A、Y362V突变形成孔结构。
[seq21]由一个序列组成，其中小鼠IL-12 p40(β)区中参与肝素结合的第277和第282位氨基酸的赖氨酸(K)突变为丙氨酸(A)、接头GGGGSGGGGSGGGGS、小鼠IL-12 p35(α)区序列、接头GGGGSGGGGS和小鼠IgG2a Fc孔DANG。
[seq22]由一个序列组成，其中小鼠IL-12 p40(β)区中参与肝素结合的第276位氨基酸的精氨酸(R)和第277、278和282位氨基酸的赖氨酸(K)突变为丙氨酸(A)、接头GGGGSGGGGSGGGGS、小鼠IL-12 p35(α)区序列、接头GGGGSGGGGS和小鼠IgG2a Fc孔DANG。
[seq23]由小鼠抗FAP重链可变区序列、接头GGGGSGGGGSGGGGS、小鼠抗FAP重链可变区序列和小鼠IgG2a Fc旋钮DANG组成。
[seq24]由小鼠抗FAP轻链可变区序列、接头GGGGSGGGGSGGGGS和小鼠抗FAP轻链序列组成。
[seq25]由小鼠抗FAP重链可变区序列、小鼠IgG2a Fc旋钮DANG、接头GGGGSGGGGSGGGGS、小鼠抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和小鼠抗FAP轻链可变区序列组成。
[seq26]由小鼠抗FAP轻链序列、接头GGGGSGGGGSGGGGS、小鼠抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和小鼠抗FAP轻链可变区序列组成。
[seq27]由小鼠抗FAP重链序列、小鼠IgG2a Fc孔DANG、接头GGGGSGGGGSGGGGS、小鼠IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和小鼠IL-12 p35(α)区序列组成。
[seq28]由小鼠抗FAP重链序列、小鼠IgG2a Fc孔DANG、接头GGGGSGGGGSGGGGS、含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和小鼠IL-12 p35(α)区序列组成。
[seq29]仅由小鼠IgG2a Fc孔DANG组成。
[seq30]仅由小鼠IgG2a Fc旋钮DANG组成。
[seq31]由小鼠抗FAP重链可变区和小鼠IgG2a Fc DANG组成。
[seq32]由含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS、小鼠IL-12 p35(α)区序列、接头GGGGSGGGGS和小鼠IgG2a Fc DANG组成。
[seq33]由小鼠抗CD20抗体18B12和小鼠IgG2a旋钮DANG的重链可变区序列组成。
[seq34]由小鼠抗CD20抗体18B12的轻链序列组成。
[seq35]仅由小鼠IgG2a Fc DANG组成。
[seq298]由小鼠IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、小鼠IL-12p35(α)区序列、接头GGGGSGGGGS和小鼠IgG2a Fc孔DANG、接头GGGGSGGGGSGGGGS、小鼠抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和小鼠抗FAP轻链可变区序列组成。
[seq299]由含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、小鼠IL-12 p35(α)区序列、接头GGGGSGGGGS和小鼠IgG2a Fc孔DANG、接头GGGGSGGGGSGGGGS、小鼠抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和小鼠抗FAP轻链可变区序列组成。
[seq300]由小鼠抗FAP重链序列、小鼠IgG2a Fc DANG、接头GGGGSGGGGSGGGGS、小鼠IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和小鼠IL-12 p35(α)区序列组成。
[seq301]由小鼠抗FAP重链序列、小鼠IgG1 Fc DANG、接头GGGGSGGGGSGGGGS、含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12的p40(β)区序列、接头GGGGSGGGGSGGGGS和小鼠IL-12 p35(α)区序列组成。
[seq302]由小鼠IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、小鼠IL-12p35(α)区序列、接头GGGGSGGGGS和小鼠IgG2a Fc DANG、接头GGGGSGGGGSGGGGS、小鼠抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和小鼠抗FAP轻链可变区序列组成。
[seq303]由含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12 p40(β)区序列、接头GGGGSGGGGSGGGGS、小鼠IL-12 p35(α)区序列、接头GGGGSGGGGS和小鼠IgG2a Fc DANG、接头GGGGSGGGGSGGGGS、小鼠抗FAP重链可变区序列、接头GGGGSGGGGSGGGGSGGGGS和小鼠抗FAP轻链可变区序列组成。
T1.01m(seq18，seq19，seq20)为一种双特异性抗体，其中靶向小鼠FAP的小鼠抗FAP序列和小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.02m(seq18，seq19，seq21)为一种双特异性抗体，其中靶向小鼠FAP的小鼠抗FAP序列和含有参与肝素结合的氨基酸突变(两个)的小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.03m(seq18，seq19，seq22)为一种双特异性抗体，其中靶向小鼠FAP的小鼠抗FAP序列和含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.04m(seq20，seq23，seq24)为一种双特异性抗体，其中以双可变结构域免疫球蛋白(DVD-Ig)形式靶向小鼠FAP的小鼠抗FAP序列和小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.05m(seq22，seq23，seq24)为一种双特异性抗体，其中以DVD-Ig形式靶向小鼠FAP的小鼠抗FAP序列和含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.06m(seq19，seq20，seq25)为一种双特异性抗体，其中小鼠抗FAP序列中靶向小鼠FAP的小鼠抗FAP序列的单链可变片段(scFv)被包括在重链的C末端和小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.07m(seq19，seq22，seq25)为一种双特异性抗体，其中小鼠抗FAP序列中靶向小鼠FAP的小鼠抗FAP序列的scFv被包括在重链的C末端和含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.08m(seq18，seq20，seq26)为一种双特异性抗体，其中小鼠抗FAP序列中靶向小鼠FAP的小鼠抗FAP序列的scFv被包括在轻链的C末端和小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.09m(seq18，seq22，seq26)为一种双特异性抗体，其中小鼠抗FAP序列中靶向小鼠FAP的小鼠抗FAP序列的scFv被包括在轻链的C末端和含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.10m(seq18，seq19，seq27)为一种抗体，其中靶向小鼠FAP的小鼠抗FAP序列和其中小鼠IL-12序列与重链的C末端连接的小鼠抗FAP序列形成旋钮入孔结构。
T1.11m(seq18，seq19，seq28)为一种抗体，其中靶向小鼠FAP的小鼠抗FAP序列和其中含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列与重链的C末端连接的小鼠抗FAP序列形成旋钮入孔结构。
T1.12m(seq18，seq19，seq29)为一种抗体，其中仅具有靶向小鼠FAP的小鼠抗FAP序列的旋钮入孔结构的效应器功能被去除。
T1.13m(seq20，seq30)为一种抗体，其中仅具有小鼠IL-12序列的旋钮入孔结构的效应器功能被去除。
T1.14m(seq21，seq30)为一种抗体，其中仅具有含有参与肝素结合的氨基酸突变(两个)的小鼠IL-12序列的旋钮入孔结构的效应器功能被去除。
T1.15m(seq22，seq30)为一种抗体，其中仅具有含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列的旋钮入孔结构的效应器功能被去除。
T1.16m(seq19，seq31)为一种靶向小鼠FAP的小鼠抗FAP抗体。
T1.17m(seq32)为一种Fc融合蛋白二聚体，仅具有含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列。
T1.18m(seq20，seq33，seq34)为一种双特异性抗体，其中靶向小鼠CD20的小鼠抗CD20(18B12)序列和小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.19m(seq21，seq33，seq34)为一种双特异性抗体，其中靶向小鼠CD20的小鼠抗CD20(18B12)序列和含有参与肝素结合的氨基酸突变(两个)的小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.20m(seq22，seq33，seq34)为一种双特异性抗体，其中靶向小鼠CD20的小鼠抗CD20序列和含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列形成旋钮入孔结构，并去除效应器功能。
T1.21m(seq29，seq33，seq34)为一种抗体，其中仅具有靶向小鼠CD20的小鼠抗CD20序列的旋钮入孔结构的效应器功能被去除。
T1.22m(seq35)为一种仅具有小鼠Fc序列的蛋白质，其中效应器功能被去除。
T1.23m(seq18，seq19，seq298)为一种双特异性抗体，其中小鼠抗FAP序列和小鼠IL-12序列(其中小鼠抗FAP序列的scFv与C末端连接)形成旋钮入孔结构，并去除效应器功能。
T1.24m(seq18，seq19，seq299)为一种双特异性抗体，其中小鼠抗FAP重链序列和含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列，其中小鼠抗FAP序列的scFv与C末端连接形成旋钮入孔结构，并去除效应器功能。
T1.25m(seq19，seq300)为一种含有小鼠抗FAP序列的Fc融合蛋白二聚体，其中小鼠IL-12序列与重链的C末端连接。
T1.26m(seq19，seq301)为一种含有小鼠抗FAP序列的Fc融合蛋白二聚体，其中含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列与重链的C末端连接。
T1.27m(seq302)为一种含有小鼠IL-12序列的Fc融合蛋白二聚体，其中小鼠抗FAP序列的scFv与C末端连接。
T1.28m(seq303)为一种Fc融合蛋白二聚体，由含有参与肝素结合的氨基酸突变(四个)的小鼠IL-12序列组成，其中小鼠抗FAP序列的scFv与C末端连接。
[seq18]抗-mu FAP HC mu IgG2a Fc旋钮DANG
[seq19]抗-mu FAP LC
[seq20]mu scIL-12-mu IgG2a Fc孔DANG
[seq21]mu scIL-12 mut1-mu IgG2a Fc孔DANG
[seq22]mu scIL-12 mut2-mu IgG2a Fc孔DANG
[seq23](抗-mu FAP VH)2,mu IgG2a Fc旋钮DANG
[seq24](抗-mu FAP VL)2
[seq25]抗-mu FAP HC mu IgG2a Fc旋钮DANG-抗-mu FAP scFv
[seq26]抗-mu FAP LC-抗-mu FAP scFv
[seq27]抗-mu FAP HC mu IgG2a Fc孔DANG-mu scIL-12
[seq28]抗-mu FAP HC mu IgG2a Fc孔DANG-mu scIL-12 mut2
[seq29]mu IgG2a Fc孔DANG
[seq30]mu IgG2a Fc旋钮DANG
[seq31]抗-mu FAP HC mu IgG2a Fc DANG
[seq32]mu scIL-12 mut2-mu IgG2a Fc DANG
[seq33]抗-mu CD20 HC mu IgG2a Fc旋钮DANG
[seq34]抗-mu CD20 LC
[seq35]mu IgG2a Fc DANG
[seq298]mu scIL-12-mu IgG2a Fc孔DANG-抗-mu FAP scFv
[seq299]mu scIL-12 mut2-mu IgG2a Fc孔DANG-抗-mu FAP scFv
[seq300]抗-mu FAP HC mu IgG2a Fc DANG-mu scIL-12
[seq301]抗-mu FAP HC mu IgG2a Fc DANG-mu scIL-12 mut2
[seq302]mu scIL-12-mu IgG2a Fc DANG-抗-mu FAP scFv
[seq303]mu scIL-12 mut2-mu IgG2a Fc DANG-抗-mu FAP scFv
制造实施例1.融合蛋白的产生
试剂和设备如下表3和表4所示。
[表3]
[表4]
| 设备和工具 | 生产商 | 型号 |
| 生物安全柜(Biosafety cabinet) | NUAIRE | LabGard class± |
| 离心机(centrifuge) | Eppendorf | 5424 |
| 凝胶成像系统(Gel Imaging System) | Tanon | 2500R |
合成的DNA片段通过PCR扩增，PCR产物用凝胶纯化。pTT5载体被限制性内切酶EcoRI和BamHI切割，然后纯化凝胶。使用In-Fusion试剂盒连接每个PCR产物和线性载体。将产生的载体转化入ECOS101 DH5α感受态细胞，并将细胞培养在含有100μg/ml氨苄青霉素的2×YT琼脂平板上。所有操作过程均根据标准转化方法进行。通过菌落PCR鉴定阳性重组体，并对重组质粒进行序列验证测序。选择单个菌落，并将种子培养物接种到5ml含有100μg/ml氨苄青霉素的2×YT培养基中。在37℃下振荡培养8小时。
此后，将种子培养物以1∶1,000的比例稀释在200ml选择性2×YT培养基中。在37℃下振荡培养16小时。通过在4℃，4,700rpm下离心10分钟收获细菌细胞。将细菌沉淀重悬于12ml的RES-EF缓冲液中。此后，加入12ml的LYS-EF缓冲液，将密封管用力翻转以充分混合，然后在室温下孵育5分钟。向裂解物中加入12ml的NEU-EF缓冲液，并用力翻转以充分快速地混合。
在将裂解物注入
Xtra柱过滤器之前，通过将裂解液管翻转3次来制备沉淀物的均匀悬浮液，以防止过滤器堵塞。此后，用10ml过滤器洗涤缓冲液FIL-EF洗涤
Xtra柱过滤器和/>
Xtra柱。通过拉出或翻转柱来去除
Xtra柱过滤器。用90ml洗涤缓冲液ENDO洗涤/>
Xtra柱。
用45ml洗涤缓冲液WASH-EF洗涤
Xtra柱。用15ml洗脱缓冲液ELU洗脱质粒DNA。将洗脱液收集在50ml离心管中。在室温下加入10.5ml异丙醇以沉淀洗脱的质粒DNA。涡旋后，将混合物静置2分钟。
此后，向沉淀中加入5ml 70％乙醇。使用移液器吸头小心地将乙醇完全从管中除去。将沉淀在室温(20℃)下干燥。此后，用1,000μl H2O溶解DNA沉淀。
制造实施例2.细胞转染和蛋白表达
制造实施例2.1.细胞转染
使用的材料和试剂如下表5所示。
[表5]
将含有完整培养基的293F种子菌株保持在130rpm，37℃和8％ CO2的振荡培养箱中。以0.3至0.4×106细胞/ml的密度培养，每2至3天更换培养基。在转染前24小时，以新的传代数为2.6×106细胞/ml制备293F细胞。将制备好的细胞置于振荡培养箱中在130rpm，37℃和8％ CO2的条件下培养。转染当天，使用新鲜培养基将细胞密度调节至5.0×106个细胞/ml的密度。在3L摇瓶中以1L的总体积进行。用50ml OPTI MEM I稀释0.4mg的HC和0.6mg的LC质粒，并通过0.22μm过滤器过滤。此后，用50ml OPTI MEM I稀释2mg的PEI以制备转染试剂。
将稀释的PEI加入DNA混合物中，然后立即混合。此后，在室温下培养15分钟。将DNA-PEI混合物加入到以2.6×106细胞/ml制备的293F细胞中。此后，将细胞置于振荡培养箱中在130rpm，37℃和8％ CO2的条件下连续培养24小时。转染24小时后，将10％蛋白胨加入到1/20的培养液中，使终浓度为0.5％。此后，将细胞置于振荡培养箱中在130rpm，37℃和8％ CO2的条件下连续培养。在转染后2至5天内每天测量和记录细胞密度/活力。在转染后7天或细胞活力低于70％时收获细胞进行纯化。
制造实施例2.2.蛋白质纯化
用于蛋白质纯化的试剂、缓冲液组成和设备如下表6至表8所示。
[表6]
[表7]
[表8]
| 设备 | 生产商 | 型号 |
| AKTA Pure | GE Healthcare | 29-0182-24 |
| 离心机(centrifuge) | Beckman | J-26xp |
| 凝胶成像系统(Gel Imaging System) | Tanon | 2500R |
| Sartopore 2过滤器(filter) | Sartorius | 5445307H9-OO-A |
使用Mabselect确定柱纯化蛋白质。具体地，通过在2,000×g，4℃下离心20分钟收获上清液。此后，用Sartopore 2过滤器过滤上清液。用缓冲液A平衡的5 ml MabSelectSure柱上样澄清的上清液。此后，用缓冲液A洗涤柱，直到A280吸光度达到基线。用10 CV缓冲液B洗涤柱。用10 CV缓冲液A洗涤柱。结合的蛋白质用6 CV缓冲液C洗脱，并加入1/6体积的缓冲液D以中和洗脱的物质。进行SDS-PAGE和SEC-HPLC分析。此后，使用HIC柱纯化蛋白质。然后将蛋白质在4℃下用缓冲液E透析过夜。用缓冲液E平衡的HIC柱上样上清液。此后，用缓冲液E洗涤柱，直到A280吸光度达到基线。结合的蛋白质通过梯度洗脱(10 CV缓冲液F 0％-40％)洗脱。结合的蛋白质用2 CV100％缓冲液F洗脱。进行SDS-PAGE分析。
将纯化的蛋白质混合，然后将蛋白质在4℃下用最终缓冲液透析过夜。此后，进行SDS-PAGE和SEC-HPLC分析。
结果，如图1至图6所示，发现一个实施方案的人蛋白和小鼠蛋白被纯化。
制造实施例3.优化双特异性抗体的产生
制造实施例3.1.鉴定包含人IL-12的融合蛋白产生的优化
下表9显示了根据人IL-12突变产生的人抗FAP/IL-12双特异性抗体的变化。括号表示蛋白质的生产规模，单位为L。括号前面的数字是将纯化蛋白质的量除以生产规模获得的每升产量。
[表9]
如上表9所示，随着人IL-12 p40(β)区参与肝素结合的氨基酸突变数量的增加，通过蛋白A柱(MabSelect Sure柱)纯化的蛋白质量的增加。结果发现，与T1.01相比，第280和第285位氨基酸的赖氨酸(K)突变为丙氨酸(A)的双特异性抗体T1.02的产量有所提高。结果发现，第280、282、285和286位氨基酸的赖氨酸(K)突变为丙氨酸(A)的双特异性抗体T1.03与T1.01相比产量提高了约2.5倍。
制造实施例3.2.鉴定包含小鼠IL-12的融合蛋白生产的优化
下表10显示了根据小鼠IL-12突变产生的小鼠抗FAP/IL-12双特异性抗体的变化。
[表10]
如上表10所示，随着小鼠IL-12 p40(β)区中参与肝素结合的氨基酸突变数量增加，通过蛋白A柱(MabSelect Sure柱)纯化的蛋白的质量增加。
在每个表中，通过将总蛋白质产量除以生产规模来比较通过蛋白质A柱后的蛋白质量。结果发现，第277、282位氨基酸的赖氨酸(K)突变为丙氨酸(A)的双特异性抗体T1.02m和第276位氨基酸的精氨酸(R)突变为丙氨酸(A)，以及第277、278和282位氨基酸的赖氨酸(K)突变为丙氨酸(A)的双特异性抗体T1.02m与T1.01m和T1.02m相比，蛋白质产量逐渐提高。此外，还发现，与使用HEK 293细胞系相比，使用CHO细胞系的T1.03m产量提高了约13倍。
制造实施例4.细胞系和细胞系培养
HEK-Blue IL-12细胞系经IL-12受体基因和STAT4诱导的SEAP报告基因转化为HEK293细胞，即人胚胎肾成纤维细胞，从Invivogen(美国圣地亚哥)获得。HEK-Blue IL-12细胞保存在含有10％ FBS(GIBCO)、100μg/ml新霉素和1×HEK-Blue的DMEM(GIBCO)选择培养基中。
人胚胎肾成纤维细胞系HEK293，小鼠结直肠癌细胞系CT26-WT，小鼠黑色素瘤细胞系B16F10和小鼠成纤维细胞系NIH3T3从ATCC(美国模式培养物集存库，美国弗吉尼亚州马纳萨斯)获得。HEK293细胞、B16F10细胞和NIH3T3细胞保存在含有10％ FBS(GIBCO)的DMEM(GIBCO)中。使用能够递送人FAP基因的慢病毒制备了人FAP(成纤维细胞活化蛋白α)在HEK293细胞中过表达的细胞系(HEK293-hFAP)。将HEK293-hFAP细胞保存在含有10％ FBS(GIBCO)和5μg/ml嘌呤霉素的DMEM(GIBCO)中。
使用能够递送小鼠FAP基因的慢病毒制备小鼠FAP(成纤维细胞活化蛋白α)在CT26-WT细胞、B16F10细胞和NIH3T3细胞中过表达的细胞系(CT26-mFAP，B16F10-mFAP和NIH3T3-mFAP)。将CT26-mFAP细胞保存在含有10％ FBS(GIBCO)和10μg/ml嘌呤霉素的RPMI-1640(GIBCO)中。将B16F10-mFAP细胞保存在含有10％ FBS(GIBCO)和10μg/ml嘌呤霉素的DMEM(GIBCO)中。将NIH3T3-mFAP细胞保存在含有10％FBS(GIBCO)和5μg/ml嘌呤霉素的DMEM(GIBCO)中。
制造实施例5.人类免疫细胞的分离和活化
经机构审查委员会(IRB)批准，从韩国红十字会获得了血液包，分离并冷冻了外周血单核细胞(PBMC)。对解冻的PBMC进行阳性选择方法，并用Easy sep(干细胞，加拿大温哥华不列颠哥伦比亚)试剂盒分离人NK细胞。分离的NK细胞在RPMI-1640(GIBCO)和含有50IU/ml人重组IL-2(rhIL-2，R&D Systems，美国明尼苏达州)的10％FBS中激活和保存。
对解冻的PBMC进行阴性选择方法，并用Easy sep(干细胞)试剂盒分离人T细胞。将人T细胞培养在涂有1μg/ml抗CD3(OKT3，Invitrogen)的平板上并活化72小时。人T细胞保存在含有10％ FBS(GIBCO)的RPMI-1640(GIBCO)中。
实施例1.融合蛋白结合亲和力的鉴定
实施例1.1.融合蛋白与重组人FAP结合的鉴定
通过表面等离子体共振(SPR)鉴定了T1.01、T1.02和T1.03与重组人FAP的结合。
具体地，用50nM NHS(N-羟基琥珀酰亚胺)和200nM EDC(1-乙基-3-(3-二甲基氨基丙基)碳二亚胺)的1:1混合物活化CM5芯片的表面，并以10μl/min的速率固定25μg/ml抗人IgG(Fc)抗体400秒。剩余的活性酯基团用1M乙醇胺封闭。将T1.01、T1.02和T1.03稀释至2μg/ml，并在用抗人IgG(Fc)抗体固定的CM5芯片上反应。将重组人FAP在1×HBS-EP+缓冲液中稀释至200nM，并通过连续稀释进行稀释。稀释的重组人FAP以30μl/min的速率反应。结合和解离时间分别为180秒和400秒。解离后，稳定60秒，然后用10mM甘氨酸pH 1.5溶液以30μl/min的速率再生30秒。
结果如图7和图8所示，发现T1.01、T1.02和T1.03可以特异性地与重组人FAP结合。
通过表面等离子体共振(SPR)鉴定了T1.04、T1.05、T1.06、T1.07、T1.08、T1.09、T1.10和T1.11与重组人FAP的结合。用50nM NHS(N-羟基琥珀酰亚胺)和200nM EDC(1-乙基-3-(3-二甲氨基丙基)碳二亚胺)的1:1混合物活化CM5芯片的表面，并以10μl/min的速率将25μg/ml抗人IgG(Fc)抗体固定400秒。剩余的活性酯基团用1M乙醇胺封闭。
具体地，将人蛋白T1.04、T1.05、T1.06、T1.07、T1.08、T1.09、T1.10和T1.11分别稀释至1μg/ml、1μg/ml、1μg/ml、1μg/ml、0.5μg/ml、0.5μg/ml、0.5μg/ml和1μg/ml，并在用抗人IgG(Fc)抗体固定的CM5芯片上反应。将重组人FAP在1×HBS-EP+缓冲液中稀释至25nM或50nM，并通过连续稀释进行稀释。稀释的重组人FAP以30μl/min的速率反应。结合和解离时间分别为180秒和400秒。解离后，稳定60秒，然后用10mM甘氨酸pH 1.5溶液以30μl/min的速率再生30秒。
结果如表11和图9和10所示，发现T1.04、T1.05、T1.06和T1.07可以与重组人FAP结合，以特异性靶向FAP。此外，如表12和图11和12所示，发现T1.08、T1.09、T1.10和T1.11可与重组人FAP结合，以特异性靶向FAP。
[表11]
[表12]
实施例1.2.鉴定小鼠蛋白与重组小鼠FAP的结合
通过表面等离子体共振(SPR)鉴定T1.01m、T1.02m和T1.03m与重组小鼠FAP的结合。
用50nM NHS(N-羟基琥珀酰亚胺)和200nM EDC(1-乙基-3-(3-二甲氨基丙基)碳二亚胺)的1:1混合物活化CM5芯片的表面，并以10μl/min的速率将25μg/ml抗小鼠IgG(Fc)抗体固定400秒。剩余的活性酯基团用1M乙醇胺封闭。将T1.01m、T1.02m和T1.03m稀释至2μg/ml，并在用抗小鼠IgG(Fc)抗体固定的CM5芯片上反应。将小鼠重组FAP在1×HBS-EP+缓冲液中稀释至200nM，并通过连续稀释进行稀释。稀释的重组小鼠FAP以30μl/min的速率反应。结合和解离时间分别为180秒和400秒。解离后，稳定60秒，然后用10mM甘氨酸pH 1.5溶液以30μl/min的速率再生30秒。
结果如图13和14所示，发现T1.01m、T1.02m和T1.03m可以与重组小鼠FAP结合，以特异性靶向FAP。
实施例1.3.鉴定与FAP表达细胞的结合
鉴定了T1.12、T1.01、T1.02和T1.03与HEK293和HEK293-hFAP细胞的结合程度。
具体地，通过将1×105个细胞/100μl悬浮在FACS缓冲液中来制备细胞系，并用T1.12、T1.01、T1.02和T1.03各1μg处理。用FACS缓冲液洗涤细胞两次。用抗人IgG抗体(Biolegend)对细胞进行染色。阴性对照仅用抗人IgG抗体(Biolegend)染色。使用BD LSR测量染色细胞的表达速率，并使用FlowJo软件进行分析。
结果如图15所示，发现T1.12、T1.01、T1.02和T1.03与人FAP表达细胞系结合99％或更多。这些结果表明，一个实施方案的融合蛋白可以与人FAP表达细胞系结合，以特异性靶向FAP。
此外，鉴定了T1.12m、T1.01m、T1.02m和T1.03m与B16F10和B16F10-mFAP细胞的结合程度。
具体地，通过将1×105个细胞/100μl悬浮在FACS缓冲液中来制备细胞系，并用T1.12m、T1.01m、T1.02m和T1.03m各1μg处理。用FACS缓冲液洗涤细胞两次。用抗小鼠IgG2a抗体(Biolegend)对细胞进行染色。阴性对照仅用抗小鼠IgG2a抗体(Biolegend)染色。使用BD LSR测量染色细胞的表达速率，并使用FlowJo软件进行分析。
结果如图16所示，发现T1.12m、T1.01m、T1.02m和T1.03m与FAP表达细胞系结合99％或更多。这些结果表明，一个实施方案的融合蛋白可以与小鼠FAP表达细胞系结合，以特异性靶向FAP。
实施例1.4.鉴定融合蛋白与重组人IL-12受体的结合
考虑到融合蛋白的IL-12必须与IL-12受体结合才能发挥作用，发现T1.01、T1.02、T1.03和T1.12与重组人IL-12受体结合。
将T1.01、T1.02和T1.03固定在平板上，结合与辣根过氧化物酶(HRP)偶联的重组人IL-12受体蛋白。具体地，执行了以下步骤：
(i)将T1.01、T1.02、T1.03和T1.12以5μg/ml悬浮，并用连续稀释进行稀释。将稀释后的T1.01、T1.02、T1.03和T1.12等分到96孔免疫板中并处理24小时。
(ii)用洗涤溶液洗涤孔，然后用1％ BSA(牛血清白蛋白，Sigma)溶液封闭1小时。
(iii)用洗涤溶液洗涤孔，然后用1nM的IL-12受体β1-生物素(IL-12Rβ1-生物素，Acrobiosystems，美国纽瓦克)处理2小时。
(iv)用洗涤溶液洗涤孔，然后用链霉亲和素-HRP处理20分钟。
(v)用洗涤溶液洗涤孔，然后用底物溶液处理20分钟。
(vi)用终止溶液处理孔，并在450nm处测量吸光度。
结果如图17所示，发现T1.01、T1.02和T1.03以浓度依赖性方式与重组人IL-12受体蛋白结合。T1.12用作对照。
实施例2.鉴定融合蛋白诱导信号传导的能力
实施例2.1.鉴定在IL-12识别细胞中的信号传导能力
考虑到已知当IL-12与IL-12受体结合时，IL-12通过诱导信号介质STAT4(信号转导器和激活剂或转录4)的磷酸化来启动信号传导，评估了一个实施方案的融合蛋白在表达IL-12受体的IL-12识别细胞中的信号传导能力。
具体地，将HEK-Blue IL-12细胞系(IL-12识别细胞)稀释至2.8×105个细胞/ml，并以180μl/孔分配。将重组人IL-12、T1.01m、T1.02m、T1.03m和T1.12m以4nM悬浮并通过连续稀释进行稀释。HEK-Blue IL-12细胞用稀释的重组人IL-12，T1.01m、T1.02m、T1.03m和T1.12m处理。处理24小时后，收集细胞上清液并与QU抗-Blue溶液(Invivogen)在96孔板中混合。使用分光光度计(Thermo Fisher)在620nm处测量报告基因表达水平。
结果如图18所示，通过620nm吸光度鉴定出在IL-12、T1.01m、T1.02m和T1.03m处理组的情况下，IL-12被识别，并且STAT4通过诱导磷酸化表达报告基因。相反，当用T1.12m处理IL-12识别细胞时，发现对照T1.12m不识别IL-12。这些结果表明，一个实施方案的融合蛋白特异性地与IL-12受体结合以诱导信号传导。
实施例2.2.鉴定在人T细胞中的信号传导能力
为了确定当IL-12与人T细胞的IL-12受体结合时，IL-12是否通过诱导信号介质STAT4的磷酸化来启动信号传导，使用AlphaLISA SureFire Ultra p-STAT4(Tyr693)检测试剂盒(PerkinElmer，美国马萨诸塞州)分析了用抗CD3(OKT3，Invitrogen)激活的人T细胞。
具体地，将人蛋白IL-12、T1.01、T1.02、T1.03和T1.12以100ng/ml悬浮并通过连续稀释进行稀释。用抗CD3(OKT3，Invitrogen)激活的人T细胞用稀释的重组人IL-12、T1.01、T1.02、T1.03和T1.12处理。处理2小时后，裂解细胞并用检测p-STAT4(磷酸化STAT4)的试剂(PerkinElmer)处理。用分光光度计在680nm的激发波长和615nm的发射波长下检测p-STAT4。
结果如图19所示，鉴定出用重组人IL-12处理的组的半最大有效浓度(EC50)为8.945pM；T1.01治疗组EC50为14.48pM；T1.02治疗组EC50为56.51pM；T1.03治疗组EC50为147.2pM。相比之下，在用T1.12处理的组(对照组)中未检测到磷酸化的STAT4。
这些结果表明，IL-12突变减弱了T细胞信号传导能力。
实施例2.3.通过人T细胞中低分子量肝素鉴定融合蛋白信号传导能力的变化
接下来，使用用抗CD3(OKT3，Invitrogen)激活的人T细胞和AlphaLISA SureFireUltra p-STAT4(Tyr693)检测试剂盒鉴定了低分子量肝素增强IL-12突变(IL-12mut1)融合蛋白的信号传导能力。
特别是，通过观察当减弱的IL-12mut2与人T细胞的IL-12受体结合时，信号介质STAT4的磷酸化诱导是否减弱，根据人T细胞中是否存在低分子量肝素(LMWH)来鉴定信号传导能力。
具体地，将重组人IL-12、T1.01、T1.02和T1.03以100ng/ml悬浮，并通过连续稀释进行稀释。活化的人T细胞用稀释的重组人IL-12、T1.01、T1.02和T1.03与低分子量肝素一起处理。处理2小时后，裂解细胞并用检测p-STAT4(PerkinElmer)的试剂处理。用分光光度计在680nm的激发波长和615nm的发射波长下检测p-STAT4。
结果如图20所示，用T1.01和低分子量肝素治疗的组的半最大有效浓度(EC50)比T1.01治疗组增加了9.4倍，用T1.02和低分子量肝素治疗的组的半最大有效浓度(EC50)比用T1.02治疗的组增加了5.5倍，用T1.03和低分子量肝素治疗组的半最大有效浓度(EC50)比T1.03治疗的组提高了4倍。
这些结果表明，当IL-12突变(IL-12mut2)添加到现有的IL-12突变(IL-12mut1)中时，通过添加低分子量肝素降低了信号传导能力的增强程度，因此IL-12被有效地减弱。
实施例3.融合蛋白细胞因子分泌能力鉴定
实施例3.1.用于细胞因子测量的酶联免疫吸附试验
对于细胞因子的测量，对储存在-20℃的上清液进行酶联免疫吸附试验(ELISA，R&Dsystems)，步骤如下：
(i)根据分析证书(CoA)稀释捕获抗体，并在96孔板上包被24小时。
(ii)用洗涤溶液洗涤孔，然后用1％ BSA(牛血清白蛋白，Sigma)溶液封闭1小时。
(iii)用洗涤溶液洗涤孔，然后对样品处理2小时。
(iv)用洗涤液洗涤孔，然后根据分析证书稀释检测抗体并等分到孔中，然后用其处理孔2小时。
(v)用洗涤溶液洗涤孔，然后用链霉亲和素-HRP处理20分钟。
(vi)用洗涤溶液洗涤孔，然后用底物溶液处理20分钟。
(vii)用终止溶液处理孔，并在450nm处测量吸光度。
实施例3.2.鉴定人T细胞中的细胞因子分泌能力
考虑到IFN-γ(干扰素-γ)分泌是一种主要的免疫反应，当人T细胞用IL-12处理时会发生IFN-γ分泌，当人T细胞用重组人IL-12、T1.12、T1.01、T1.02和T1.03处理时，评估了IFN-γ分泌能力。
具体地，用抗CD3(OKT3，Invitrogen)激活的人T细胞被稀释至5×105个细胞/ml，并以200μl/孔分配在96孔板中。将重组人IL-12、T1.12、T1.01、T1.02和T1.03稀释至10nM并以20μl/孔分配。处理48小时后，收集细胞上清液，并将样品储存在-80℃。
结果如图21所示，发现用重组人IL-12处理的样品具有平均1,640pg/ml的IFN-γ；用T1.01处理的样品平均具有1.115pg/ml的IFN-γ；用T1.02处理的样品平均具有845pg/ml的IFN-γ；用T1.03处理的样品平均具有607pg/ml的IFN-γ。相比之下，发现用T1.12作为对照处理的样品没有IFN-γ。
这些结果表明，T1.01、T1.02和T1.03作用于人T细胞，以诱导IFN-γ分泌。
实施例3.3.鉴定人NK细胞中的细胞因子分泌能力
考虑到IFN-γ(干扰素-γ)分泌是一种主要的免疫反应，当人NK细胞用IL-12处理时发生IFN-γ分泌，本发明人评估了用重组人IL-2(R&D systems)激活的人NK细胞用重组人IL-12、T1.12、T1.01、T1.02和T1.03处理时的IFN-γ分泌能力。
具体地，用重组人IL-2(R&D Systems)激活的人NK细胞被稀释至5×105个细胞/ml，并以200μl/孔分配在96孔板中。将重组人IL-12、T1.12、T1.01、T1.02和T1.03稀释至10nM并以20μl/孔分配。处理24小时后，收集细胞上清液，样品在-80℃保存。
结果如图22所示，发现用重组人IL-12处理的样品平均具有180pg/ml的IFN-γ；用T1.01处理的样品平均具有205pg/ml的IFN-γ；用T1.02处理的样品平均具有133pg/ml的IFN-γ；用T1.03处理的样品平均具有80pg/ml的IFN-γ。相比之下，发现用T1.12作为对照处理的样品没有IFN-γ。这些结果表明，T1.01、T1.02和T1.03作用于人NK细胞，以诱导IFN-γ分泌。
实施例4.融合蛋白在结直肠癌动物模型中的抗癌功效评价
实施例4.1.通过共注射表达FAP的成纤维细胞评估结直肠癌动物模型中的抗癌功效
考虑到融合蛋白为具有抗FAP序列结构和IL-12序列结构的双抗形式，并且FAP在许多肿瘤微环境中存在的成纤维细胞中过表达，在小鼠成纤维细胞系NIH3T3细胞中过表达小鼠FAP后，在与CT26(小鼠结直肠癌细胞系)以1:1共注射的肿瘤动物模型中评估肿瘤生长抑制能力。
小鼠结直肠癌细胞系CT26和小鼠成纤维细胞系NIH-3T3用于制备表达FAP的肿瘤动物模型。然后，制备NIH-3T3作为表达FAP的细胞系。
具体地，将过表达小鼠FAP的NIH-3T3细胞和培养的CT26细胞分别以1×106个细胞/50μl的浓度重悬于Hanks的平衡盐溶液(HBSS，Gibco)中，并将细胞以1:1的比例混合，然后使用1cc注射器(25G)以每只小鼠100μl移植到6周龄BALB/c小鼠右胁的皮下区域，以获得表达FAP的成纤维细胞共注射动物模型。使用数字游标卡尺通过测量肿瘤的短轴和长轴来测量肿瘤大小，并使用(短轴，mm)2×(长轴，mm)×0.5的计算公式每周测量两次肿瘤大小。
接下来，对于药物疗效评估，当肿瘤大小达到100mm3时，将小鼠随机分组。每个实验组由10只动物组成，作为对照，50μg/100μl的T1.24m以3天的间隔腹膜内施用3次，间隔3天。在测试组中，10μg/100μl和50μg/100μl的T1.02m和50μg/100μl的T1.01m分别以3天的间隔腹膜内给药3次，以评估肿瘤生长抑制能力。
结果如图23所示，当比较第14天的肿瘤大小时，发现与给予50μg T1.24m作为对照的组相比，给予10μg和50μg T1.02m的组分别具有93.2％和92.7％的优异的肿瘤生长抑制能力。此外，观察到与给予50μg T1.24m作为对照的组相比，给予50μg T1.01m的组肿瘤生长抑制为91.9％。
此外，如图24所示，在给药后第24天，与对照组相比，在给予T1.01m和T1.02m的组中观察到完全缓解的受试者。
这些结果表明，一个实施方案的融合蛋白在结直肠癌动物模型中具有优异的抗癌功效。
实施例4.2.表达FAP的结直肠癌动物模型中抗癌功效的评价
在结直肠癌的情况下，考虑到FAP在肿瘤细胞本身中的高表达，为了评估抗癌作用，在小鼠结直肠癌细胞系CT26细胞中诱导小鼠FAP过表达的肿瘤模型中评估了肿瘤生长抑制能力。
为了制备表达FAP的小鼠肿瘤动物模型，在小鼠结直肠癌细胞系CT26中诱导FAP过表达。具体地，将培养物中的FAP过表达的CT26细胞重悬于Hanks的平衡盐溶液(HBSS，Gibco)中，然后使用1cc注射器(25G)以每只小鼠每100μl的1×106个肿瘤细胞移植到6周龄BALB/c小鼠的左背侧皮下区域，以获得表达FAP的小鼠结直肠癌动物模型。使用数字游标卡尺通过测量肿瘤的短轴和长轴来测量肿瘤大小，并使用(短轴，mm)2×(长轴，mm)×0.5的计算公式每周测量两次肿瘤大小。
接下来，对于药物疗效评估，当肿瘤大小达到100mm3时，将小鼠随机分组。每个实验组由8只动物组成，作为对照，50μg/100μl T1.24m以3天的间隔腹膜内施用4次。在测试组中，10μg/100μl和100μg/100μl的T1.01m，以及2μg/100μl、10μg/100μl和100μg/100μl的T1.02m分别以3天的间隔腹膜内给药4次，以评估肿瘤生长抑制能力。
结果如图25所示，发现与给予50μg T1.24m作为对照的组相比，给予10μg和100μgT1.01m的组分别具有84.9％和85.6％的高肿瘤生长抑制能力。此外，观察到与以T1.24m作为对照的组相比，用T1.02m给药的组分别具有80.1％、90.5％和89.8％的高肿瘤生长抑制能力。
此外，经鉴定，各给药组在给药后第30天均存在完全缓解(CR)的受试者，同时存在肿瘤生长抑制，并且根据给药情况，在测试期间未观察到体重的变化。这些结果表明，一个实施方案的融合蛋白在结直肠癌动物模型中具有优异的抗癌功效。
实施例4.3.融合蛋白对完全缓解小鼠复发性实体癌生长抑制的评价
为了评估融合蛋白治疗后是否可以通过诱导长期免疫应答来抑制肿瘤复发，在与成纤维细胞NIH-3T3和CT26细胞共注射的肿瘤模型中通过施用T1.01m达到完全缓解的受试者进行了肿瘤再激发。没有治疗史的BALB/c小鼠用作对照小鼠。
将4T1细胞皮下注射至对照小鼠和给予T1.01m达到完全缓解的小鼠的左胁，以及CT26细胞皮下注射至对照小鼠和给予T1.01m达到完全缓解的小鼠的右胁，得到肿瘤复发模型。
具体地，在过表达FAP的成纤维细胞NIH-3T3和CT26细胞共注射的模型中，在小鼠中诱导肿瘤复发模型，其中通过施用T1.01m表现出完全缓解。CT26细胞和4T1细胞分别以1×106个细胞/100μl的浓度悬浮在Hanks的平衡盐溶液(HBSS，Gibco)中，并使用1cc注射器(25G)将CT26细胞移植到小鼠右胁的皮下区域。通过将4T1细胞皮下移植到同一小鼠的左胁来评估肿瘤的形成和生长。
结果如图26和27所示，发现移植的4T1肿瘤和CT26肿瘤均在没有治疗史的对照小鼠中生长，而在给予T1.01m后达到完全缓解的小鼠中，4T1肿瘤生长，但CT26肿瘤的生长受到抑制。这些结果表明，一个实施方案的融合蛋白可以抑制肿瘤复发。
实施例4.4.根据融合蛋白的IL-12氨基酸突变评估活性降低
为了降低由于IL-12过度激活免疫系统而导致的体内毒性，本发明人使用含有与肝素结合的氨基酸序列突变的IL-12序列结构，通过阻断与IL-12受体的结合来诱导活性降低，并通过肿瘤动物模型对此进行了鉴定。
在抗FAP抗体中，将参与肝素结合的氨基酸突变的T1.02m和T1.03m与T1.01m进行比较，并以磷酸盐缓冲盐水(PBS)作为对照。然后，T1.02m具有小鼠IL-12序列结构，其中含有参与肝素结合的氨基酸突变(两个)与抗FAP序列结构。T1.03m为具有IL-12序列结构的融合蛋白，其含有参与肝素结合的突变(四个)氨基酸以及抗FAP序列结构。
为了根据氨基酸突变的存在和程度评估IL-12活性的变化，通过在PBS中以5×105个细胞/100μl的浓度重悬制备FAP过表达小鼠结直肠癌CT26，并在将细胞移植到5周龄雌性BALB/c小鼠中制备的肿瘤动物模型中评估肿瘤生长抑制能力。
具体地，当模型中肿瘤的大小达到100mm3时，将小鼠随机分组。每个实验组由8只动物组成，对照的尾静脉注射一次100μl磷酸盐缓冲盐水(PBS)、T1.01m、T1.02m和T1.03m各以10μg的剂量静脉内给药一次。
结果如图28所示，发现T1.01m、T1.02m和T1.03m给药组在给药后15天与对照组相比均具有优异的肿瘤生长抑制能力。
此外，发现与给予T1.01m的组相比，在给予T1.03m(具有含有参与肝素结合的氨基酸突变(四个)的IL-12和小鼠抗FAP序列)的组中，肿瘤生长抑制能力降低。这些结果表明，与其他实验组和对照组相比，T1.03m(具有含有参与肝素结合的氨基酸突变(四个)的IL-12序列结构)给药组中的IL-12活性降低。
实施例4.5.单次给予IL-12氨基酸突变融合蛋白后抗癌效果的评价
为了评估由于含有参与肝素结合的氨基酸突变(四个)的序列结构而降低IL-12活性的融合蛋白的抗癌作用，在移植FAP过表达小鼠结直肠癌细胞系CT26的肿瘤模型中评估肿瘤生长抑制能力。
具体地，将肿瘤细胞移植到6周龄BALB/c小鼠的右背侧，当动物模型的肿瘤大小达到70至100mm3时，将小鼠随机分组并进行给药。作为对照，施用PBS，作为测试组，以2μg、10μg和100μg的剂量静脉内施用100μl T1.03m一次。以与实施例4.1相同的方式测量肿瘤的大小。
结果如图29所示，观察到与对照组相比，给予2μg、10μg和100μg T1.03m的组具有较高的肿瘤生长抑制能力。在测试期间未观察到体重变化。这些结果表明，T1.03m由于含有参与肝素结合的氨基酸突变(四个)的序列结构而降低了IL-12活性，在一定浓度或更高浓度下具有优异的抗癌功效。
实施例5.融合蛋白在黑色素瘤动物模型中的抗癌功效评价
为了通过融合蛋白的免疫激活鉴定其抗癌作用，将小鼠FAP在已知免疫细胞浸润较少的小鼠黑色素瘤细胞系B16F10中过表达，然后移植到C57BL/6J小鼠体内，并评价肿瘤生长抑制能力。
具体地，将培养的细胞重悬于Hanks的平衡盐溶液(HBSS，Gibco)中，然后以每只小鼠100μl的1×106个肿瘤细胞移植到6周龄C57BL/6J小鼠的左背侧的皮下区域。
接着，对于药物疗效进行评估，当肿瘤大小达到70至100mm3时，将小鼠随机分组。作为对照，给予PBS，作为测试组，T1.03m以10μg和100μg的剂量静脉内施用一次。
结果如图30所示，观察到与对照相比，给予10μg和100μg T1.03m的两组均具有较高的肿瘤生长抑制能力。在测试期间未观察到体重变化。这些结果表明，T1.03m由于含有参与肝素结合的氨基酸突变(四个)的序列结构而降低了IL-12活性，即使在黑色素瘤动物模型中也具有优异的抗癌功效。
实施例6.融合蛋白在肺癌动物模型中的抗癌功效评价
实施例6.1.IL-12氨基酸突变融合蛋白在肺癌动物模型中的抗癌功效评价
考虑到FAP在肿瘤周围微环境中存在的成纤维细胞中过表达，在小鼠成纤维细胞系NIH-3T3中过表达FAP，然后与小鼠肺癌细胞系LLC1以1:1的比例共注射，以制备肿瘤动物模型，并评价肿瘤生长抑制能力。
具体地，将过表达FAP的NIH-3T3细胞系和LLC1细胞分别以1×106个细胞/50μl的浓度重悬于Hanks的平衡盐溶液(HBSS，Gibco)中，并将细胞以1:1的比例混合，然后使用1cc注射器(25G)以每只小鼠100μl移植到6周龄C57BL/6J小鼠右胁的皮下区域。
接着，对于药物疗效进行评估，当肿瘤大小达到70至100mm3时，将小鼠随机分组。作为对照，给予PBS，作为测试组，T1.03m以10μg和100μg的剂量静脉内施用一次。
结果如图31所示，观察到与对照组相比，给予10μg或100μg T1.03m的两组均具有优异的肿瘤生长抑制能力。在测试期间未观察到体重变化。这些结果表明，T1.03m由于含有参与肝素结合的氨基酸突变(四个)的序列结构而降低IL-12活性。T1.03m识别肿瘤微环境的靶因子，因此，即使在肺癌动物模型中也具有出色的抗癌功效。
实施例6.2.通过融合蛋白共注射评价肺癌动物模型中的癌症靶向功效
为了比较抗FAP序列结构和IL-12序列结构形成旋钮入孔(旋钮-入-孔)结构的双抗型融合蛋白的癌症靶向性，在过表达FAP的NIH-3T3(小鼠成纤维细胞系)和LLC1(小鼠肺癌细胞系)共注射(比例为1∶1)的动物模型中鉴定肿瘤生长抑制能力。
具体地，对于药物疗效进行评估，当肿瘤大小达到70至100mm3时，将小鼠随机分组。作为对照，PBS每周腹膜内给药两次。以T1.16m或T1.17m单独给药组、T1.16m和T1.17m联合给药组(T1.16m+T1.17m)，以及T1.03m组为试验组，以评价肿瘤生长抑制能力。T1.16m和T1.17m分别为抗FAP和IL-12的二聚体，每周腹膜内给药2次，剂量为0.01μg，T1.03m为单体融合蛋白，每周腹膜内给药2次，剂量为0.02μg，以观察肿瘤生长抑制能力。
结果如图32所示，观察到与对照相比，T1.03m给药组在给药后10天的时间点具有优异的肿瘤生长抑制能力。单独给予T1.16m或T1.17m的组，与各联合给药组进行比较，发现单独给予T1.03m的组具有优异的肿瘤生长抑制能力。这些结果表明，与仅靶向FAP的情况或与没有癌症靶向的IL-12相比，一个实施方案的融合蛋白的协同作用是显着的。
SEQUENCE LISTING
<110> 治纳辅医药科技有限公司
<120> 一种包含IL-12和抗FAP抗体的融合蛋白及其应用
<130> P22118161WP
<150> KR 10-2020-0100229
<151> 2020-08-11
<160> 305
<170> PatentIn version 3.5
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<223> 抗-hu FAP HC hu IgG1 Fc 旋钮 DANG
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20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Lys
755
<210> 4
<211> 755
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut1-hu IgG1 Fc 孔 DANG
<400> 4
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Lys Arg Glu Ala Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Lys
755
<210> 5
<211> 755
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2-hu IgG1 Fc 孔 DANG
<400> 5
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Lys
755
<210> 6
<211> 593
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-hu FAP VH)2-hu IgG1 Fc 旋钮 DANG
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
130 135 140
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
145 150 155 160
Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val
165 170 175
Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro
180 185 190
Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr
195 200 205
Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser
210 215 220
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile
225 230 235 240
Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
260 265 270
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
275 280 285
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
290 295 300
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
305 310 315 320
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
325 330 335
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
340 345 350
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
355 360 365
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
370 375 380
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
385 390 395 400
Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp
405 410 415
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
420 425 430
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val
435 440 445
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
450 455 460
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
465 470 475 480
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
485 490 495
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
500 505 510
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
515 520 525
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
530 535 540
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
545 550 555 560
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
565 570 575
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
580 585 590
Lys
<210> 7
<211> 348
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-hu FAP VL)2
<400> 7
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
130 135 140
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
145 150 155 160
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
225 230 235 240
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
245 250 255
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
260 265 270
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
275 280 285
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
290 295 300
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
305 310 315 320
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
325 330 335
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
340 345
<210> 8
<211> 726
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc 旋钮 DANG-抗-hu FAP scFv
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
465 470 475 480
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr
485 490 495
Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln
500 505 510
Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn
515 520 525
Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser
530 535 540
Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
545 550 555 560
Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu
565 570 575
Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
580 585 590
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
595 600 605
Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
610 615 620
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln
625 630 635 640
Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
645 650 655
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr
660 665 670
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr
675 680 685
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val
690 695 700
Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly
705 710 715 720
Thr Lys Val Glu Ile Lys
725
<210> 9
<211> 492
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP LC-抗-hu FAP scFv
<400> 9
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly
210 215 220
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
225 230 235 240
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
245 250 255
Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val
260 265 270
Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro
275 280 285
Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr
290 295 300
Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser
305 310 315 320
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile
325 330 335
Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly
340 345 350
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr
370 375 380
Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile
385 390 395 400
Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn
405 410 415
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
420 425 430
Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser
435 440 445
Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
450 455 460
Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Phe Ser Tyr Pro
465 470 475 480
Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
485 490
<210> 10
<211> 986
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc 孔 DANG-hu scIL-12
<400> 10
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
450 455 460
Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu
465 470 475 480
Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys
485 490 495
Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser
500 505 510
Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe
515 520 525
Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser
530 535 540
His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr
545 550 555 560
Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg
565 570 575
Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr
580 585 590
Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser
595 600 605
Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu
610 615 620
Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln
625 630 635 640
Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val
645 650 655
Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser
660 665 670
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
675 680 685
Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr
690 695 700
Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys
705 710 715 720
Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe
725 730 735
Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile
740 745 750
Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp
755 760 765
Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly
785 790 795 800
Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser
805 810 815
Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr
820 825 830
Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr
835 840 845
Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu
850 855 860
Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser
865 870 875 880
Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu
885 890 895
Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu
900 905 910
Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala
915 920 925
Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val
930 935 940
Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile
945 950 955 960
Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile
965 970 975
Asp Arg Val Met Ser Tyr Leu Asn Ala Ser
980 985
<210> 11
<211> 986
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc 孔 DANG-hu scIL-12 mut2
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
450 455 460
Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu
465 470 475 480
Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys
485 490 495
Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser
500 505 510
Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe
515 520 525
Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser
530 535 540
His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr
545 550 555 560
Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg
565 570 575
Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr
580 585 590
Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser
595 600 605
Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu
610 615 620
Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln
625 630 635 640
Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val
645 650 655
Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser
660 665 670
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
675 680 685
Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr
690 695 700
Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys
705 710 715 720
Val Gln Val Gln Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe
725 730 735
Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile
740 745 750
Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp
755 760 765
Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly
785 790 795 800
Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser
805 810 815
Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr
820 825 830
Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr
835 840 845
Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu
850 855 860
Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser
865 870 875 880
Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu
885 890 895
Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu
900 905 910
Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala
915 920 925
Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val
930 935 940
Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile
945 950 955 960
Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile
965 970 975
Asp Arg Val Met Ser Tyr Leu Asn Ala Ser
980 985
<210> 12
<211> 227
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc 孔 DANG
<400> 12
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 13
<211> 227
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc 旋钮 DANG
<400> 13
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 14
<211> 454
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc DANG
<400> 14
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Lys
450
<210> 15
<211> 755
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2-hu IgG1 Fc DANG
<400> 15
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Lys
755
<210> 16
<211> 451
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu CD20 HC hu IgG1 Fc 旋钮 DANG
<400> 16
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 17
<211> 213
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu CD20 LC
<400> 17
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 18
<211> 447
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 旋钮 DANG
<400> 18
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys
210 215 220
Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
245 250 255
Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp
260 265 270
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser
290 295 300
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320
Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile
325 330 335
Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro
340 345 350
Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Trp Cys Met
355 360 365
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn
370 375 380
Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn
405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu
420 425 430
His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
435 440 445
<210> 19
<211> 213
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LC
<400> 19
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 20
<211> 764
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12-mu IgG2a Fc 孔 DANG
<400> 20
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
755 760
<210> 21
<211> 764
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut1-mu IgG2a Fc 孔 DANG
<400> 21
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Ala Lys
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
755 760
<210> 22
<211> 764
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2-mu IgG2a Fc 孔 DANG
<400> 22
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
755 760
<210> 23
<211> 579
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-mu FAP VH)2, mu IgG2a Fc 旋钮 DANG
<400> 23
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala
130 135 140
Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr
145 150 155 160
Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly
165 170 175
Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr
180 185 190
Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser
195 200 205
Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala
210 215 220
Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser
245 250 255
Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val
260 265 270
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu
275 280 285
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
290 295 300
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr
305 310 315 320
Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro
325 330 335
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr
340 345 350
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
355 360 365
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
370 375 380
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu
385 390 395 400
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
405 410 415
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu
420 425 430
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
435 440 445
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
450 455 460
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
465 470 475 480
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
485 490 495
Leu Trp Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
500 505 510
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
515 520 525
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
530 535 540
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
545 550 555 560
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
565 570 575
Pro Gly Lys
<210> 24
<211> 334
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-mu FAP VL)2
<400> 24
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser
115 120 125
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
130 135 140
Ser Ala Ser Ser Gly Val Asn Phe Met His Trp Tyr Gln Gln Lys Ser
145 150 155 160
Gly Thr Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser
165 170 175
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
180 185 190
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
195 200 205
Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
210 215 220
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
225 230 235 240
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
245 250 255
Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
260 265 270
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
275 280 285
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
290 295 300
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
305 310 315 320
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
325 330
<210> 25
<211> 705
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 旋钮 DANG-抗-mu FAP scFv
<400> 25
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys
210 215 220
Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
245 250 255
Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp
260 265 270
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser
290 295 300
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320
Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile
325 330 335
Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro
340 345 350
Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Trp Cys Met
355 360 365
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn
370 375 380
Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn
405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu
420 425 430
His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
450 455 460
Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val
465 470 475 480
Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile
485 490 495
Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu
500 505 510
Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly
515 520 525
Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu
530 535 540
Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg
545 550 555 560
Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala
595 600 605
Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala
610 615 620
Ser Ser Gly Val Asn Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr
625 630 635 640
Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val
645 650 655
Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr
660 665 670
Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln
675 680 685
Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
690 695 700
Lys
705
<210> 26
<211> 471
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LC-抗-mu FAP scFv
<400> 26
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
210 215 220
Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala
225 230 235 240
Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr
245 250 255
Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly
260 265 270
Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr
275 280 285
Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser
290 295 300
Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala
305 310 315 320
Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly
325 330 335
Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly
340 345 350
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val
355 360 365
Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val
370 375 380
Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met His Trp Tyr
385 390 395 400
Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser
405 410 415
Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala
435 440 445
Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly
450 455 460
Gly Thr Lys Leu Glu Ile Lys
465 470
<210> 27
<211> 982
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 孔 DANG-mu scIL-12
<400> 27
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys
210 215 220
Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
245 250 255
Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp
260 265 270
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser
290 295 300
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320
Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile
325 330 335
Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro
340 345 350
Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala
355 360 365
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn
370 375 380
Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn
405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu
420 425 430
His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu
450 455 460
Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala
465 470 475 480
Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp
485 490 495
Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys
500 505 510
Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr
515 520 525
Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His
530 535 540
Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys
545 550 555 560
Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe
565 570 575
Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile
580 585 590
Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met
595 600 605
Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu
610 615 620
Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu
625 630 635 640
Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys
645 650 655
Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro
660 665 670
Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val
675 680 685
Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr
690 695 700
Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met
705 710 715 720
Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu
725 730 735
Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln
740 745 750
Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val
755 760 765
Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys
785 790 795 800
Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys
805 810 815
Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile
820 825 830
Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys
835 840 845
Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu
850 855 860
Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser
865 870 875 880
Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met
885 890 895
Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn
900 905 910
His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu
915 920 925
Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro
930 935 940
Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile
945 950 955 960
Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met
965 970 975
Gly Tyr Leu Ser Ser Ala
980
<210> 28
<211> 982
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 孔 DANG-mu scIL-12 mut2
<400> 28
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys
210 215 220
Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
245 250 255
Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp
260 265 270
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser
290 295 300
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320
Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile
325 330 335
Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro
340 345 350
Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala
355 360 365
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn
370 375 380
Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn
405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu
420 425 430
His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu
450 455 460
Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala
465 470 475 480
Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp
485 490 495
Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys
500 505 510
Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr
515 520 525
Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His
530 535 540
Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys
545 550 555 560
Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe
565 570 575
Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile
580 585 590
Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met
595 600 605
Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu
610 615 620
Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu
625 630 635 640
Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys
645 650 655
Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro
660 665 670
Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val
675 680 685
Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr
690 695 700
Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala Glu Lys Met
705 710 715 720
Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu
725 730 735
Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln
740 745 750
Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val
755 760 765
Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys
785 790 795 800
Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys
805 810 815
Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile
820 825 830
Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys
835 840 845
Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu
850 855 860
Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser
865 870 875 880
Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met
885 890 895
Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn
900 905 910
His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu
915 920 925
Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro
930 935 940
Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile
945 950 955 960
Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met
965 970 975
Gly Tyr Leu Ser Ser Ala
980
<210> 29
<211> 233
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc 孔 DANG
<400> 29
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
20 25 30
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
35 40 45
Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
50 55 60
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
65 70 75 80
Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
85 90 95
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
100 105 110
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
115 120 125
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
130 135 140
Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp Phe Met Pro
145 150 155 160
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
165 170 175
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
180 185 190
Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
195 200 205
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
210 215 220
Lys Ser Phe Ser Arg Thr Pro Gly Lys
225 230
<210> 30
<211> 233
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc 旋钮 DANG
<400> 30
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
20 25 30
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
35 40 45
Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
50 55 60
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
65 70 75 80
Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
85 90 95
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
100 105 110
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
115 120 125
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
130 135 140
Thr Lys Lys Gln Val Thr Leu Trp Cys Met Val Thr Asp Phe Met Pro
145 150 155 160
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
165 170 175
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
180 185 190
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
195 200 205
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
210 215 220
Lys Ser Phe Ser Arg Thr Pro Gly Lys
225 230
<210> 31
<211> 447
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc DANG
<400> 31
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys
210 215 220
Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
245 250 255
Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp
260 265 270
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser
290 295 300
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320
Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile
325 330 335
Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro
340 345 350
Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met
355 360 365
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn
370 375 380
Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn
405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu
420 425 430
His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
435 440 445
<210> 32
<211> 764
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2-mu IgG2a Fc DANG
<400> 32
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
755 760
<210> 33
<211> 451
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu CD20 HC mu IgG2a Fc 旋钮 DANG
<400> 33
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asp Pro Ser Asp Asn Tyr Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Glu Gly Tyr Tyr Gly Ser Ser Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr
180 185 190
Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr
210 215 220
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met
245 250 255
Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu
260 265 270
Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val
275 280 285
His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu
290 295 300
Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly
305 310 315 320
Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile
325 330 335
Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val
340 345 350
Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr
355 360 365
Leu Trp Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu
370 375 380
Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val
405 410 415
Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val
420 425 430
His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr
435 440 445
Pro Gly Lys
450
<210> 34
<211> 213
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu CD20 LC
<400> 34
Gln Ile Val Met Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Arg Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Thr Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Lys Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 35
<211> 233
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc DANG
<400> 35
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
20 25 30
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
35 40 45
Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
50 55 60
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
65 70 75 80
Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
85 90 95
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
100 105 110
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
115 120 125
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
130 135 140
Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro
145 150 155 160
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
165 170 175
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
180 185 190
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
195 200 205
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
210 215 220
Lys Ser Phe Ser Arg Thr Pro Gly Lys
225 230
<210> 36
<211> 1362
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc 旋钮 DANG的DNA序列
<400> 36
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60
agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120
cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180
aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240
atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300
atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360
acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420
agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480
gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540
ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600
ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660
aaggtggagc caaagtcctg tgataagacc cacacatgcc ccccttgtcc tgcaccagag 720
ctgctgggag gaccaagcgt gttcctgttt ccacccaagc ccaaggacac cctgatgatc 780
tctcgcaccc cagaggtgac atgcgtggtg gtggccgtga gccacgagga ccccgaggtg 840
aagtttaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gccaagagag 900
gagcagtacg gctccaccta tagggtggtg tctgtgctga cagtgctgca ccaggattgg 960
ctgaacggca aggagtataa gtgcaaggtg tccaataagg ccctgcccgc ccctatcgag 1020
aagaccatct ctaaggcaaa gggacagcct agggagccac aggtgtacac cctgcctcca 1080
tcccgggacg agctgacaaa gaaccaggtg tctctgtggt gtctggtgaa gggcttctat 1140
ccctctgata tcgccgtgga gtgggagagc aatggccagc ctgagaacaa ttacaagacc 1200
acaccccctg tgctggacag cgatggctcc ttctttctgt atagcaagct gaccgtggat 1260
aagtcccggt ggcagcaggg caacgtgttt tcttgtagcg tgatgcacga ggccctgcac 1320
aatcactaca cacagaagtc cctgtctctg agccctggca ag 1362
<210> 37
<211> 660
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP LC的DNA序列
<400> 37
gacatcgtga tgacccagtc ccctgattct ctggccgtga gcctgggaga gagggcaaca 60
atcaactgca agagctccca gagcctgctg tactcccgca accagaagaa ttacctggcc 120
tggtatcagc agaagcccgg ccagccccct aagctgctga tcttctgggc atctaccagg 180
gagagcggag tgcctgacag attttctggc agcggcttcg gcacagactt caccctgaca 240
atctctagcc tgcaggccga ggacgtggcc gtgtactatt gccagcagta cttctcctat 300
cctctgacct ttggccaggg cacaaaggtg gagatcaaga ggaccgtggc agcaccaagc 360
gtgttcatct ttccaccctc cgacgagcag ctgaagtccg gcaccgcctc tgtggtgtgc 420
ctgctgaaca atttctaccc aagggaggcc aaggtgcagt ggaaggtgga taacgccctg 480
cagagcggca attcccagga gtctgtgacc gagcaggaca gcaaggattc cacatattct 540
ctgtcctcta ccctgacact gtctaaggcc gattacgaga agcacaaggt gtatgcatgc 600
gaggtgaccc accagggact gagctcccca gtgacaaagt cctttaatcg gggcgagtgt 660
<210> 38
<211> 2265
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12-hu IgG1 Fc 孔 DANG的DNA序列
<400> 38
atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60
ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120
gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180
ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240
ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300
ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360
tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420
tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480
gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540
gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600
tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660
ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720
tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg caagtccaag 780
agggagaaga aggaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840
aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900
gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960
tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020
cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080
tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140
gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200
acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260
ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320
aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380
gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440
tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500
ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560
ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620
gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680
atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740
gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800
gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860
tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920
gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980
cctagccgcg atgagctgac caagaaccag gtgtccctgt cttgtgccgt gaagggcttc 2040
tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100
accacaccac ccgtgctgga ctccgatggc tctttctttc tggtgagcaa gctgacagtg 2160
gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220
cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaag 2265
<210> 39
<211> 2265
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut1-hu IgG1 Fc 孔 DANG的DNA序列
<400> 39
atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60
ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120
gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180
ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240
ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300
ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360
tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420
tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480
gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540
gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600
tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660
ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720
tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg agcatccaag 780
agggaggcaa aggaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840
aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900
gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960
tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020
cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080
tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140
gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200
acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260
ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320
aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380
gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440
tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500
ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560
ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620
gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680
atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740
gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800
gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860
tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920
gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980
cctagccgcg atgagctgac caagaaccag gtgtccctgt cttgtgccgt gaagggcttc 2040
tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100
accacaccac ccgtgctgga ctccgatggc tctttctttc tggtgagcaa gctgacagtg 2160
gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220
cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaag 2265
<210> 40
<211> 2265
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2-hu IgG1 Fc 孔 DANG的DNA序列
<400> 40
atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60
ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120
gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180
ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240
ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300
ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360
tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420
tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480
gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540
gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600
tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660
ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720
tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg cgcctccgct 780
agggaggccg ctgaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840
aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900
gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960
tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020
cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080
tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140
gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200
acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260
ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320
aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380
gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440
tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500
ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560
ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620
gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680
atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740
gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800
gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860
tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920
gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980
cctagccgcg atgagctgac caagaaccag gtgtccctgt cttgtgccgt gaagggcttc 2040
tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100
accacaccac ccgtgctgga ctccgatggc tctttctttc tggtgagcaa gctgacagtg 2160
gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220
cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaag 2265
<210> 41
<211> 1779
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-hu FAP VH)2-hu IgG1 Fc 旋钮 DANG的DNA序列
<400> 41
caagtgcagc tggtgcagag cggcgccgag gtgaaaaagc ctggcgcttc tgtgaaggtg 60
tcttgcaaga cctccagata cacattcacc gagtacacca tccactgggt gcggcaggcc 120
cctggacagc ggctggaatg gatcggaggc atcaacccca acaacggcat tccaaattac 180
aaccagaagt tcaagggcag agtgacaatc accgttgaca ccagcgccag caccgcttat 240
atggaactga gcagcctgag aagcgaggat acagccgtgt actactgtgc cagaagacgg 300
atcgcctacg gctacgacga gggccacgcc atggactact ggggccaggg cacactggtc 360
accgtgtcct ctggcggcgg cggcagcggc ggcggcggca gcggaggagg aggtagccag 420
gtccagctgg tgcagtctgg agcagaggtg aagaagccag gagcctctgt gaaggtgagc 480
tgcaagacct ccagatacac cttcacagag tatacaatcc actgggtgcg ccaggcacct 540
ggacagcggc tggagtggat cggaggcatc aaccccaaca atggcatccc taactacaat 600
cagaagttta agggcagagt gaccatcaca gtggacacct ccgcctctac agcctatatg 660
gagctgagct ccctgaggag cgaggatacc gccgtgtact attgcgcccg gagaaggatc 720
gcctacggct atgacgaggg ccacgccatg gattactggg gccagggcac cctggtgaca 780
gtgtctagcg cctctaccaa gggaccaagc gtgttcccac tggcaccatc ctctaagagc 840
acctccggag gaacagccgc cctgggctgt ctggtgaagg actatttccc agagcccgtg 900
acagtgtcct ggaactctgg cgccctgacc tccggagtgc acacatttcc tgccgtgctg 960
cagagctccg gcctgtacag cctgtctagc gtggtgaccg tgccatcctc tagcctgggc 1020
acccagacat atatctgcaa cgtgaatcac aagcctagca atacaaaggt ggacaagaag 1080
gtggagccaa agtcctgtga taagacccac acatgccccc cttgtcctgc accagagctg 1140
ctgggaggac caagcgtgtt cctgtttcca cccaagccca aggacaccct gatgatctct 1200
cgcaccccag aggtgacatg cgtggtggtg gccgtgagcc acgaggaccc cgaggtgaag 1260
tttaactggt acgtggatgg cgtggaggtg cacaatgcca agaccaagcc aagagaggag 1320
cagtacggct ccacctatag ggtggtgtct gtgctgacag tgctgcacca ggattggctg 1380
aacggcaagg agtataagtg caaggtgtcc aataaggccc tgcccgcccc tatcgagaag 1440
accatctcta aggcaaaggg acagcctagg gagccacagg tgtacaccct gcctccatcc 1500
cgggacgagc tgacaaagaa ccaggtgtct ctgtggtgtc tggtgaaggg cttctatccc 1560
tctgatatcg ccgtggagtg ggagagcaat ggccagcctg agaacaatta caagaccaca 1620
ccccctgtgc tggacagcga tggctccttc tttctgtata gcaagctgac cgtggataag 1680
tcccggtggc agcagggcaa cgtgttttct tgtagcgtga tgcacgaggc cctgcacaat 1740
cactacacac agaagtccct gtctctgagc cctggcaag 1779
<210> 42
<211> 1044
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-hu FAP VL)2的DNA序列
<400> 42
gatatcgtga tgacccagag ccccgacagc ctggccgtgt ccctgggcga acgggccaca 60
atcaactgca agtccagcca gtctctgctg tacagcagaa accagaagaa ttacctggct 120
tggtatcagc agaaacctgg ccaacctcca aagctgctga tcttctgggc cagcaccaga 180
gagagcggcg tgcctgatag attcagcggc agcggatttg gcaccgactt caccctgacc 240
atcagcagcc tccaggccga ggacgtggcc gtctactact gtcagcaata cttcagctac 300
cccctgacat tcggccaggg cacaaaggtg gaaatcaagg gcggcggagg ctctggcggc 360
ggcggatctg gaggtggcgg ctccgacatc gtgatgacac agtctcctga ttctctggcc 420
gtgagcctgg gagagagggc aacaatcaac tgcaagagct cccagagcct gctgtactcc 480
cgcaaccaga agaattacct ggcctggtat cagcagaagc ccggccagcc ccctaagctg 540
ctgatcttct gggcatctac cagggagagc ggagtgcctg acagattttc tggcagcggc 600
ttcggcacag acttcaccct gacaatctct agcctgcagg ccgaggacgt ggccgtgtac 660
tattgccagc agtacttctc ctatcctctg acctttggcc agggcacaaa ggtggagatc 720
aagaggaccg tggcagcacc aagcgtgttc atctttccac cctccgacga gcagctgaag 780
tccggcaccg cctctgtggt gtgcctgctg aacaatttct acccaaggga ggccaaggtg 840
cagtggaagg tggataacgc cctgcagagc ggcaattccc aggagtctgt gaccgagcag 900
gacagcaagg attccacata ttctctgtcc tctaccctga cactgtctaa ggccgattac 960
gagaagcaca aggtgtatgc atgcgaggtg acccaccagg gactgagctc cccagtgaca 1020
aagtccttta atcggggcga gtgt 1044
<210> 43
<211> 2178
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc 旋钮 DANG-抗-hu FAP scFv的DNA序列
<400> 43
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60
agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120
cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180
aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240
atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300
atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360
acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420
agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480
gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540
ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600
ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660
aaggtggagc caaagtcctg tgataagacc cacacatgcc ccccttgtcc tgcaccagag 720
ctgctgggag gaccaagcgt gttcctgttt ccacccaagc ccaaggacac cctgatgatc 780
tctcgcaccc cagaggtgac atgcgtggtg gtggccgtga gccacgagga ccccgaggtg 840
aagtttaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gccaagagag 900
gagcagtacg gctccaccta tagggtggtg tctgtgctga cagtgctgca ccaggattgg 960
ctgaacggca aggagtataa gtgcaaggtg tccaataagg ccctgcccgc ccctatcgag 1020
aagaccatct ctaaggcaaa gggacagcct agggagccac aggtgtacac cctgcctcca 1080
tcccgggacg agctgacaaa gaaccaggtg tctctgtggt gtctggtgaa gggcttctat 1140
ccctctgata tcgccgtgga gtgggagagc aatggccagc ctgagaacaa ttacaagacc 1200
acaccccctg tgctggacag cgatggctcc ttctttctgt atagcaagct gaccgtggat 1260
aagtcccggt ggcagcaggg caacgtgttt tcttgtagcg tgatgcacga ggccctgcac 1320
aatcactaca cacagaagtc cctgtctctg agccctggca agggcggcgg cggcagcggc 1380
ggcggcggca gcggaggagg aggtagccaa gtgcagctgg tgcagagcgg cgccgaggtg 1440
aaaaagcctg gcgcttctgt gaaggtgtct tgcaagacct ccagatacac attcaccgag 1500
tacaccatcc actgggtgcg gcaggcccct ggacagcggc tggaatggat cggaggcatc 1560
aaccccaaca acggcattcc aaattacaac cagaagttca agggcagagt gacaatcacc 1620
gttgacacca gcgccagcac cgcttatatg gaactgagca gcctgagaag cgaggataca 1680
gccgtgtact actgtgccag aagacggatc gcctacggct acgacgaggg ccacgccatg 1740
gactactggg gccagggcac actggtcacc gtgtcctctg gtggaggtgg ctcaggagga 1800
ggcggttctg gcggaggagg tagtggaggt ggcggctccg atatcgtgat gacccagagc 1860
cccgacagcc tggccgtgtc cctgggcgaa cgggccacaa tcaactgcaa gtccagccag 1920
tctctgctgt acagcagaaa ccagaagaat tacctggctt ggtatcagca gaaacctggc 1980
caacctccaa agctgctgat cttctgggcc agcaccagag agagcggcgt gcctgataga 2040
ttcagcggca gcggatttgg caccgacttc accctgacca tcagcagcct ccaggccgag 2100
gacgtggccg tctactactg tcagcaatac ttcagctacc ccctgacatt cggccagggc 2160
acaaaggtgg aaatcaag 2178
<210> 44
<211> 1476
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP LC-抗-hu FAP scFv的DNA序列
<400> 44
gacatcgtga tgacccagtc ccctgattct ctggccgtga gcctgggaga gagggcaaca 60
atcaactgca agagctccca gagcctgctg tactcccgca accagaagaa ttacctggcc 120
tggtatcagc agaagcccgg ccagccccct aagctgctga tcttctgggc atctaccagg 180
gagagcggag tgcctgacag attttctggc agcggcttcg gcacagactt caccctgaca 240
atctctagcc tgcaggccga ggacgtggcc gtgtactatt gccagcagta cttctcctat 300
cctctgacct ttggccaggg cacaaaggtg gagatcaaga ggaccgtggc agcaccaagc 360
gtgttcatct ttccaccctc cgacgagcag ctgaagtccg gcaccgcctc tgtggtgtgc 420
ctgctgaaca atttctaccc aagggaggcc aaggtgcagt ggaaggtgga taacgccctg 480
cagagcggca attcccagga gtctgtgacc gagcaggaca gcaaggattc cacatattct 540
ctgtcctcta ccctgacact gtctaaggcc gattacgaga agcacaaggt gtatgcatgc 600
gaggtgaccc accagggact gagctcccca gtgacaaagt cctttaatcg gggcgagtgt 660
ggcggcggcg gcagcggcgg cggcggcagc ggaggaggag gtagccaagt gcagctggtg 720
cagagcggcg ccgaggtgaa aaagcctggc gcttctgtga aggtgtcttg caagacctcc 780
agatacacat tcaccgagta caccatccac tgggtgcggc aggcccctgg acagcggctg 840
gaatggatcg gaggcatcaa ccccaacaac ggcattccaa attacaacca gaagttcaag 900
ggcagagtga caatcaccgt tgacaccagc gccagcaccg cttatatgga actgagcagc 960
ctgagaagcg aggatacagc cgtgtactac tgtgccagaa gacggatcgc ctacggctac 1020
gacgagggcc acgccatgga ctactggggc cagggcacac tggtcaccgt gtcctctggt 1080
ggaggtggct caggaggagg cggttctggc ggaggaggta gtggaggtgg cggctccgat 1140
atcgtgatga cccagagccc cgacagcctg gccgtgtccc tgggcgaacg ggccacaatc 1200
aactgcaagt ccagccagtc tctgctgtac agcagaaacc agaagaatta cctggcttgg 1260
tatcagcaga aacctggcca acctccaaag ctgctgatct tctgggccag caccagagag 1320
agcggcgtgc ctgatagatt cagcggcagc ggatttggca ccgacttcac cctgaccatc 1380
agcagcctcc aggccgagga cgtggccgtc tactactgtc agcaatactt cagctacccc 1440
ctgacattcg gccagggcac aaaggtggaa atcaag 1476
<210> 45
<211> 2958
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc 孔 DANG-hu scIL-12的DNA序列
<400> 45
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60
agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120
cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180
aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240
atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300
atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360
acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420
agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480
gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540
ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600
ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660
aaggtggagc caaagtcctg tgacaagacc cacacatgcc caccatgtcc agcacctgag 720
ctgctgggag gaccatccgt gttcctgttt cctccaaagc ccaaggatac actgatgatc 780
agccgcacac ctgaggtgac ctgcgtggtg gtggccgtgt cccacgagga ccccgaggtg 840
aagtttaact ggtacgtgga cggcgtggag gtgcacaatg ccaagaccaa gcccagggag 900
gagcagtacg gctctacata tcgcgtggtg agcgtgctga ccgtgctgca ccaggactgg 960
ctgaacggca aggagtacaa gtgcaaggtg tctaataagg ccctgccagc ccccatcgag 1020
aagaccatca gcaaggcaaa gggacagcca agggagcctc aggtgtatac actgccccct 1080
agccgcgatg agctgaccaa gaaccaggtg tccctgtctt gtgccgtgaa gggcttctac 1140
ccatccgaca tcgccgtgga gtgggagtct aatggccagc ccgagaacaa ttataagacc 1200
acaccacccg tgctggactc cgatggctct ttctttctgg tgagcaagct gacagtggac 1260
aagtccagat ggcagcaggg caacgtgttt agctgctccg tgatgcacga ggccctgcac 1320
aatcactaca cccagaagtc tctgagcctg tcccctggcg gtggaggtgg ctcaggagga 1380
ggcggttctg gcggaggagg tagtatctgg gagctgaaga aggacgtgta cgtggtggag 1440
ctggactggt atcctgatgc cccaggcgag atggtggtgc tgacctgcga cacacccgag 1500
gaggatggca tcacctggac actggatcag agctccgagg tgctgggcag cggcaagacc 1560
ctgacaatcc aggtgaagga gttcggcgac gccggccagt acacctgtca caagggagga 1620
gaggtgctga gccactccct gctgctgctg cacaagaagg aggacggcat ctggagcaca 1680
gacatcctga aggatcagaa ggagccaaag aacaagacct tcctgcggtg cgaggccaag 1740
aattattccg gccggttcac ctgttggtgg ctgaccacaa tctccaccga tctgacattt 1800
tctgtgaagt ctagcagggg ctcctctgac ccccagggag tgacatgcgg agcagccacc 1860
ctgagcgccg agcgggtgag aggcgataac aaggagtacg agtattccgt ggagtgccag 1920
gaggactctg cctgtcctgc agcagaggag tccctgccaa tcgaagtgat ggtggatgcc 1980
gtgcacaagc tgaagtacga gaattataca agctccttct ttatcaggga catcatcaag 2040
cctgatcccc ctaagaacct gcagctgaag ccactgaaga atagccgcca ggtggaggtg 2100
tcctgggagt acccagacac ctggtccaca ccccactctt atttcagcct gaccttttgc 2160
gtgcaggtgc agggcaagtc caagagggag aagaaggacc gcgtgttcac cgataagaca 2220
tctgccaccg tgatctgtcg gaagaacgcc tctatcagcg tgcgggccca ggatagatac 2280
tattctagct cctggagcga gtgggcctcc gtgccttgtt ctggaggagg aggcagcggc 2340
ggaggaggct ccggaggagg aggctctaga aatctgccag tggcaacccc tgacccagga 2400
atgttccctt gcctgcacca ctctcagaac ctgctgcggg ccgtgagcaa tatgctgcag 2460
aaggccagac agacactgga gttttacccc tgtaccagcg aggagatcga ccacgaggat 2520
atcacaaagg ataagacctc cacagtggag gcctgcctgc ctctggagct gaccaagaac 2580
gagagctgtc tgaacagccg ggagacatct ttcatcacca acggcagctg cctggcctcc 2640
agaaagacat cttttatgat ggccctgtgc ctgtctagca tctacgagga cctgaagatg 2700
tatcaggtgg agttcaagac catgaacgcc aagctgctga tggacccaaa gcggcagatc 2760
tttctggatc agaatatgct ggccgtgatc gacgagctga tgcaggccct gaacttcaat 2820
agcgagacag tgccccagaa gtcctctctg gaggagcctg acttctacaa gaccaagatc 2880
aagctgtgca tcctgctgca cgccttccgg atcagagccg tgaccatcga tagagtgatg 2940
agctatctga acgcaagc 2958
<210> 46
<211> 2958
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc 孔 DANG-hu scIL-12 mut2的DNA序列
<400> 46
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60
agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120
cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180
aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240
atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300
atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360
acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420
agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480
gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540
ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600
ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660
aaggtggagc caaagtcctg tgacaagacc cacacatgcc caccatgtcc agcacctgag 720
ctgctgggag gaccatccgt gttcctgttt cctccaaagc ccaaggatac actgatgatc 780
agccgcacac ctgaggtgac ctgcgtggtg gtggccgtgt cccacgagga ccccgaggtg 840
aagtttaact ggtacgtgga cggcgtggag gtgcacaatg ccaagaccaa gcccagggag 900
gagcagtacg gctctacata tcgcgtggtg agcgtgctga ccgtgctgca ccaggactgg 960
ctgaacggca aggagtacaa gtgcaaggtg tctaataagg ccctgccagc ccccatcgag 1020
aagaccatca gcaaggcaaa gggacagcca agggagcctc aggtgtatac actgccccct 1080
agccgcgatg agctgaccaa gaaccaggtg tccctgtctt gtgccgtgaa gggcttctac 1140
ccatccgaca tcgccgtgga gtgggagtct aatggccagc ccgagaacaa ttataagacc 1200
acaccacccg tgctggactc cgatggctct ttctttctgg tgagcaagct gacagtggac 1260
aagtccagat ggcagcaggg caacgtgttt agctgctccg tgatgcacga ggccctgcac 1320
aatcactaca cccagaagtc tctgagcctg tcccctggcg gtggaggtgg ctcaggagga 1380
ggcggttctg gcggaggagg tagtatctgg gagctgaaga aggacgtgta cgtggtggag 1440
ctggactggt atcctgatgc cccaggcgag atggtggtgc tgacctgcga cacacccgag 1500
gaggatggca tcacctggac actggatcag agctccgagg tgctgggcag cggcaagacc 1560
ctgacaatcc aggtgaagga gttcggcgac gccggccagt acacctgtca caagggagga 1620
gaggtgctga gccactccct gctgctgctg cacaagaagg aggacggcat ctggagcaca 1680
gacatcctga aggatcagaa ggagccaaag aacaagacct tcctgcggtg cgaggccaag 1740
aattattccg gccggttcac ctgttggtgg ctgaccacaa tctccaccga tctgacattt 1800
tctgtgaagt ctagcagggg ctcctctgac ccccagggag tgacatgcgg agcagccacc 1860
ctgagcgccg agcgggtgag aggcgataac aaggagtacg agtattccgt ggagtgccag 1920
gaggactctg cctgtcctgc agcagaggag tccctgccaa tcgaagtgat ggtggatgcc 1980
gtgcacaagc tgaagtacga gaattataca agctccttct ttatcaggga catcatcaag 2040
cctgatcccc ctaagaacct gcagctgaag ccactgaaga atagccgcca ggtggaggtg 2100
tcctgggagt acccagacac ctggtccaca ccccactctt atttcagcct gaccttttgc 2160
gtgcaggtgc agggcgcctc cgctagggag gccgctgacc gcgtgttcac cgataagaca 2220
tctgccaccg tgatctgtcg gaagaacgcc tctatcagcg tgcgggccca ggatagatac 2280
tattctagct cctggagcga gtgggcctcc gtgccttgtt ctggaggagg aggcagcggc 2340
ggaggaggct ccggaggagg aggctctaga aatctgccag tggcaacccc tgacccagga 2400
atgttccctt gcctgcacca ctctcagaac ctgctgcggg ccgtgagcaa tatgctgcag 2460
aaggccagac agacactgga gttttacccc tgtaccagcg aggagatcga ccacgaggat 2520
atcacaaagg ataagacctc cacagtggag gcctgcctgc ctctggagct gaccaagaac 2580
gagagctgtc tgaacagccg ggagacatct ttcatcacca acggcagctg cctggcctcc 2640
agaaagacat cttttatgat ggccctgtgc ctgtctagca tctacgagga cctgaagatg 2700
tatcaggtgg agttcaagac catgaacgcc aagctgctga tggacccaaa gcggcagatc 2760
tttctggatc agaatatgct ggccgtgatc gacgagctga tgcaggccct gaacttcaat 2820
agcgagacag tgccccagaa gtcctctctg gaggagcctg acttctacaa gaccaagatc 2880
aagctgtgca tcctgctgca cgccttccgg atcagagccg tgaccatcga tagagtgatg 2940
agctatctga acgcaagc 2958
<210> 47
<211> 681
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc 孔 DANG的DNA序列
<400> 47
gacaagaccc acacatgccc accttgtcca gcaccagagc tgctgggagg accatccgtg 60
ttcctgtttc cacccaagcc caaggatacc ctgatgatca gcaggacccc agaggtgaca 120
tgcgtggtgg tggccgtgtc ccacgaggac cctgaggtga agttcaactg gtacgtggat 180
ggcgtggagg tgcacaatgc caagacaaag ccacgggagg agcagtacgg cagcacctat 240
agagtggtgt ccgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtacaag 300
tgcaaggtgt ctaataaggc cctgcctgcc ccaatcgaga agaccatcag caaggcaaag 360
ggacagccaa gggagcctca ggtgtatacc ctgcctccaa gccgcgacga gctgacaaag 420
aaccaggtga gcctgtcctg tgccgtgaag ggcttctacc cttccgatat cgccgtggag 480
tgggagtcta atggccagcc agagaacaat tataagacca caccccctgt gctggactcc 540
gatggctctt tctttctggt gtctaagctg accgtggata agagcaggtg gcagcagggc 600
aacgtgtttt cttgtagcgt gatgcacgag gccctgcaca atcactatac acagaagtcc 660
ctgtctctga gccctggcaa g 681
<210> 48
<211> 681
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc 旋钮 DANG的DNA序列
<400> 48
gacaagaccc acacatgccc accttgtcca gcaccagagc tgctgggagg accatccgtg 60
ttcctgtttc cacccaagcc caaggatacc ctgatgatca gcaggacccc agaggtgaca 120
tgcgtggtgg tggccgtgtc ccacgaggac cctgaggtga agttcaactg gtacgtggat 180
ggcgtggagg tgcacaatgc caagacaaag ccacgggagg agcagtacgg ctccacctat 240
agagtggtgt ctgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtataag 300
tgcaaggtgt ctaataaggc cctgcctgcc ccaatcgaga agaccatcag caaggcaaag 360
ggacagccaa gggagcctca ggtgtacacc ctgcctccat cccgcgacga gctgacaaag 420
aaccaggtgt ctctgtggtg tctggtgaag ggcttctatc cttctgatat cgccgtggag 480
tgggagagca atggccagcc agagaacaat tacaagacca caccccctgt gctggactct 540
gatggcagct tctttctgta tagcaagctg accgtggata agtccaggtg gcagcagggc 600
aacgtgttta gctgttccgt gatgcacgag gccctgcaca atcactacac acagaagtct 660
ctgagcctgt cccctggcaa g 681
<210> 49
<211> 1365
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc DANG的DNA序列
<400> 49
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagcctc tgtgaaggtg 60
agctgcaaga cctccagata caccttcaca gagtatacaa tccactgggt gcgccaggca 120
cctggacagc ggctggagtg gatcggaggc atcaacccca acaatggcat ccctaactac 180
aatcagaagt ttaagggcag agtgaccatc acagtggaca cctccgcctc tacagcctat 240
atggagctga gctccctgag gagcgaggat accgccgtgt actattgcgc ccggagaagg 300
atcgcctacg gctatgacga gggccacgcc atggattact ggggccaggg caccctggtg 360
acagtgtcta gcgcctctac caagggacca agcgtgttcc cactggcacc atcctctaag 420
agcacctccg gaggaacagc cgccctgggc tgtctggtga aggactattt cccagagccc 480
gtgacagtgt cctggaactc tggcgccctg acctccggag tgcacacatt tcctgccgtg 540
ctgcagagct ccggcctgta cagcctgtct agcgtggtga ccgtgccatc ctctagcctg 600
ggcacccaga catatatctg caacgtgaat cacaagccta gcaatacaaa ggtggacaag 660
aaggtggagc caaagtcctg tgataagacc cacacatgcc ccccttgtcc tgcaccagag 720
ctgctgggag gaccaagcgt gttcctgttt ccacccaagc ccaaggacac cctgatgatc 780
tctcgcaccc cagaggtgac atgcgtggtg gtggccgtga gccacgagga ccccgaggtg 840
aagtttaact ggtacgtgga tggcgtggag gtgcacaatg ccaagaccaa gccaagagag 900
gagcagtacg gctccaccta tagggtggtg tctgtgctga cagtgctgca ccaggattgg 960
ctgaacggca aggagtataa gtgcaaggtg tccaataagg ccctgcccgc ccctatcgag 1020
aagaccatct ctaaggcaaa gggacagcct agggagccac aggtgtacac cctgcctcca 1080
tcccgggacg agctgacaaa gaaccaggtg tctctgacgt gtctggtgaa gggcttctat 1140
ccctctgata tcgccgtgga gtgggagagc aatggccagc ctgagaacaa ttacaagacc 1200
acaccccctg tgctggacag cgatggctcc ttctttctgt atagcaagct gaccgtggat 1260
aagtcccggt ggcagcaggg caacgtgttt tcttgtagcg tgatgcacga ggccctgcac 1320
aatcactaca cacagaagtc cctgtctctg agccctggca agtga 1365
<210> 50
<211> 2268
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2-hu IgG1 Fc DANG的DNA序列
<400> 50
atctgggagc tgaagaagga cgtgtacgtg gtggagctgg actggtatcc tgatgcccca 60
ggcgagatgg tggtgctgac ctgcgacaca cccgaggagg atggcatcac ctggacactg 120
gatcagagct ccgaggtgct gggcagcggc aagaccctga caatccaggt gaaggagttc 180
ggcgacgccg gccagtacac ctgtcacaag ggaggagagg tgctgagcca ctccctgctg 240
ctgctgcaca agaaggagga cggcatctgg agcacagaca tcctgaagga tcagaaggag 300
ccaaagaaca agaccttcct gcggtgcgag gccaagaatt attccggccg gttcacctgt 360
tggtggctga ccacaatctc caccgatctg acattttctg tgaagtctag caggggctcc 420
tctgaccccc agggagtgac atgcggagca gccaccctga gcgccgagcg ggtgagaggc 480
gataacaagg agtacgagta ttccgtggag tgccaggagg actctgcctg tcctgcagca 540
gaggagtccc tgccaatcga agtgatggtg gatgccgtgc acaagctgaa gtacgagaat 600
tatacaagct ccttctttat cagggacatc atcaagcctg atccccctaa gaacctgcag 660
ctgaagccac tgaagaatag ccgccaggtg gaggtgtcct gggagtaccc agacacctgg 720
tccacacccc actcttattt cagcctgacc ttttgcgtgc aggtgcaggg cgcctccgct 780
agggaggccg ctgaccgcgt gttcaccgat aagacatctg ccaccgtgat ctgtcggaag 840
aacgcctcta tcagcgtgcg ggcccaggat agatactatt ctagctcctg gagcgagtgg 900
gcctccgtgc cttgttctgg aggaggaggc agcggcggag gaggctccgg aggaggaggc 960
tctagaaatc tgccagtggc aacccctgac ccaggaatgt tcccttgcct gcaccactct 1020
cagaacctgc tgcgggccgt gagcaatatg ctgcagaagg ccagacagac actggagttt 1080
tacccctgta ccagcgagga gatcgaccac gaggatatca caaaggataa gacctccaca 1140
gtggaggcct gcctgcctct ggagctgacc aagaacgaga gctgtctgaa cagccgggag 1200
acatctttca tcaccaacgg cagctgcctg gcctccagaa agacatcttt tatgatggcc 1260
ctgtgcctgt ctagcatcta cgaggacctg aagatgtatc aggtggagtt caagaccatg 1320
aacgccaagc tgctgatgga cccaaagcgg cagatctttc tggatcagaa tatgctggcc 1380
gtgatcgacg agctgatgca ggccctgaac ttcaatagcg agacagtgcc ccagaagtcc 1440
tctctggagg agcctgactt ctacaagacc aagatcaagc tgtgcatcct gctgcacgcc 1500
ttccggatca gagccgtgac catcgataga gtgatgagct atctgaacgc aagcggcggc 1560
ggaggctctg gaggaggcgg cagcgacaag acccacacat gcccaccatg tccagcacct 1620
gagctgctgg gaggaccatc cgtgttcctg tttcctccaa agcccaagga tacactgatg 1680
atcagccgca cacctgaggt gacctgcgtg gtggtggccg tgtcccacga ggaccccgag 1740
gtgaagttta actggtacgt ggacggcgtg gaggtgcaca atgccaagac caagcccagg 1800
gaggagcagt acggctctac atatcgcgtg gtgagcgtgc tgaccgtgct gcaccaggac 1860
tggctgaacg gcaaggagta caagtgcaag gtgtctaata aggccctgcc agcccccatc 1920
gagaagacca tcagcaaggc aaagggacag ccaagggagc ctcaggtgta tacactgccc 1980
cctagccgcg atgagctgac caagaaccag gtgtccctga cttgtctcgt gaagggcttc 2040
tacccatccg acatcgccgt ggagtgggag tctaatggcc agcccgagaa caattataag 2100
accacaccac ccgtgctgga ctccgatggc tctttctttc tgtacagcaa gctgacagtg 2160
gacaagtcca gatggcagca gggcaacgtg tttagctgct ccgtgatgca cgaggccctg 2220
cacaatcact acacccagaa gtctctgagc ctgtcccctg gcaagtga 2268
<210> 51
<211> 1353
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu CD20 HC hu IgG1 Fc 旋钮 DANG的DNA序列
<400> 51
caggtgcagc tgcagcagcc aggagcagag ctggtgaagc ctggagcctc tgtgaagatg 60
agctgcaagg cctccggcta caccttcaca agctataaca tgcactgggt gaagcagacc 120
ccaggaaggg gactggagtg gatcggagcc atctaccctg gcaacggcga cacatcctat 180
aatcagaagt ttaagggcaa ggccaccctg acagccgata agagctcctc taccgcctac 240
atgcagctga gctccctgac aagcgaggac tccgccgtgt actattgcgc cagaagcacc 300
tactatggcg gcgattggta cttcaacgtg tggggagcag gaaccacagt gaccgtgtct 360
gccgccagca caaagggacc atccgtgttt ccactggcac catctagcaa gtctaccagc 420
ggaggaacag ccgccctggg atgtctggtg aaggactact tcccagagcc cgtgaccgtg 480
tcctggaact ctggcgccct gacctccgga gtgcacacat ttcccgccgt gctgcagtcc 540
tctggcctgt actctctgag ctccgtggtg accgtgcctt ctagctccct gggcacccag 600
acatatatct gcaacgtgaa tcacaagcct tccaatacaa aggtggacaa gaaggtggag 660
ccaaagtctt gtgataagac ccacacatgc cccccttgtc ctgcaccaga gctgctggga 720
ggaccaagcg tgttcctgtt tccacccaag cccaaggaca ccctgatgat cagcaggacc 780
cctgaggtga catgcgtggt ggtggccgtg tcccacgagg acccagaggt gaagttcaac 840
tggtacgtgg atggcgtgga ggtgcacaat gccaagacaa agccacggga ggagcagtac 900
ggctctacct atagagtggt gagcgtgctg acagtgctgc accaggattg gctgaacggc 960
aaggagtata agtgcaaggt gtctaataag gccctgcccg cccctatcga gaagaccatc 1020
agcaaggcca agggccagcc tagggagcca caggtgtaca ccctgcctcc atctcgcgac 1080
gagctgacaa agaaccaggt gagcctgtgg tgtctggtga agggcttcta tccaagcgat 1140
atcgccgtgg agtgggagtc caatggccag cccgagaaca attacaagac cacaccccct 1200
gtgctggaca gcgatggctc cttctttctg tattccaagc tgaccgtgga taagtctaga 1260
tggcagcagg gcaacgtgtt ttcctgttct gtgatgcacg aggccctgca caatcactac 1320
acacagaaga gcctgtccct gtctcctggc aag 1353
<210> 52
<211> 639
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu CD20 LC的DNA序列
<400> 52
cagatcgtgc tgagccagtc cccagcaatc ctgtctgcca gccctggaga gaaggtgacc 60
atgacatgcc gggccagctc ctctgtgagc tacatccact ggttccagca gaagccaggc 120
agctccccta agccatggat ctatgccaca agcaacctgg catccggagt gcccgtgcgg 180
ttttccggct ctggcagcgg cacctcctac tctctgacaa tcagcagagt ggaggcagag 240
gacgcagcaa cctactattg ccagcagtgg acctccaatc cccctacatt cggcggcggc 300
accaagctgg agatcaagag gacagtggcc gccccttccg tgttcatctt tccaccctct 360
gacgagcagc tgaagtctgg caccgccagc gtggtgtgcc tgctgaacaa cttctaccca 420
cgcgaggcca aggtgcagtg gaaggtggat aacgccctgc agagcggcaa ttcccaggag 480
tctgtgacag agcaggacag caaggattcc acctattctc tgtctagcac cctgacactg 540
agcaaggccg attacgagaa gcacaaggtg tatgcctgcg aggtgacaca ccagggcctg 600
tcctctcccg tgaccaagtc cttcaacagg ggcgagtgt 639
<210> 53
<211> 1341
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 旋钮 DANG的DNA序列
<400> 53
caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60
agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120
accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180
aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240
atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300
acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360
acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420
accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480
ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540
ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600
gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg gggccccaca 660
atcaagccat gtccaccttg caagtgtcca gcacctaatc tgctgggagg acctagcgtg 720
ttcatctttc cacccaagat caaggacgtg ctgatgatct ctctgagccc tatcgtgacc 780
tgcgtggtgg tggccgtgtc tgaggacgat ccagatgtgc agatcagctg gttcgtgaac 840
aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900
agagtggtgt ctgccctgcc catccagcac caggactgga tgtccggcaa ggagtttaag 960
tgcaaggtga acaataagga tctgccagcc cccatcgaga ggaccatctc taagcctaag 1020
ggcagcgtgc gcgcaccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080
aagcaggtga cactgtggtg tatggtgacc gacttcatgc cagaggatat ctacgtggag 1140
tggaccaaca atggcaagac agagctgaac tataagaata cagagcccgt gctggacagc 1200
gatggctcct actttatgta tagcaagctg agggtggaga agaagaactg ggtggagcgc 1260
aattcctact cttgtagcgt ggtgcacgag ggcctgcaca accaccacac cacaaagtcc 1320
ttttctagaa cccccggcaa g 1341
<210> 54
<211> 639
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LC的DNA序列
<400> 54
cagatcgtgc tgacacagtc ccctgccatc atgtctgcca gcccaggcga gaaggtgacc 60
atgacatgct ctgccagctc cggcgtgaac ttcatgcact ggtaccagca gaagtctggc 120
acaagcccca agcggtggat cttcgacacc tccaagctgg cctctggcgt gcctgccaga 180
ttttccggct ctggcagcgg cacatcctat tctctgacca tctctagcat ggaggccgag 240
gacgccgcca cctactattg ccagcagtgg agcttcaatc cccctacatt tggcggcggc 300
accaagctgg agatcaagag ggcagatgca gcaccaacag tgtccatctt tccaccctcc 360
tctgagcagc tgaccagcgg aggagcatcc gtggtgtgct tcctgaacaa cttctacccc 420
aaggacatca acgtgaagtg gaagatcgat ggctctgaga ggcagaacgg cgtgctgaat 480
agctggacag accaggattc caaggactct acctatagca tgagctccac cctgacactg 540
accaaggatg agtacgagag gcacaatagc tatacatgcg aggccaccca caagacaagc 600
acctccccta tcgtgaagtc cttcaaccgc aatgagtgt 639
<210> 55
<211> 2292
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12-mu IgG2a Fc 孔 DANG的DNA序列
<400> 55
atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60
ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120
gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180
ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240
ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300
aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360
gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420
agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480
gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540
acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600
acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660
cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720
cactcctact tctccctgaa gttctttgtg agaatccaga gaaagaagga gaagatgaag 780
gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840
gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900
tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960
ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020
tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080
ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140
acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200
accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260
atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320
caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380
atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440
cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500
ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560
gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620
tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680
ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740
gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800
gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860
tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920
aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980
agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040
acactgtctt gtgccgtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100
aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160
tacttcatgg tgagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220
agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280
acccctggca ag 2292
<210> 56
<211> 2292
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut1-mu IgG2a Fc 孔 DANG的DNA序列
<400> 56
atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60
ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120
gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180
ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240
ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300
aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360
gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420
agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480
gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540
acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600
acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660
cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720
cactcctact tctccctgaa gttctttgtg agaatccaga gagccaagga gaagatggcc 780
gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840
gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900
tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960
ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020
tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080
ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140
acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200
accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260
atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320
caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380
atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440
cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500
ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560
gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620
tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680
ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740
gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800
gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860
tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920
aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980
agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040
acactgtctt gtgccgtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100
aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160
tacttcatgg tgagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220
agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280
acccctggca ag 2292
<210> 57
<211> 2292
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2-mu IgG2a Fc 孔 DANG的DNA序列
<400> 57
atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60
ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120
gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180
ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240
ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300
aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360
gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420
agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480
gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540
acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600
acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660
cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720
cactcctact tctccctgaa gttctttgtg agaatccagg ctgccgccga gaagatggcc 780
gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840
gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900
tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960
ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020
tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080
ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140
acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200
accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260
atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320
caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380
atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440
cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500
ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560
gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620
tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680
ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740
gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800
gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860
tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920
aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980
agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040
acactgtctt gtgccgtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100
aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160
tacttcatgg tgagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220
agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280
acccctggca ag 2292
<210> 58
<211> 1737
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-mu FAP VH)2, mu IgG2a 旋钮 DANG的DNA序列
<400> 58
caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60
agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120
accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180
aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240
atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300
acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cggaggtgga 360
ggctcaggtg gtggcggatc tggaggaggc ggtagtcagg tgcagctgca gcagtccgga 420
gcagagctgg caaggcctgg agcctctgtg aacctgagct gcaaggcctc cggctacacc 480
ttcacaaaca atggcatcaa ttggctgaag cagaggaccg gacagggact ggagtggatc 540
ggcgagatct acccaagatc taccaacaca ctgtataatg agaagttcaa gggcaaggcc 600
accctgacag cagaccggag ctccaacacc gcctacatgg agctgagaag cctgacatcc 660
gaggattctg ccgtgtattt ttgtgcacgc accctgacag cacccttcgc cttttgggga 720
cagggcaccc tggtgacagt gagcgccgcc aagaccacag caccaagcgt gtatccactg 780
gcacccgtgt gcggcgatac cacaggctct agcgtgaccc tgggctgtct ggtgaagggc 840
tacttccctg agccagtgac cctgacatgg aacagcggct ctctgtcctc tggcgtgcac 900
acctttcctg ccgtgctgca gtccgatctg tatacactga gctcctctgt gaccgtgaca 960
agctccacct ggcccagcca gtccatcaca tgcaacgtgg cccaccctgc ctctagcacc 1020
aaggtggaca agaagatcga gccacggggc cccacaatca agccatgtcc accttgcaag 1080
tgtccagcac ctaatctgct gggaggacct agcgtgttca tctttccacc caagatcaag 1140
gacgtgctga tgatctctct gagccctatc gtgacctgcg tggtggtggc cgtgtctgag 1200
gacgatccag atgtgcagat cagctggttc gtgaacaatg tggaggtgca caccgcccag 1260
acccagacac accgggagga ctacggctcc acactgagag tggtgtctgc cctgcccatc 1320
cagcaccagg actggatgtc cggcaaggag tttaagtgca aggtgaacaa taaggatctg 1380
ccagccccca tcgagaggac catctctaag cctaagggca gcgtgcgcgc accacaggtg 1440
tatgtgctgc ctccacccga ggaggagatg accaagaagc aggtgacact gtggtgtatg 1500
gtgaccgact tcatgccaga ggatatctac gtggagtgga ccaacaatgg caagacagag 1560
ctgaactata agaatacaga gcccgtgctg gacagcgatg gctcctactt tatgtatagc 1620
aagctgaggg tggagaagaa gaactgggtg gagcgcaatt cctactcttg tagcgtggtg 1680
cacgagggcc tgcacaacca ccacaccaca aagtcctttt ctagaacccc cggcaag 1737
<210> 59
<211> 1002
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-mu FAP VL)2的DNA序列
<400> 59
cagatcgtgc tgacacagtc ccctgccatc atgtctgcca gcccaggcga gaaggtgacc 60
atgacatgct ctgccagctc cggcgtgaac ttcatgcact ggtaccagca gaagtctggc 120
acaagcccca agcggtggat cttcgacacc tccaagctgg cctctggcgt gcctgccaga 180
ttttccggct ctggcagcgg cacatcctat tctctgacca tctctagcat ggaggccgag 240
gacgccgcca cctactattg ccagcagtgg agcttcaatc cccctacatt tggcggcggc 300
accaagctgg agatcaaggg aggtggaggc tcaggtggtg gcggatctgg aggaggcggt 360
agtcagatcg tgctgacaca gtcccctgcc atcatgtctg ccagcccagg cgagaaggtg 420
accatgacat gctctgccag ctccggcgtg aacttcatgc actggtacca gcagaagtct 480
ggcacaagcc ccaagcggtg gatcttcgac acctccaagc tggcctctgg cgtgcctgcc 540
agattttccg gctctggcag cggcacatcc tattctctga ccatctctag catggaggcc 600
gaggacgccg ccacctacta ttgccagcag tggagcttca atccccctac atttggcggc 660
ggcaccaagc tggagatcaa gagggcagat gcagcaccaa cagtgtccat ctttccaccc 720
tcctctgagc agctgaccag cggaggagca tccgtggtgt gcttcctgaa caacttctac 780
cccaaggaca tcaacgtgaa gtggaagatc gatggctctg agaggcagaa cggcgtgctg 840
aatagctgga cagaccagga ttccaaggac tctacctata gcatgagctc caccctgaca 900
ctgaccaagg atgagtacga gaggcacaat agctatacat gcgaggccac ccacaagaca 960
agcacctccc ctatcgtgaa gtccttcaac cgcaatgagt gt 1002
<210> 60
<211> 2115
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 旋钮 DANG-抗-mu FAP scFv的DNA序列
<400> 60
caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60
agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120
accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180
aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240
atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300
acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360
acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420
accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480
ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540
ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600
gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg gggccccaca 660
atcaagccat gtccaccttg caagtgtcca gcacctaatc tgctgggagg acctagcgtg 720
ttcatctttc cacccaagat caaggacgtg ctgatgatct ctctgagccc tatcgtgacc 780
tgcgtggtgg tggccgtgtc tgaggacgat ccagatgtgc agatcagctg gttcgtgaac 840
aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900
agagtggtgt ctgccctgcc catccagcac caggactgga tgtccggcaa ggagtttaag 960
tgcaaggtga acaataagga tctgccagcc cccatcgaga ggaccatctc taagcctaag 1020
ggcagcgtgc gcgcaccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080
aagcaggtga cactgtggtg tatggtgacc gacttcatgc cagaggatat ctacgtggag 1140
tggaccaaca atggcaagac agagctgaac tataagaata cagagcccgt gctggacagc 1200
gatggctcct actttatgta tagcaagctg agggtggaga agaagaactg ggtggagcgc 1260
aattcctact cttgtagcgt ggtgcacgag ggcctgcaca accaccacac cacaaagtcc 1320
ttttctagaa cccccggcaa gggaggtgga ggctcaggtg gtggcggatc tggaggaggc 1380
ggtagtcagg tgcagctgca gcagtccgga gcagagctgg caaggcctgg agcctctgtg 1440
aacctgagct gcaaggcctc cggctacacc ttcacaaaca atggcatcaa ttggctgaag 1500
cagaggaccg gacagggact ggagtggatc ggcgagatct acccaagatc taccaacaca 1560
ctgtataatg agaagttcaa gggcaaggcc accctgacag cagaccggag ctccaacacc 1620
gcctacatgg agctgagaag cctgacatcc gaggattctg ccgtgtattt ttgtgcacgc 1680
accctgacag cacccttcgc cttttgggga cagggcaccc tggtgacagt gagcgccggt 1740
ggcggaggat caggaggagg cggtagtggc ggcggaggtt ctggtggagg aggtagccag 1800
atcgtgctga cacagtcccc tgccatcatg tctgccagcc caggcgagaa ggtgaccatg 1860
acatgctctg ccagctccgg cgtgaacttc atgcactggt accagcagaa gtctggcaca 1920
agccccaagc ggtggatctt cgacacctcc aagctggcct ctggcgtgcc tgccagattt 1980
tccggctctg gcagcggcac atcctattct ctgaccatct ctagcatgga ggccgaggac 2040
gccgccacct actattgcca gcagtggagc ttcaatcccc ctacatttgg cggcggcacc 2100
aagctggaga tcaag 2115
<210> 61
<211> 1413
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LC-抗-mu FAP scFv的DNA序列
<400> 61
cagatcgtgc tgacacagtc ccctgccatc atgtctgcca gcccaggcga gaaggtgacc 60
atgacatgct ctgccagctc cggcgtgaac ttcatgcact ggtaccagca gaagtctggc 120
acaagcccca agcggtggat cttcgacacc tccaagctgg cctctggcgt gcctgccaga 180
ttttccggct ctggcagcgg cacatcctat tctctgacca tctctagcat ggaggccgag 240
gacgccgcca cctactattg ccagcagtgg agcttcaatc cccctacatt tggcggcggc 300
accaagctgg agatcaagag ggcagatgca gcaccaacag tgtccatctt tccaccctcc 360
tctgagcagc tgaccagcgg aggagcatcc gtggtgtgct tcctgaacaa cttctacccc 420
aaggacatca acgtgaagtg gaagatcgat ggctctgaga ggcagaacgg cgtgctgaat 480
agctggacag accaggattc caaggactct acctatagca tgagctccac cctgacactg 540
accaaggatg agtacgagag gcacaatagc tatacatgcg aggccaccca caagacaagc 600
acctccccta tcgtgaagtc cttcaaccgc aatgagtgtg gaggtggagg ctcaggtggt 660
ggcggatctg gaggaggcgg tagtcaggtg cagctgcagc agtccggagc agagctggca 720
aggcctggag cctctgtgaa cctgagctgc aaggcctccg gctacacctt cacaaacaat 780
ggcatcaatt ggctgaagca gaggaccgga cagggactgg agtggatcgg cgagatctac 840
ccaagatcta ccaacacact gtataatgag aagttcaagg gcaaggccac cctgacagca 900
gaccggagct ccaacaccgc ctacatggag ctgagaagcc tgacatccga ggattctgcc 960
gtgtattttt gtgcacgcac cctgacagca cccttcgcct tttggggaca gggcaccctg 1020
gtgacagtga gcgccggtgg cggaggatca ggaggaggcg gtagtggcgg cggaggttct 1080
ggtggaggag gtagccagat cgtgctgaca cagtcccctg ccatcatgtc tgccagccca 1140
ggcgagaagg tgaccatgac atgctctgcc agctccggcg tgaacttcat gcactggtac 1200
cagcagaagt ctggcacaag ccccaagcgg tggatcttcg acacctccaa gctggcctct 1260
ggcgtgcctg ccagattttc cggctctggc agcggcacat cctattctct gaccatctct 1320
agcatggagg ccgaggacgc cgccacctac tattgccagc agtggagctt caatccccct 1380
acatttggcg gcggcaccaa gctggagatc aag 1413
<210> 62
<211> 2946
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 孔 DANG-mu scIL-12的DNA序列
<400> 62
caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60
agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120
accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180
aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240
atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300
acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360
acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420
accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480
ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540
ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600
gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg cggccccaca 660
atcaagccat gccccccttg caagtgtcct gcaccaaatc tgctgggagg accatccgtg 720
ttcatctttc cacccaagat caaggacgtg ctgatgatca gcctgtcccc aatcgtgacc 780
tgcgtggtcg tggccgtgag cgaggacgat cctgatgtgc agatctcctg gttcgtgaac 840
aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900
agagtggtgt ctgccctgcc catccagcac caggactgga tgagcggcaa ggagtttaag 960
tgcaaggtga acaataagga tctgcccgcc cctatcgagc ggacaatctc taagcctaag 1020
ggcagcgtga gagccccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080
aagcaggtga cactgtcttg tgccgtgacc gacttcatgc ctgaggatat ctatgtggag 1140
tggaccaaca atggcaagac agagctgaac tacaagaata cagagccagt gctggactcc 1200
gatggctctt acttcatggt gagcaagctg agggtggaga agaagaactg ggtggagcgc 1260
aattcttaca gctgctccgt ggtgcacgag ggcctgcaca accaccacac cacaaagtct 1320
tttagccgga cccctggcgg tggaggtggc tcaggaggag gcggttctgg cggaggaggt 1380
agtatgtggg agctggagaa ggacgtgtac gtggtggagg tggattggac acctgacgcc 1440
cccggcgaga cagtgaacct gacatgcgat acccctgagg aggatgatat cacatggacc 1500
tccgatcaga gacacggcgt gatcggcagc ggcaagaccc tgacaatcac cgtgaaggag 1560
tttctggatg ccggccagta cacctgtcac aagggcggcg agacactgag ccactcccac 1620
ctgctgctgc acaagaagga gaatggcatc tggtccaccg agatcctgaa gaacttcaag 1680
aacaagacct tcctgaagtg tgaggcccct aattactccg gcaggtttac atgctcctgg 1740
ctggtgcaga gaaacatgga cctgaagttt aatatcaaga gctcctcctc cagccccgat 1800
agcagagccg tgacctgtgg catggccagc ctgagcgccg agaaggtgac cctggatcag 1860
agggattacg agaagtactc cgtgtcctgt caggaggatg tgacatgtcc tacagccgag 1920
gagacactgc ctatcgagct ggccctggag gccaggcagc agaataagta cgagaactac 1980
agcacaagct ttttcatcag ggacatcatc aagcccgatc cccccaagaa cctgcagatg 2040
aagcccctga agaacagcca ggtggaggtg tcctgggagt accctgatag ctggtccacc 2100
cctcactcct acttctccct gaagttcttt gtgagaatcc agagaaagaa ggagaagatg 2160
aaggagacag aggagggctg caatcagaag ggcgccttcc tggtggagaa gacatccacc 2220
gaggtgcagt gtaagggcgg caacgtgtgc gtgcaggccc aggacagata ctacaattcc 2280
agctgtagca agtgggcctg tgtgccttgt agagtgagat ccggcggcgg cggctccgga 2340
ggaggaggaa gcggaggagg cggctccaga gtgatccctg tgtccggccc tgccagatgt 2400
ctgtcccaga gcagaaacct gctgaagacc acagacgaca tggtgaagac agccagagag 2460
aagctgaagc actacagctg caccgccgag gacatcgacc acgaggatat cacaagagac 2520
cagacatcca ccctgaagac atgtctgcct ctggagctgc acaagaatga gtcctgcctg 2580
gccaccagag agacctccag caccaccagg ggcagctgcc tgccccctca gaagacctcc 2640
ctgatgatga cactgtgcct gggcagcatc tacgaggacc tgaagatgta ccagaccgag 2700
ttccaggcca tcaatgccgc cctgcagaac cacaaccacc agcagatcat cctggataag 2760
ggcatgctgg tggccatcga cgagctgatg cagagcctga accacaatgg cgagaccctg 2820
aggcagaagc ctcctgtggg cgaggccgat ccctacagag tgaagatgaa gctgtgtatc 2880
ctgctgcacg ccttttccac aagggtggtg accatcaaca gggtcatggg ctacctgtcc 2940
agcgcc 2946
<210> 63
<211> 2946
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc 孔 DANG-mu scIL-12 mut2的DNA序列
<400> 63
caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60
agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120
accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180
aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240
atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300
acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360
acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420
accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480
ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540
ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600
gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg cggccccaca 660
atcaagccat gccccccttg caagtgtcct gcaccaaatc tgctgggagg accatccgtg 720
ttcatctttc cacccaagat caaggacgtg ctgatgatca gcctgtcccc aatcgtgacc 780
tgcgtggtcg tggccgtgag cgaggacgat cctgatgtgc agatctcctg gttcgtgaac 840
aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900
agagtggtgt ctgccctgcc catccagcac caggactgga tgagcggcaa ggagtttaag 960
tgcaaggtga acaataagga tctgcccgcc cctatcgagc ggacaatctc taagcctaag 1020
ggcagcgtga gagccccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080
aagcaggtga cactgtcttg tgccgtgacc gacttcatgc ctgaggatat ctatgtggag 1140
tggaccaaca atggcaagac agagctgaac tacaagaata cagagccagt gctggactcc 1200
gatggctctt acttcatggt gagcaagctg agggtggaga agaagaactg ggtggagcgc 1260
aattcttaca gctgctccgt ggtgcacgag ggcctgcaca accaccacac cacaaagtct 1320
tttagccgga cccctggcgg tggaggtggc tcaggaggag gcggttctgg cggaggaggt 1380
agtatgtggg agctggagaa ggacgtgtac gtggtggagg tggattggac acctgacgcc 1440
cccggcgaga cagtgaacct gacatgcgat acccctgagg aggatgatat cacatggacc 1500
tccgatcaga gacacggcgt gatcggcagc ggcaagaccc tgacaatcac cgtgaaggag 1560
tttctggatg ccggccagta cacctgtcac aagggcggcg agacactgag ccactcccac 1620
ctgctgctgc acaagaagga gaatggcatc tggtccaccg agatcctgaa gaacttcaag 1680
aacaagacct tcctgaagtg tgaggcccct aattactccg gcaggtttac atgctcctgg 1740
ctggtgcaga gaaacatgga cctgaagttt aatatcaaga gctcctcctc cagccccgat 1800
agcagagccg tgacctgtgg catggccagc ctgagcgccg agaaggtgac cctggatcag 1860
agggattacg agaagtactc cgtgtcctgt caggaggatg tgacatgtcc tacagccgag 1920
gagacactgc ctatcgagct ggccctggag gccaggcagc agaataagta cgagaactac 1980
agcacaagct ttttcatcag ggacatcatc aagcccgatc cccccaagaa cctgcagatg 2040
aagcccctga agaacagcca ggtggaggtg tcctgggagt accctgatag ctggtccacc 2100
cctcactcct acttctccct gaagttcttt gtgagaatcc aggctgccgc cgagaagatg 2160
gccgagacag aggagggctg caatcagaag ggcgccttcc tggtggagaa gacatccacc 2220
gaggtgcagt gtaagggcgg caacgtgtgc gtgcaggccc aggacagata ctacaattcc 2280
agctgtagca agtgggcctg tgtgccttgt agagtgagat ccggcggcgg cggctccgga 2340
ggaggaggaa gcggaggagg cggctccaga gtgatccctg tgtccggccc tgccagatgt 2400
ctgtcccaga gcagaaacct gctgaagacc acagacgaca tggtgaagac agccagagag 2460
aagctgaagc actacagctg caccgccgag gacatcgacc acgaggatat cacaagagac 2520
cagacatcca ccctgaagac atgtctgcct ctggagctgc acaagaatga gtcctgcctg 2580
gccaccagag agacctccag caccaccagg ggcagctgcc tgccccctca gaagacctcc 2640
ctgatgatga cactgtgcct gggcagcatc tacgaggacc tgaagatgta ccagaccgag 2700
ttccaggcca tcaatgccgc cctgcagaac cacaaccacc agcagatcat cctggataag 2760
ggcatgctgg tggccatcga cgagctgatg cagagcctga accacaatgg cgagaccctg 2820
aggcagaagc ctcctgtggg cgaggccgat ccctacagag tgaagatgaa gctgtgtatc 2880
ctgctgcacg ccttttccac aagggtggtg accatcaaca gggtcatggg ctacctgtcc 2940
agcgcc 2946
<210> 64
<211> 699
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc 孔 DANG的DNA序列
<400> 64
gagccaaggg gccccaccat caagccatgc cccccttgca agtgtcctgc accaaacctg 60
ctgggaggac caagcgtgtt catctttcca cccaagatca aggacgtgct gatgatcagc 120
ctgtccccca tcgtgacatg cgtggtggtg gccgtgtccg aggacgatcc tgatgtgcag 180
atctcttggt tcgtgaacaa tgtggaggtg cacaccgccc agacccagac acaccgggag 240
gactatggct ctacactgag agtggtgagc gccctgccca tccagcacca ggactggatg 300
agcggcaagg agtttaagtg caaggtgaac aataaggatc tgcccgcccc tatcgagcgg 360
accatcagca agcctaaggg ctccgtgaga gccccacagg tgtacgtgct gcctccaccc 420
gaggaggaga tgaccaagaa gcaggtgaca ctgagctgtg ccgtgaccga cttcatgcct 480
gaggatatct acgtggagtg gaccaacaat ggcaagacag agctgaacta taagaataca 540
gagccagtgc tggactccga tggctcttac tttatggtgt ccaagctgag ggtggagaag 600
aagaactggg tggagcgcaa ttcttatagc tgctccgtgg tgcacgaggg cctgcacaat 660
caccacacca caaagtcttt cagcagaacc cctggcaag 699
<210> 65
<211> 699
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc 旋钮 DANG的DNA序列
<400> 65
gagccaaggg gccccaccat caagccatgc cccccttgca agtgtcctgc accaaacctg 60
ctgggaggac caagcgtgtt catctttcca cccaagatca aggacgtgct gatgatcagc 120
ctgtccccca tcgtgacatg cgtggtggtg gccgtgtccg aggacgatcc tgatgtgcag 180
atctcttggt tcgtgaacaa tgtggaggtg cacaccgccc agacccagac acaccgggag 240
gactacggct ctacactgag agtggtgagc gccctgccca tccagcacca ggactggatg 300
tccggcaagg agtttaagtg caaggtgaac aataaggatc tgcccgcccc tatcgagcgg 360
accatcagca agcctaaggg ctccgtgaga gccccacagg tgtatgtgct gcctccaccc 420
gaggaggaga tgaccaagaa gcaggtgaca ctgtggtgta tggtgaccga cttcatgcct 480
gaggatatct acgtggagtg gaccaacaat ggcaagacag agctgaacta taagaataca 540
gagccagtgc tggactccga tggctcttac tttatgtatt ctaagctgag ggtggagaag 600
aagaactggg tggagcgcaa ttcttacagc tgctccgtgg tgcacgaggg cctgcacaat 660
caccacacca caaagtcttt cagcagaacc cctggcaag 699
<210> 66
<211> 1344
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc DANG的DNA序列
<400> 66
caggtgcagc tgcagcagtc cggagcagag ctggcaaggc ctggagcctc tgtgaacctg 60
agctgcaagg cctccggcta caccttcaca aacaatggca tcaattggct gaagcagagg 120
accggacagg gactggagtg gatcggcgag atctacccaa gatctaccaa cacactgtat 180
aatgagaagt tcaagggcaa ggccaccctg acagcagacc ggagctccaa caccgcctac 240
atggagctga gaagcctgac atccgaggat tctgccgtgt atttttgtgc acgcaccctg 300
acagcaccct tcgccttttg gggacagggc accctggtga cagtgagcgc cgccaagacc 360
acagcaccaa gcgtgtatcc actggcaccc gtgtgcggcg ataccacagg ctctagcgtg 420
accctgggct gtctggtgaa gggctacttc cctgagccag tgaccctgac atggaacagc 480
ggctctctgt cctctggcgt gcacaccttt cctgccgtgc tgcagtccga tctgtataca 540
ctgagctcct ctgtgaccgt gacaagctcc acctggccca gccagtccat cacatgcaac 600
gtggcccacc ctgcctctag caccaaggtg gacaagaaga tcgagccacg gggccccaca 660
atcaagccat gtccaccttg caagtgtcca gcacctaatc tgctgggagg acctagcgtg 720
ttcatctttc cacccaagat caaggacgtg ctgatgatct ctctgagccc tatcgtgacc 780
tgcgtggtgg tggccgtgtc tgaggacgat ccagatgtgc agatcagctg gttcgtgaac 840
aatgtggagg tgcacaccgc ccagacccag acacaccggg aggactacgg ctccacactg 900
agagtggtgt ctgccctgcc catccagcac caggactgga tgtccggcaa ggagtttaag 960
tgcaaggtga acaataagga tctgccagcc cccatcgaga ggaccatctc taagcctaag 1020
ggcagcgtgc gcgcaccaca ggtgtatgtg ctgcctccac ccgaggagga gatgaccaag 1080
aagcaggtga cactgacgtg tatggtgacc gacttcatgc cagaggatat ctacgtggag 1140
tggaccaaca atggcaagac agagctgaac tataagaata cagagcccgt gctggacagc 1200
gatggctcct actttatgta tagcaagctg agggtggaga agaagaactg ggtggagcgc 1260
aattcctact cttgtagcgt ggtgcacgag ggcctgcaca accaccacac cacaaagtcc 1320
ttttctagaa cccccggcaa gtga 1344
<210> 67
<211> 2292
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2-mu IgG2a Fc DANG的DNA序列
<400> 67
atgtgggagc tggagaagga cgtgtacgtg gtggaggtgg attggacacc tgacgccccc 60
ggcgagacag tgaacctgac atgcgatacc cctgaggagg atgatatcac atggacctcc 120
gatcagagac acggcgtgat cggcagcggc aagaccctga caatcaccgt gaaggagttt 180
ctggatgccg gccagtacac ctgtcacaag ggcggcgaga cactgagcca ctcccacctg 240
ctgctgcaca agaaggagaa tggcatctgg tccaccgaga tcctgaagaa cttcaagaac 300
aagaccttcc tgaagtgtga ggcccctaat tactccggca ggtttacatg ctcctggctg 360
gtgcagagaa acatggacct gaagtttaat atcaagagct cctcctccag ccccgatagc 420
agagccgtga cctgtggcat ggccagcctg agcgccgaga aggtgaccct ggatcagagg 480
gattacgaga agtactccgt gtcctgtcag gaggatgtga catgtcctac agccgaggag 540
acactgccta tcgagctggc cctggaggcc aggcagcaga ataagtacga gaactacagc 600
acaagctttt tcatcaggga catcatcaag cccgatcccc ccaagaacct gcagatgaag 660
cccctgaaga acagccaggt ggaggtgtcc tgggagtacc ctgatagctg gtccacccct 720
cactcctact tctccctgaa gttctttgtg agaatccagg ctgccgccga gaagatggcc 780
gagacagagg agggctgcaa tcagaagggc gccttcctgg tggagaagac atccaccgag 840
gtgcagtgta agggcggcaa cgtgtgcgtg caggcccagg acagatacta caattccagc 900
tgtagcaagt gggcctgtgt gccttgtaga gtgagatccg gcggcggcgg ctccggagga 960
ggaggaagcg gaggaggcgg ctccagagtg atccctgtgt ccggccctgc cagatgtctg 1020
tcccagagca gaaacctgct gaagaccaca gacgacatgg tgaagacagc cagagagaag 1080
ctgaagcact acagctgcac cgccgaggac atcgaccacg aggatatcac aagagaccag 1140
acatccaccc tgaagacatg tctgcctctg gagctgcaca agaatgagtc ctgcctggcc 1200
accagagaga cctccagcac caccaggggc agctgcctgc cccctcagaa gacctccctg 1260
atgatgacac tgtgcctggg cagcatctac gaggacctga agatgtacca gaccgagttc 1320
caggccatca atgccgccct gcagaaccac aaccaccagc agatcatcct ggataagggc 1380
atgctggtgg ccatcgacga gctgatgcag agcctgaacc acaatggcga gaccctgagg 1440
cagaagcctc ctgtgggcga ggccgatccc tacagagtga agatgaagct gtgtatcctg 1500
ctgcacgcct tttccacaag ggtggtgacc atcaacaggg tcatgggcta cctgtccagc 1560
gccggcggcg gcggcagcgg aggaggaggc tccgagccac gcggccccac aatcaagcca 1620
tgcccccctt gcaagtgtcc tgcaccaaat ctgctgggag gaccatccgt gttcatcttt 1680
ccacccaaga tcaaggacgt gctgatgatc agcctgtccc caatcgtgac ctgcgtggtc 1740
gtggccgtga gcgaggacga tcctgatgtg cagatctcct ggttcgtgaa caatgtggag 1800
gtgcacaccg cccagaccca gacacaccgg gaggactacg gctccacact gagagtggtg 1860
tctgccctgc ccatccagca ccaggactgg atgagcggca aggagtttaa gtgcaaggtg 1920
aacaataagg atctgcccgc ccctatcgag cggacaatct ctaagcctaa gggcagcgtg 1980
agagccccac aggtgtatgt gctgcctcca cccgaggagg agatgaccaa gaagcaggtg 2040
acactgactt gtatggtgac cgacttcatg cctgaggata tctatgtgga gtggaccaac 2100
aatggcaaga cagagctgaa ctacaagaat acagagccag tgctggactc cgatggctct 2160
tacttcatgt acagcaagct gagggtggag aagaagaact gggtggagcg caattcttac 2220
agctgctccg tggtgcacga gggcctgcac aaccaccaca ccacaaagtc ttttagccgg 2280
acccctggca ag 2292
<210> 68
<211> 1353
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu CD20 HC mu IgG2a Fc 旋钮 DANG的DNA序列
<400> 68
caggtgcagc tgcagcagcc aggagcagag ctggtgaggc caggcacctc tgtgaagctg 60
agctgcaagg cctccggcta caccttcaca tcttattgga tgcactggat caagcagagg 120
ccaggacagg gactggagtg gatcggcgtg atcgacccct ccgataacta caccaagtac 180
aaccagaagt ttaagggcaa ggccaccctg acagtggaca ccagctcctc tacagcctac 240
atgcagctga gctccctgac atccgaggat tctgccgtgt atttctgtgc ccgggagggc 300
tactatggct ctagcccatg gtttgcctac tggggccagg gcaccctggt gacagtgtcc 360
tctgccaaga ccacagcccc cagcgtgtat cctctggccc cagtgtgcgg cgataccaca 420
ggcagctccg tgaccctggg ctgtctggtg aagggctact tccctgagcc agtgaccctg 480
acatggaact ctggcagcct gtctagcgga gtgcacacct ttccagccgt gctgcagtcc 540
gatctgtata cactgtcctc tagcgtgacc gtgacatcct ctacctggcc ctcccagtct 600
atcacatgca acgtggccca ccctgccagc tccaccaagg tggacaagaa gatcgagccc 660
cggggcccta caatcaagcc atgtccacct tgcaagtgtc cagcacctaa tctgctggga 720
ggacctagcg tgttcatctt tccacccaag atcaaggacg tgctgatgat cagcctgtcc 780
cctatcgtga cctgcgtggt ggtggccgtg agcgaggacg atccagatgt gcagatctcc 840
tggttcgtga acaatgtgga ggtgcacacc gcccagaccc agacacaccg ggaggactac 900
ggctccacac tgagagtggt gtctgccctg cctatccagc accaggactg gatgtccggc 960
aaggagttta agtgcaaggt gaacaataag gatctgccag cccccatcga gcggaccatc 1020
tctaagccta agggcagcgt gagagcccca caggtgtatg tgctgcctcc acccgaggag 1080
gagatgacca agaagcaggt gacactgtgg tgtatggtga ccgacttcat gcctgaggat 1140
atctacgtgg agtggaccaa caatggcaag acagagctga actataagaa tacagagcca 1200
gtgctggaca gcgatggctc ctactttatg tatagcaagc tgagggtgga gaagaagaac 1260
tgggtggagc gcaattctta cagctgttcc gtggtgcacg agggcctgca caatcaccac 1320
accacaaagt ctttcagcag aacccccggc aag 1353
<210> 69
<211> 639
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu CD20 LC的DNA序列
<400> 69
cagatcgtga tgagccagtc ccctgccatc ctgtccgcca gccctggcga gaaggtgaca 60
atgacctgca gggccagatc ctccgtgtcc tacatccact ggtaccagca gaagcccggc 120
agcagcccta agccctggat ctacgccacc agcaacctgg ccagcggcgt gcctggcaga 180
ttttccggct ccggcagcgg caccagctac agcctgacaa tcacaagggt ggaggccgag 240
gatgccgcca catactactg ccagcagtgg agctccaagc ctcccacctt cggcggcggc 300
accaagctgg agatcaagag gaccgacgcc gcccccaccg tgtccatctt tcccccttcc 360
tccgagcagc tgacctccgg cggcgcttcc gtggtgtgtt tcctgaataa tttctaccct 420
aaggatatca acgtgaagtg gaagatcgat ggcagcgaga ggcagaatgg cgtgctgaat 480
agctggaccg accaggacag caaggatagc acctacagca tgagctccac actgaccctg 540
acaaaggacg agtacgagag gcacaattcc tacacatgtg aggccacaca caagacctcc 600
acctccccta tcgtgaagtc cttcaacagg aacgagtgc 639
<210> 70
<211> 702
<212> DNA
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc DANG的DNA序列
<400> 70
gagcccagag gccccacaat caagccttgc cccccttgca aatgtcccgc ccccaatctg 60
ctgggaggcc cttccgtctt catcttcccc cccaagatca aggacgtgct gatgatctct 120
ctgagcccca tcgtgacatg cgtggtggtg gccgtgagcg aggacgatcc cgacgtgcag 180
atcagctggt tcgtcaacaa cgtggaggtg cataccgccc aaacacagac ccatagagag 240
gactacggct ccacactgag agtggtgtcc gctctgccca tccagcatca agactggatg 300
agcggcaagg agttcaagtg caaggtgaac aacaaggatc tgcccgcccc tatcgagagg 360
accatctcca agcccaaagg ctccgtgaga gctccccaag tgtatgtgct gcctcccccc 420
gaggaggaga tgaccaagaa gcaagtgaca ctgacatgca tggtgaccga tttcatgccc 480
gaagacatct acgtggagtg gaccaacaac ggcaagaccg agctcaacta caagaacacc 540
gagcccgtgc tcgacagcga cggcagctac ttcatgtaca gcaagctgag ggtcgagaag 600
aaaaactggg tggagaggaa cagctacagc tgtagcgtgg tgcacgaggg actgcacaac 660
caccatacca ccaagagctt ctccagaaca cccggcaagt ga 702
<210> 71
<211> 222
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC
<400> 71
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
210 215 220
<210> 72
<211> 257
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP scFv
<400> 72
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
145 150 155 160
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
165 170 175
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
180 185 190
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
195 200 205
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
210 215 220
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
225 230 235 240
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
245 250 255
Lys
<210> 73
<211> 518
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12
<400> 73
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser
515
<210> 74
<211> 306
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 p40
<400> 74
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser
305
<210> 75
<211> 197
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 p35
<400> 75
Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys Leu
1 5 10 15
His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln Lys
20 25 30
Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile Asp
35 40 45
His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu
50 55 60
Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr
65 70 75 80
Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser Phe
85 90 95
Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met Tyr
100 105 110
Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro Lys
115 120 125
Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu Leu
130 135 140
Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser Ser
145 150 155 160
Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile Leu
165 170 175
Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met Ser
180 185 190
Tyr Leu Asn Ala Ser
195
<210> 76
<211> 518
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut1
<400> 76
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Lys Arg Glu Ala Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser
515
<210> 77
<211> 306
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut1 p40
<400> 77
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Lys Arg Glu Ala Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser
305
<210> 78
<211> 518
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2
<400> 78
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser
515
<210> 79
<211> 306
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2 p40
<400> 79
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser
305
<210> 80
<211> 224
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu CD20 HC
<400> 80
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
<210> 81
<211> 361
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> (抗-hu FAP VH)2
<400> 81
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val
130 135 140
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
145 150 155 160
Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val
165 170 175
Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro
180 185 190
Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr
195 200 205
Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser
210 215 220
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile
225 230 235 240
Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly
245 250 255
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
260 265 270
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
275 280 285
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
290 295 300
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
305 310 315 320
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
325 330 335
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
340 345 350
Ser Asn Thr Lys Val Asp Lys Lys Val
355 360
<210> 82
<211> 209
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc DANG
<400> 82
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
1 5 10 15
Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp
20 25 30
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
35 40 45
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val
50 55 60
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
65 70 75 80
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
85 90 95
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
100 105 110
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
115 120 125
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
130 135 140
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
145 150 155 160
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
165 170 175
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
180 185 190
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
195 200 205
Lys
<210> 83
<211> 214
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC
<400> 83
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile
210
<210> 84
<211> 243
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP scFv
<400> 84
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser
130 135 140
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
145 150 155 160
Ser Ala Ser Ser Gly Val Asn Phe Met His Trp Tyr Gln Gln Lys Ser
165 170 175
Gly Thr Ser Pro Lys Arg Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser
180 185 190
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
195 200 205
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Trp Ser Phe Asn Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 85
<211> 521
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12
<400> 85
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala
515 520
<210> 86
<211> 313
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 p40
<400> 86
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser
305 310
<210> 87
<211> 193
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 p35
<400> 87
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
1 5 10 15
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
20 25 30
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
35 40 45
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
50 55 60
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
65 70 75 80
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
85 90 95
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
100 105 110
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
115 120 125
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
130 135 140
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
145 150 155 160
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
165 170 175
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
180 185 190
Ala
<210> 88
<211> 521
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut1
<400> 88
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Ala Lys
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala
515 520
<210> 89
<211> 313
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut1 p40
<400> 89
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Ala Lys
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser
305 310
<210> 90
<211> 521
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2
<400> 90
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala
515 520
<210> 91
<211> 313
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2 p40
<400> 91
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser
305 310
<210> 92
<211> 218
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu CD20 HC
<400> 92
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asp Pro Ser Asp Asn Tyr Thr Lys Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Glu Gly Tyr Tyr Gly Ser Ser Pro Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr
180 185 190
Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile
210 215
<210> 93
<211> 10
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 接头1
<400> 93
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 94
<211> 15
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 接头2
<400> 94
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 95
<211> 20
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 接头3
<400> 95
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 96
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HCDR1
<400> 96
Glu Tyr Thr Ile His
1 5
<210> 97
<211> 17
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HCDR2
<400> 97
Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 98
<211> 15
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HCDR3
<400> 98
Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr
1 5 10 15
<210> 99
<211> 17
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP LCDR1
<400> 99
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 100
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP LCDR2
<400> 100
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 101
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP LCDR3
<400> 101
Gln Gln Tyr Phe Ser Tyr Pro Leu Thr
1 5
<210> 102
<211> 124
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HCVR
<400> 102
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 103
<211> 113
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP LCVR
<400> 103
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 104
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HCDR1
<400> 104
Asn Asn Gly Ile Asn
1 5
<210> 105
<211> 17
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HCDR2
<400> 105
Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 106
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HCDR3
<400> 106
Thr Leu Thr Ala Pro Phe Ala Phe
1 5
<210> 107
<211> 10
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LCDR1
<400> 107
Ser Ala Ser Ser Gly Val Asn Phe Met His
1 5 10
<210> 108
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LCDR2
<400> 108
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 109
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LCDR3
<400> 109
Gln Gln Trp Ser Phe Asn Pro Pro Thr
1 5
<210> 110
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HCVR
<400> 110
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 111
<211> 107
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP LCVR
<400> 111
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Phe Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 112
<211> 23
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 铰链
<400> 112
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro
20
<210> 113
<211> 14
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 铰链-芯 1
<400> 113
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
1 5 10
<210> 114
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 铰链-芯 2
<400> 114
Asp Lys Thr His Thr Cys Pro Pro Cys
1 5
<210> 115
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 铰链-芯 3
<400> 115
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10
<210> 116
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 铰链-芯 4
<400> 116
Cys Pro Pro Cys Pro
1 5
<210> 117
<211> 4
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 铰链-芯 5
<400> 117
Cys Pro Pro Cys
1
<210> 118
<211> 28
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 铰链 接头
<400> 118
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
1 5 10 15
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
20 25
<210> 119
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a 铰链
<400> 119
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
<210> 120
<211> 26
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a 铰链 接头
<400> 120
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Arg Gly Pro Thr
1 5 10 15
Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
20 25
<210> 121
<211> 328
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IL-12 p40 wt_AAD56386
<400> 121
Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu
1 5 10 15
Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser
325
<210> 122
<211> 219
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IL-12 p35 wt_AAK84425
<400> 122
Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val Leu Leu
1 5 10 15
Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro Asp Pro
20 25 30
Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val
35 40 45
Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys
50 55 60
Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser
65 70 75 80
Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys
85 90 95
Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala
100 105 110
Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr
115 120 125
Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys
130 135 140
Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu
145 150 155 160
Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr
165 170 175
Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys
180 185 190
Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr
195 200 205
Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser
210 215
<210> 123
<211> 335
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IL-12 p40 wt_AAA39296
<400> 123
Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu
1 5 10 15
Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val
20 25 30
Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln
50 55 60
Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys
65 70 75 80
Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr
85 90 95
Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp
100 105 110
Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys
115 120 125
Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln
130 135 140
Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro
145 150 155 160
Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys
165 170 175
Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln
180 185 190
Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu
195 200 205
Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser
210 215 220
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
225 230 235 240
Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro
245 250 255
Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val
260 265 270
Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys
275 280 285
Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln
290 295 300
Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn
305 310 315 320
Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser
325 330 335
<210> 124
<211> 215
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IL-12 p35 wt_AAK39292
<400> 124
Met Cys Gln Ser Arg Tyr Leu Leu Phe Leu Ala Thr Leu Ala Leu Leu
1 5 10 15
Asn His Leu Ser Leu Ala Arg Val Ile Pro Val Ser Gly Pro Ala Arg
20 25 30
Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val
35 40 45
Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp
50 55 60
Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr
65 70 75 80
Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg
85 90 95
Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr
100 105 110
Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys
115 120 125
Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His
130 135 140
Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp
145 150 155 160
Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys
165 170 175
Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys
180 185 190
Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val
195 200 205
Met Gly Tyr Leu Ser Ser Ala
210 215
<210> 125
<211> 252
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IL-12 p40_X1
<400> 125
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys
245 250
<210> 126
<211> 42
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IL-12 p40_X2
<400> 126
Asp Arg Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys
1 5 10 15
Asn Ala Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser
20 25 30
Trp Ser Glu Trp Ala Ser Val Pro Cys Ser
35 40
<210> 127
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641 HCDR1
<400> 127
Glu Tyr Thr Ile His
1 5
<210> 128
<211> 17
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641 HCDR2
<400> 128
Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 129
<211> 15
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641 HCDR3
<400> 129
Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr
1 5 10 15
<210> 130
<211> 17
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641 LCDR1
<400> 130
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 131
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641 LCDR2
<400> 131
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 132
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641 LCDR3
<400> 132
Gln Gln Tyr Phe Ser Tyr Pro Leu Thr
1 5
<210> 133
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1 HCDR1
<400> 133
Ser His Ala Met Ser
1 5
<210> 134
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1 HCDR2
<400> 134
Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 135
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1 HCDR3
<400> 135
Gly Trp Leu Gly Asn Phe Asp Tyr
1 5
<210> 136
<211> 12
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1 LCDR1
<400> 136
Arg Ala Ser Gln Ser Val Ser Arg Ser Tyr Leu Ala
1 5 10
<210> 137
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1 LCDR2
<400> 137
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 138
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1 LCDR3
<400> 138
Gln Gln Gly Gln Val Ile Pro Pro Thr
1 5
<210> 139
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9 HCDR1
<400> 139
Ser Tyr Ala Met Ser
1 5
<210> 140
<211> 17
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9 HCDR2
<400> 140
Ala Ile Ile Gly Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 141
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9 HCDR3
<400> 141
Gly Trp Phe Gly Gly Phe Asn Tyr
1 5
<210> 142
<211> 12
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9 LCDR1
<400> 142
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu Ala
1 5 10
<210> 143
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9 LCDR2
<400> 143
Val Gly Ser Arg Arg Ala Thr
1 5
<210> 144
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9 LCDR3
<400> 144
Gln Gln Gly Ile Met Leu Pro Pro Thr
1 5
<210> 145
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705 HCDR1
<400> 145
Glu Asn Ile Ile His
1 5
<210> 146
<211> 17
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705 HCDR2
<400> 146
Trp Phe His Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asp
<210> 147
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705 HCDR3
<400> 147
His Gly Gly Thr Gly Arg Gly Ala Met Asp Tyr
1 5 10
<210> 148
<211> 15
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705 LCDR1
<400> 148
Arg Ala Ser Lys Ser Val Ser Thr Ser Ala Tyr Ser Tyr Met His
1 5 10 15
<210> 149
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705 LCDR2
<400> 149
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 150
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705 LCDR3
<400> 150
Gln His Ser Arg Glu Leu Pro Tyr Thr
1 5
<210> 151
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2 HCDR1
<400> 151
Ser Tyr Ala Met Ser
1 5
<210> 152
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2 HCDR2
<400> 152
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 153
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2 HCDR3
<400> 153
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 154
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2 LCDR1
<400> 154
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 155
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2 LCDR2
<400> 155
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 156
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2 LCDR3
<400> 156
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 157
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8 HCDR1
<400> 157
Ser Tyr Ala Met Ser
1 5
<210> 158
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8 HCDR2
<400> 158
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 159
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8 HCDR3
<400> 159
Tyr Cys Ala Lys Gly Trp Leu Gly
1 5
<210> 160
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8 LCDR1
<400> 160
Arg Ala Ser Gln Ser Val Ser Arg Ser Tyr Leu
1 5 10
<210> 161
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8 LCDR2
<400> 161
Ile Gly Ala Ser Thr Arg Ala
1 5
<210> 162
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8 LCDR3
<400> 162
Cys Gln Gln Gly Gln Val Ile Pro Pro
1 5
<210> 163
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9 HCDR1
<400> 163
Ser Tyr Ala Met Ser
1 5
<210> 164
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9 HCDR2
<400> 164
Ala Ile Gly Val Ser Thr Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 165
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9 HCDR3
<400> 165
Tyr Cys Ala Lys Gly Trp Leu Gly
1 5
<210> 166
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9 LCDR1
<400> 166
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu
1 5 10
<210> 167
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9 LCDR2
<400> 167
Tyr Gly Ala Ser Ser Arg Ala
1 5
<210> 168
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9 LCDR3
<400> 168
Cys Gln Gln Gly Gln Leu Ile Pro Pro
1 5
<210> 169
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3 HCDR1
<400> 169
Ser Tyr Ala Met Ser
1 5
<210> 170
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3 HCDR2
<400> 170
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 171
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3 HCDR3
<400> 171
Tyr Cys Ala Lys Gly Trp Leu Gly
1 5
<210> 172
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3 LCDR1
<400> 172
Arg Ala Ser Gln Ser Val Ser Ser Asn Tyr Leu
1 5 10
<210> 173
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3 LCDR2
<400> 173
Tyr Gly Ala Tyr Ile Arg Ala
1 5
<210> 174
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3 LCDR3
<400> 174
Cys Gln Gln Gly Gln Val Ile Pro Pro
1 5
<210> 175
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1 HCDR1
<400> 175
Ser Tyr Ala Met Ser
1 5
<210> 176
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1 HCDR2
<400> 176
Ala Ile Ile Ser Ser Gly Gly Leu Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 177
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1 HCDR3
<400> 177
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 178
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1 LCDR1
<400> 178
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 179
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1 LCDR2
<400> 179
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 180
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1 LCDR3
<400> 180
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 181
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8 HCDR1
<400> 181
Ser Tyr Ala Met Ser
1 5
<210> 182
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8 HCDR2
<400> 182
Ala Ile Ile Gly Ser Gly Ser Arg Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 183
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8 HCDR3
<400> 183
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 184
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8 LCDR1
<400> 184
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 185
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8 LCDR2
<400> 185
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 186
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8 LCDR3
<400> 186
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 187
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8 HCDR1
<400> 187
Ser Tyr Ala Met Ser
1 5
<210> 188
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8 HCDR2
<400> 188
Ala Ile Trp Gly Gly Gly Arg Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 189
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8 HCDR3
<400> 189
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 190
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8 LCDR1
<400> 190
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 191
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8 LCDR2
<400> 191
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 192
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8 LCDR3
<400> 192
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 193
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1 HCDR1
<400> 193
Ser Tyr Ala Met Ser
1 5
<210> 194
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1 HCDR2
<400> 194
Ala Ile Ile Ser Ser Gly Ala Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 195
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1 HCDR3
<400> 195
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 196
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1 LCDR1
<400> 196
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 197
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1 LCDR2
<400> 197
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 198
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1 LCDR3
<400> 198
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 199
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3 HCDR1
<400> 199
Ser Tyr Ala Met Ser
1 5
<210> 200
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3 HCDR2
<400> 200
Ala Ile Leu Ala Ser Gly Ala Ile Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 201
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3 HCDR3
<400> 201
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 202
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3 LCDR1
<400> 202
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 203
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3 LCDR2
<400> 203
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 204
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3 LCDR3
<400> 204
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 205
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1 HCDR1
<400> 205
Ser Tyr Ala Met Ser
1 5
<210> 206
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1 HCDR2
<400> 206
Gly Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 207
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1 HCDR3
<400> 207
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 208
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1 LCDR1
<400> 208
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 209
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1 LCDR2
<400> 209
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 210
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1 LCDR3
<400> 210
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 211
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8 HCDR1
<400> 211
Ser Tyr Ala Met Ser
1 5
<210> 212
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8 HCDR2
<400> 212
Ala Ile Leu Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 213
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8 HCDR3
<400> 213
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 214
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8 LCDR1
<400> 214
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 215
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8 LCDR2
<400> 215
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 216
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8 LCDR3
<400> 216
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 217
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9 HCDR1
<400> 217
Ser Phe Ala Met Ser
1 5
<210> 218
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9 HCDR2
<400> 218
Ala Ile Ile Gly Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 219
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9 HCDR3
<400> 219
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 220
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9 LCDR1
<400> 220
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 221
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9 LCDR2
<400> 221
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 222
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9 LCDR3
<400> 222
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 223
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3 HCDR1
<400> 223
Ser Tyr Ala Met Ser
1 5
<210> 224
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3 HCDR2
<400> 224
Ala Ile Ile Gly Ser Gly Ser Ile Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 225
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3 HCDR3
<400> 225
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 226
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3 LCDR1
<400> 226
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 227
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3 LCDR2
<400> 227
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 228
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3 LCDR3
<400> 228
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 229
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11 HCDR1
<400> 229
Ser Tyr Ala Met Ser
1 5
<210> 230
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11 HCDR2
<400> 230
Ala Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 231
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11 HCDR3
<400> 231
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 232
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11 LCDR1
<400> 232
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 233
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11 LCDR2
<400> 233
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 234
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11 LCDR3
<400> 234
Cys Gln Gln Gly Ile Met Leu Pro Pro
1 5
<210> 235
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7 HCDR1
<400> 235
Ser Tyr Ala Met Ser
1 5
<210> 236
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7 HCDR2
<400> 236
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 237
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7 HCDR3
<400> 237
Tyr Cys Ala Lys Gly Trp Phe Gly
1 5
<210> 238
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7 LCDR1
<400> 238
Arg Ala Ser Gln Ser Val Thr Ser Ser Tyr Leu
1 5 10
<210> 239
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7 LCDR2
<400> 239
Asn Val Gly Ser Arg Arg Ala
1 5
<210> 240
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7 LCDR3
<400> 240
Cys Gln Gln Ala Ile Met Leu Pro Pro
1 5
<210> 241
<211> 5
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10 HCDR1
<400> 241
Ser Ser Ala Met Ser
1 5
<210> 242
<211> 16
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10 HCDR2
<400> 242
Ala Ile Ser Thr Asn Gly Asn Tyr Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
<210> 243
<211> 8
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10 HCDR3
<400> 243
Tyr Cys Ala Lys Gly Trp Leu Gly
1 5
<210> 244
<211> 11
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10 LCDR1
<400> 244
Arg Ala Ser Gln Ser Val Ser Arg Ser Tyr Leu
1 5 10
<210> 245
<211> 7
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10 LCDR2
<400> 245
Ile Gly Ala Ser Thr Arg Ala
1 5
<210> 246
<211> 9
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10 LCDR3
<400> 246
Cys Gln Gln Gly Gln Val Ile Pro Pro
1 5
<210> 247
<211> 157
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> DARPin AMG-506/MP-0310
<400> 247
Asp Leu Gly Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln Asp Asp
1 5 10 15
Glu Val Arg Glu Leu Leu Lys Ala Gly Ala Asp Val Asn Ala Lys Asp
20 25 30
Val Leu Gly Trp Thr Pro Leu His Leu Ala Ala Phe Glu Gly His Leu
35 40 45
Glu Ile Val Glu Val Leu Leu Lys Ala Gly Ala Asp Val Asn Ala Lys
50 55 60
Asp Lys Lys Gly Trp Thr Pro Leu Gln Leu Ala Ala Arg Thr Gly His
65 70 75 80
Leu Glu Ile Val Glu Val Leu Leu Lys Ala Gly Ala Asp Val Asn Ala
85 90 95
Lys Asp His Ile Gly Ala Thr Pro Leu His Leu Ala Ala Trp Gln Gly
100 105 110
His Pro Glu Ile Val Glu Val Leu Leu Lys Ala Gly Ala Asp Val Asn
115 120 125
Ala Gln Asp Lys Ser Gly Lys Thr Pro Ala Asp Leu Ala Ala Asp Ala
130 135 140
Gly His Glu Asp Ile Ala Glu Val Leu Gln Lys Ala Ala
145 150 155
<210> 248
<211> 124
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641的VH
<400> 248
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 249
<211> 113
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> NG-641的VL
<400> 249
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 250
<211> 116
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1的VH
<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 His
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Trp Ala Ser Gly Glu Gln Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 251
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 28H1的VL
<400> 251
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 252
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9的VH
<400> 252
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ala Ser 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 253
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B9的VL
<400> 253
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 254
<211> 121
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705的VH
<400> 254
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Asn
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Phe His Pro Gly Ser Gly Ser Ile Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Thr Ala Asp Thr Ser Thr Ser Thr Val
65 70 75 80
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg His Gly Gly Thr Gly Arg Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 255
<211> 112
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> OMTX-705的VL
<400> 255
Asp Ile Gln Met Ile Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Lys Ser Val Ser Thr Ser
20 25 30
Ala Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Arg
85 90 95
Glu Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
<210> 256
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2的VH
<400> 256
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 257
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3F2的VL
<400> 257
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Tyr Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 258
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8的VH
<400> 258
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser 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 Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 259
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4G8的VL
<400> 259
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 260
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9的VH
<400> 260
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
Ala Met Ser Trp Val Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Gly Val Ser Thr Gly Ser 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 Cys
85 90 95
Ala Lys Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 261
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 3D9的VL
<400> 261
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Lys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Leu Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 262
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3的VH
<400> 262
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser 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 Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 263
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 4B3的VL
<400> 263
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Tyr Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 264
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1的VH
<400> 264
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Ser Ser Gly Gly Leu 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 265
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 19G1的VL
<400> 265
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Gly Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 266
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8的VH
<400> 266
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Lys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ser Arg 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 267
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 20G8的VL
<400> 267
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 268
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8的VH
<400> 268
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Trp Gly Gly Gly Arg Ser 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 269
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5B8的VL
<400> 269
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 270
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1的VH
<400> 270
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Ser Ser Gly Ala Ser 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 271
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 5F1的VL
<400> 271
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 272
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3的VH
<400> 272
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Ala Ser Gly Ala Ile 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 273
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 14B3的VL
<400> 273
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Gly Pro Gly Gly Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 274
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1的VH
<400> 274
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ile Gly Ser Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Asp Phe Thr Ile Ser Arg Asp Asn Ser Gly 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 Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 275
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F1的VL
<400> 275
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 276
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8的VH
<400> 276
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Leu Gly Ser Gly Gly Ser 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 277
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 16F8的VL
<400> 277
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 278
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9的VH
<400> 278
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 Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ser 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 279
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O3C9的VL
<400> 279
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 280
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3的VH
<400> 280
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Ser Ile 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 281
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 22A3的VL
<400> 281
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 282
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11的VH
<400> 282
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ile Gly Ser Gly Gly Ile 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 283
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 29B11的VL
<400> 283
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 284
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7的VH
<400> 284
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
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser 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 Cys
85 90 95
Ala Lys Gly Trp Phe Gly Gly Phe Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 285
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> O2D7的VL
<400> 285
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Asn Val Gly Ser Arg Arg Ala Thr Gly Thr Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ala Ile Met Leu Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 286
<211> 117
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10的VH
<400> 286
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 Ser
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Thr Asn Gly Asn Tyr 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 Cys
85 90 95
Ala Lys Gly Trp Leu Gly Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 287
<211> 108
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 23C10的VL
<400> 287
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Ile Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Gln Val Ile Pro
85 90 95
Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 288
<211> 227
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc 旋钮
<400> 288
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 289
<211> 227
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc 孔
<400> 289
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 290
<211> 233
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc 旋钮
<400> 290
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
20 25 30
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
35 40 45
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
50 55 60
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
65 70 75 80
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
85 90 95
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
100 105 110
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
115 120 125
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
130 135 140
Thr Lys Lys Gln Val Thr Leu Trp Cys Met Val Thr Asp Phe Met Pro
145 150 155 160
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
165 170 175
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
180 185 190
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
195 200 205
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
210 215 220
Lys Ser Phe Ser Arg Thr Pro Gly Lys
225 230
<210> 291
<211> 233
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc 孔
<400> 291
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
20 25 30
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
35 40 45
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
50 55 60
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
65 70 75 80
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
85 90 95
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
100 105 110
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
115 120 125
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
130 135 140
Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp Phe Met Pro
145 150 155 160
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
165 170 175
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
180 185 190
Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
195 200 205
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
210 215 220
Lys Ser Phe Ser Arg Thr Pro Gly Lys
225 230
<210> 292
<211> 1026
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12-hu IgG1 Fc 孔 DANG-抗-hu FAP scFv
<400> 292
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
755 760 765
Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
770 775 780
Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu
785 790 795 800
Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp
805 810 815
Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys
820 825 830
Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala
835 840 845
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
850 855 860
Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met
865 870 875 880
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
885 890 895
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
900 905 910
Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu
915 920 925
Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr
930 935 940
Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
945 950 955 960
Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly
965 970 975
Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu
980 985 990
Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln
995 1000 1005
Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
1010 1015 1020
Glu Ile Lys
1025
<210> 293
<211> 1026
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2-hu IgG1 Fc 孔 DANG-抗-hu FAP scFv
<400> 293
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
755 760 765
Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
770 775 780
Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu
785 790 795 800
Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp
805 810 815
Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys
820 825 830
Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala
835 840 845
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
850 855 860
Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met
865 870 875 880
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
885 890 895
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
900 905 910
Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu
915 920 925
Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr
930 935 940
Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
945 950 955 960
Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly
965 970 975
Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu
980 985 990
Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln
995 1000 1005
Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
1010 1015 1020
Glu Ile Lys
1025
<210> 294
<211> 986
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc DANG-hu scIL-12
<400> 294
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
450 455 460
Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu
465 470 475 480
Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys
485 490 495
Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser
500 505 510
Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe
515 520 525
Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser
530 535 540
His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr
545 550 555 560
Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg
565 570 575
Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr
580 585 590
Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser
595 600 605
Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu
610 615 620
Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln
625 630 635 640
Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val
645 650 655
Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser
660 665 670
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
675 680 685
Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr
690 695 700
Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys
705 710 715 720
Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe
725 730 735
Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile
740 745 750
Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp
755 760 765
Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly
785 790 795 800
Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser
805 810 815
Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr
820 825 830
Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr
835 840 845
Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu
850 855 860
Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser
865 870 875 880
Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu
885 890 895
Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu
900 905 910
Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala
915 920 925
Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val
930 935 940
Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile
945 950 955 960
Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile
965 970 975
Asp Arg Val Met Ser Tyr Leu Asn Ala Ser
980 985
<210> 295
<211> 986
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-hu FAP HC hu IgG1 Fc DANG-hu scIL-12 mut2
<400> 295
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
450 455 460
Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu
465 470 475 480
Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys
485 490 495
Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser
500 505 510
Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe
515 520 525
Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser
530 535 540
His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr
545 550 555 560
Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg
565 570 575
Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr
580 585 590
Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser
595 600 605
Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu
610 615 620
Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln
625 630 635 640
Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val
645 650 655
Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser
660 665 670
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
675 680 685
Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr
690 695 700
Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys
705 710 715 720
Val Gln Val Gln Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe
725 730 735
Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile
740 745 750
Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp
755 760 765
Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly
785 790 795 800
Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser
805 810 815
Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr
820 825 830
Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr
835 840 845
Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu
850 855 860
Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser
865 870 875 880
Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu
885 890 895
Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu
900 905 910
Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala
915 920 925
Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val
930 935 940
Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile
945 950 955 960
Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile
965 970 975
Asp Arg Val Met Ser Tyr Leu Asn Ala Ser
980 985
<210> 296
<211> 1026
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12-hu IgG1 Fc DANG-抗-hu FAP scFv
<400> 296
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
755 760 765
Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
770 775 780
Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu
785 790 795 800
Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp
805 810 815
Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys
820 825 830
Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala
835 840 845
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
850 855 860
Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met
865 870 875 880
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
885 890 895
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
900 905 910
Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu
915 920 925
Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr
930 935 940
Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
945 950 955 960
Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly
965 970 975
Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu
980 985 990
Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln
995 1000 1005
Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
1010 1015 1020
Glu Ile Lys
1025
<210> 297
<211> 1026
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu scIL-12 mut2-hu IgG1 Fc DANG-抗-hu FAP scFv
<400> 297
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Ala Ser Ala Arg Glu Ala Ala Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
660 665 670
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
755 760 765
Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
770 775 780
Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu
785 790 795 800
Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp
805 810 815
Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys
820 825 830
Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala
835 840 845
Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
850 855 860
Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met
865 870 875 880
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
885 890 895
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
900 905 910
Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu
915 920 925
Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr
930 935 940
Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
945 950 955 960
Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly
965 970 975
Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu
980 985 990
Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln
995 1000 1005
Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
1010 1015 1020
Glu Ile Lys
1025
<210> 298
<211> 1021
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12-mu IgG2a Fc 孔 DANG-抗-mu FAP scFv
<400> 298
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser
755 760 765
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln
770 775 780
Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys
785 790 795 800
Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys
805 810 815
Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg
820 825 830
Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu
835 840 845
Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu
850 855 860
Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala
865 870 875 880
Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly
885 890 895
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
900 905 910
Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala
915 920 925
Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val
930 935 940
Asn Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg
945 950 955 960
Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe
965 970 975
Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met
980 985 990
Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn
995 1000 1005
Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1010 1015 1020
<210> 299
<211> 1021
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2-mu IgG2a Fc 孔 DANG-抗-mu FAP scFv
<400> 299
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Ser Cys Ala Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Val Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser
755 760 765
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln
770 775 780
Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys
785 790 795 800
Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys
805 810 815
Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg
820 825 830
Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu
835 840 845
Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu
850 855 860
Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala
865 870 875 880
Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly
885 890 895
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
900 905 910
Gly Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala
915 920 925
Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val
930 935 940
Asn Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg
945 950 955 960
Trp Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe
965 970 975
Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met
980 985 990
Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn
995 1000 1005
Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1010 1015 1020
<210> 300
<211> 982
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc DANG-mu scIL-12
<400> 300
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys
210 215 220
Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
245 250 255
Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp
260 265 270
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser
290 295 300
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320
Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile
325 330 335
Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro
340 345 350
Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met
355 360 365
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn
370 375 380
Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn
405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu
420 425 430
His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu
450 455 460
Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala
465 470 475 480
Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp
485 490 495
Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys
500 505 510
Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr
515 520 525
Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His
530 535 540
Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys
545 550 555 560
Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe
565 570 575
Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile
580 585 590
Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met
595 600 605
Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu
610 615 620
Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu
625 630 635 640
Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys
645 650 655
Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro
660 665 670
Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val
675 680 685
Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr
690 695 700
Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met
705 710 715 720
Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu
725 730 735
Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln
740 745 750
Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val
755 760 765
Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys
785 790 795 800
Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys
805 810 815
Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile
820 825 830
Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys
835 840 845
Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu
850 855 860
Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser
865 870 875 880
Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met
885 890 895
Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn
900 905 910
His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu
915 920 925
Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro
930 935 940
Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile
945 950 955 960
Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met
965 970 975
Gly Tyr Leu Ser Ser Ala
980
<210> 301
<211> 982
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> 抗-mu FAP HC mu IgG2a Fc DANG-mu scIL-12 mut2
<400> 301
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp
180 185 190
Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
195 200 205
Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys
210 215 220
Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
245 250 255
Pro Ile Val Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp
260 265 270
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Thr His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser
290 295 300
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
305 310 315 320
Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile
325 330 335
Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro
340 345 350
Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met
355 360 365
Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn
370 375 380
Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn
405 410 415
Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu
420 425 430
His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Trp Glu
450 455 460
Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala
465 470 475 480
Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp
485 490 495
Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys
500 505 510
Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr
515 520 525
Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His
530 535 540
Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys
545 550 555 560
Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe
565 570 575
Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile
580 585 590
Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met
595 600 605
Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu
610 615 620
Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu
625 630 635 640
Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys
645 650 655
Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro
660 665 670
Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val
675 680 685
Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr
690 695 700
Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala Glu Lys Met
705 710 715 720
Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu
725 730 735
Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln
740 745 750
Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val
755 760 765
Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
770 775 780
Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys
785 790 795 800
Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys
805 810 815
Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile
820 825 830
Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys
835 840 845
Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu
850 855 860
Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser
865 870 875 880
Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met
885 890 895
Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn
900 905 910
His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu
915 920 925
Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro
930 935 940
Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile
945 950 955 960
Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met
965 970 975
Gly Tyr Leu Ser Ser Ala
980
<210> 302
<211> 1020
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12-mu IgG2a Fc DANG-抗-mu FAP scFv
<400> 302
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Arg Lys Lys
245 250 255
Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Ser Gly
755 760 765
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser
770 775 780
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys
785 790 795 800
Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln
805 810 815
Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser
820 825 830
Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
835 840 845
Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr
850 855 860
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro
865 870 875 880
Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly
885 890 895
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
900 905 910
Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser
915 920 925
Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn
930 935 940
Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp
945 950 955 960
Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
965 970 975
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
980 985 990
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro
995 1000 1005
Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1010 1015 1020
<210> 303
<211> 1020
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu scIL-12 mut2-mu IgG2a Fc DANG-抗-mu FAP scFv
<400> 303
Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu Val Asp Trp Thr
1 5 10 15
Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His Gly Val Ile Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe Leu Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser His Ser His Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr Glu Ile Leu Lys
85 90 95
Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala Pro Asn Tyr Ser
100 105 110
Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn Met Asp Leu Lys
115 120 125
Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser Arg Ala Val Thr
130 135 140
Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr Leu Asp Gln Arg
145 150 155 160
Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp Val Thr Cys Pro
165 170 175
Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu Glu Ala Arg Gln
180 185 190
Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe Ile Arg Asp Ile
195 200 205
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys Pro Leu Lys Asn
210 215 220
Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser Trp Ser Thr Pro
225 230 235 240
His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile Gln Ala Ala Ala
245 250 255
Glu Lys Met Ala Glu Thr Glu Glu Gly Cys Asn Gln Lys Gly Ala Phe
260 265 270
Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys Gly Gly Asn Val
275 280 285
Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser Cys Ser Lys Trp
290 295 300
Ala Cys Val Pro Cys Arg Val Arg Ser Gly Gly Gly Gly Ser Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
325 330 335
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
340 345 350
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
355 360 365
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
370 375 380
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
385 390 395 400
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
405 410 415
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
420 425 430
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
435 440 445
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
450 455 460
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
465 470 475 480
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
485 490 495
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
500 505 510
Arg Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly
515 520 525
Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
530 535 540
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
545 550 555 560
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
565 570 575
Thr Cys Val Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile
580 585 590
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
595 600 605
His Arg Glu Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro
610 615 620
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
625 630 635 640
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
645 650 655
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
660 665 670
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp
675 680 685
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
690 695 700
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
705 710 715 720
Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
725 730 735
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
740 745 750
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Ser Gly
755 760 765
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser
770 775 780
Gly Ala Glu Leu Ala Arg Pro Gly Ala Ser Val Asn Leu Ser Cys Lys
785 790 795 800
Ala Ser Gly Tyr Thr Phe Thr Asn Asn Gly Ile Asn Trp Leu Lys Gln
805 810 815
Arg Thr Gly Gln Gly Leu Glu Trp Ile Gly Glu Ile Tyr Pro Arg Ser
820 825 830
Thr Asn Thr Leu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr
835 840 845
Ala Asp Arg Ser Ser Asn Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr
850 855 860
Ser Glu Asp Ser Ala Val Tyr Phe Cys Ala Arg Thr Leu Thr Ala Pro
865 870 875 880
Phe Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly
885 890 895
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
900 905 910
Gly Ser Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser
915 920 925
Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn
930 935 940
Phe Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp
945 950 955 960
Ile Phe Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
965 970 975
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
980 985 990
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro
995 1000 1005
Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1010 1015 1020
<210> 304
<211> 227
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> hu IgG1 Fc
<400> 304
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 305
<211> 233
<212> PRT
<213> Artificial Sequence（人工序列）
<220>
<223> mu IgG2a Fc
<400> 305
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
20 25 30
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
35 40 45
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
50 55 60
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
65 70 75 80
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
85 90 95
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
100 105 110
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
115 120 125
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
130 135 140
Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro
145 150 155 160
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
165 170 175
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
180 185 190
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
195 200 205
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
210 215 220
Lys Ser Phe Ser Arg Thr Pro Gly Lys
225 230
Claims (34)
1.一种融合蛋白，其包括：
包含IL-12或其变体的第一单体；和
包含特异性结合FAP(成纤维细胞活化蛋白α)的抗原结合位点的第二单体。
2.根据权利要求1所述的融合蛋白，其特征在于，IL-12或其变体包含IL-12A(p35)或其变体；和IL-12B(p40)或其变体。
3.根据权利要求2所述的融合蛋白，其特征在于，所述IL-12或其变体包含以下结构式(I)或(II)：
N'-Y-[接头(1)]o-Z-C'(I)
N'-Z-[接头(1)]o-Y-C'(II)
在结构式(I)和(II)中，
N'为融合蛋白的N末端，
C'为融合蛋白的C末端，
Y为IL-12A或其变体，
Z为IL-12B或其变体，
所述接头(1)为肽接头，并且
o为0或1。
4.根据权利要求2所述的融合蛋白，其特征在于，所述IL-12B(p40)的变体包含在如SEQID NO:74所示的氨基酸序列中通过取代选自由K258A、K260A、K263A和K264A组成的组中的至少一个而获得的氨基酸序列。
5.根据权利要求2所述的融合蛋白，其特征在于，所述IL-12B(p40)包含如SEQ ID NO:74或SEQ ID NO:86所示的氨基酸序列。
6.根据权利要求4所述的融合蛋白，其特征在于，所述IL-12B(p40)的变体包含如SEQID NO:77、SEQ ID NO:79、SEQ ID NO:89或SEQ ID NO:91所示的氨基酸序列。
7.根据权利要求2所述的融合蛋白，其特征在于，所述IL-12A(p35)包含如SEQ ID NO:75或SEQ ID NO:87所示的氨基酸序列。
8.根据权利要求1所述的融合蛋白，其特征在于，所述IL-12包含如SEQ ID NO:73、SEQID NO:76、SEQ ID NO:78、SEQ ID NO:85、SEQ ID NO:88或SEQ ID NO:90所示的氨基酸序列。
9.根据权利要求1所述的融合蛋白，其特征在于，所述特异性结合FAP的抗原结合位点包括：
包含如SEQ ID NO:96所示的HCDR1，如SEQ ID NO:97所示的HCDR2和如SEQ ID NO:98所示的HCDR3的重链可变区，以及包含如SEQ ID NO:99所示的LCDR1，如SEQ ID NO:100所示的LCDR2和如SEQ ID NO:101所示的LCDR3的轻链可变区；
包含如SEQ ID NO:104所示的HCDR1，如SEQ ID NO:105所示的HCDR2和如SEQ ID NO:106所示的HCDR3的重链可变区，以及包含如SEQ ID NO:107所示的LCDR1，如SEQ ID NO:108所示的LCDR2和如SEQ ID NO:109所示的LCDR3的轻链可变区；
包含如SEQ ID NO:127所示的HCDR1，如SEQ ID NO:128所示的HCDR2和如SEQ ID NO:129所示的HCDR3的重链可变区，以及包含如SEQ ID NO:130所示的LCDR1，如SEQ ID NO:131所示的LCDR2和如SEQ ID NO:132所示的LCDR3的轻链可变区；
包含如SEQ ID NO:133所示的HCDR1，如SEQ ID NO:134所示的HCDR2和如SEQ ID NO:135所示的HCDR3的重链可变区，以及包含如SEQ ID NO:136所示的LCDR1，如SEQ ID NO:137所示的LCDR2和如SEQ ID NO:138所示的LCDR3的轻链可变区；
包含如SEQ ID NO:139所示的HCDR1，如SEQ ID NO:140所示的HCDR2和如SEQ ID NO:141所示的HCDR3的重链可变区，以及包含如SEQ ID NO:142所示的LCDR1，如SEQ ID NO:143所示的LCDR2和如SEQ ID NO:144所示的LCDR3的轻链可变区；
包含如SEQ ID NO:145所示的HCDR1，如SEQ ID NO:146所示的HCDR2和如SEQ ID NO:147所示的HCDR3的重链可变区，以及包含如SEQ ID NO:148所示的LCDR1，如SEQ ID NO:149所示的LCDR2和如SEQ ID NO:150所示的LCDR3的轻链可变区；
包含如SEQ ID NO:151所示的HCDR1，如SEQ ID NO:152所示的HCDR2和如SEQ ID NO:153所示的HCDR3的重链可变区，以及包含如SEQ ID NO:154所示的LCDR1，如SEQ ID NO:155所示的LCDR2和如SEQ ID NO:156所示的LCDR3的轻链可变区；
一个包含如SEQ ID NO:157所示的HCDR1，如SEQ ID NO:158所示的HCDR2和如SEQ IDNO:159所示的HCDR3的重链可变区，以及包含如SEQ ID NO:160所示的LCDR1，如SEQ ID NO:161所示的LCDR2和如SEQ ID NO:162所示的LCDR3的轻链可变区；
包含如SEQ ID NO:163所示的HCDR1，如SEQ ID NO:164所示的HCDR2和如SEQ ID NO:165所示的HCDR3的重链可变区，以及包含如SEQ ID NO:166所示的LCDR1，如SEQ ID NO:167所示的LCDR2和如SEQ ID NO:168所示的LCDR3的轻链可变区；
包含如SEQ ID NO:169所示的HCDR1，如SEQ ID NO:170所示的HCDR2和如SEQ ID NO:171所示的HCDR3的重链可变区，以及包含如SEQ ID NO:172所示的LCDR1，如SEQ ID NO:173所示的LCDR2和如SEQ ID NO:174所示的LCDR3的轻链可变区；
包含如SEQ ID NO:175所示的HCDR1，如SEQ ID NO:176所示的HCDR2和如SEQ ID NO:177所示的HCDR3的重链可变区，以及包含如SEQ ID NO:178所示的LCDR1，如SEQ ID NO:179所示的LCDR2和如SEQ ID NO:180所示的LCDR3的轻链可变区；
包含如SEQ ID NO:181所示的HCDR1，如SEQ ID NO:182所示的HCDR2和如SEQ ID NO:183所示的HCDR3的重链可变区，以及包含如SEQ ID NO:184所示的LCDR1，如SEQ ID NO:185所示的LCDR2和如SEQ ID NO:186所示的LCDR3的轻链可变区；
包含如SEQ ID NO:187所示的HCDR1，如SEQ ID NO:188所示的HCDR2和如SEQ ID NO:189所示的HCDR3的重链可变区，以及包含如SEQ ID NO:190所示的LCDR1，如SEQ ID NO:191所示的LCDR2和如SEQ ID NO:192所示的LCDR3的轻链可变区；
包含如SEQ ID NO:193所示的HCDR1，如SEQ ID NO:194所示的HCDR2和如SEQ ID NO:195所示的HCDR3的重链可变区，以及包含如SEQ ID NO:196所示的LCDR1，如SEQ ID NO:197所示的LCDR2和如SEQ ID NO:198所示的LCDR3的轻链可变区；
包含如SEQ ID NO:199所示的HCDR1，如SEQ ID NO:200所示的HCDR2和如SEQ ID NO:201所示的HCDR3的重链可变区，以及包含如SEQ ID NO:202所示的LCDR1，如SEQ ID NO:203所示的LCDR2和如SEQ ID NO:204所示的LCDR3的轻链可变区；
包含如SEQ ID NO:205所示的HCDR1，如SEQ ID NO:206所示的HCDR2和如SEQ ID NO:207所示的HCDR3的重链可变区，以及包含如SEQ ID NO:208所示的LCDR1，如SEQ ID NO:209所示的LCDR2和如SEQ ID NO:210所示的LCDR3的轻链可变区；
包含如SEQ ID NO:211所示的HCDR1，如SEQ ID NO:212所示的HCDR2和如SEQ ID NO:213所示的HCDR3的重链可变区，以及包含如SEQ ID NO:214所示的LCDR1，如SEQ ID NO:215所示的LCDR2和如SEQ ID NO:216所示的LCDR3的轻链可变区；
包含如SEQ ID NO:217所示的HCDR1，如SEQ ID NO:218所示的HCDR2和如SEQ ID NO:219所示的HCDR3的重链可变区，以及包含如SEQ ID NO:220所示的LCDR1，如SEQ ID NO:221所示的LCDR2和如SEQ ID NO:222所示的LCDR3的轻链可变区；
包含如SEQ ID NO:223所示的HCDR1，如SEQ ID NO:224所示的HCDR2和如SEQ ID NO:225所示的HCDR3的重链可变区，以及包含如SEQ ID NO:226所示的LCDR1，如SEQ ID NO:227所示的LCDR2和如SEQ ID NO:228所示的LCDR3的轻链可变区；
包含如SEQ ID NO:229所示的HCDR1，如SEQ ID NO:230所示的HCDR2和如SEQ ID NO:231所示的HCDR3的重链可变区，以及包含如SEQ ID NO:232所示的LCDR1，如SEQ ID NO:233所示的LCDR2和如SEQ ID NO:234所示的LCDR3的轻链可变区；
包含如SEQ ID NO:235所示的HCDR1，如SEQ ID NO:236所示的HCDR2和如SEQ ID NO:237所示的HCDR3的重链可变区，以及包含如SEQ ID NO:238所示的LCDR1，如SEQ ID NO:239所示的LCDR2和如SEQ ID NO:240所示的LCDR3的轻链可变区；或
包含如SEQ ID NO:241所示的HCDR1，如SEQ ID NO:242所示的HCDR2和如SEQ ID NO:243所示的HCDR3的重链可变区，以及包含如SEQ ID NO:244所示的LCDR1，如SEQ ID NO:245所示的LCDR2和如SEQ ID NO:246所示的LCDR3的轻链可变区。
10.根据权利要求1所述的融合蛋白，其特征在于，所述特异性结合FAP的抗原结合位点包含：
如SEQ ID NO:102所示的重链可变区和如SEQ ID NO:103所示的轻链可变区；
如SEQ ID NO:110所示的重链可变区和如SEQ ID NO:111所示的轻链可变区；
如SEQ ID NO:248所示的重链可变区和如SEQ ID NO:249所示的轻链可变区；
如SEQ ID NO:250所示的重链可变区和如SEQ ID NO:251所示的轻链可变区；
如SEQ ID NO:252所示的重链可变区和如SEQ ID NO:253所示的轻链可变区；
如SEQ ID NO:254所示的重链可变区和如SEQ ID NO:255所示的轻链可变区；
如SEQ ID NO:256所示的重链可变区和如SEQ ID NO:257所示的轻链可变区；
如SEQ ID NO:258所示的重链可变区和如SEQ ID NO:259所示的轻链可变区；
如SEQ ID NO:260所示的重链可变区和如SEQ ID NO:261所示的轻链可变区；
如SEQ ID NO:262所示的重链可变区和如SEQ ID NO:263所示的轻链可变区；
如SEQ ID NO:264所示的重链可变区和如SEQ ID NO:265所示的轻链可变区；
如SEQ ID NO:266所示的重链可变区和如SEQ ID NO:267所示的轻链可变区；
如SEQ ID NO:268所示的重链可变区和如SEQ ID NO:269所示的轻链可变区；
如SEQ ID NO:270所示的重链可变区和如SEQ ID NO:271所示的轻链可变区；
如SEQ ID NO:272所示的重链可变区和如SEQ ID NO:273所示的轻链可变区；
如SEQ ID NO:274所示的重链可变区和如SEQ ID NO:275所示的轻链可变区；
如SEQ ID NO:276所示的重链可变区和如SEQ ID NO:277所示的轻链可变区；
如SEQ ID NO:278所示的重链可变区和如SEQ ID NO:279所示的轻链可变区；
如SEQ ID NO:280所示的重链可变区和如SEQ ID NO:281所示的轻链可变区；
如SEQ ID NO:282所示的重链可变区和如SEQ ID NO:283所示的轻链可变区；
如SEQ ID NO:284所示的重链可变区和如SEQ ID NO:285所示的轻链可变区；
如SEQ ID NO:286所示的重链可变区和如SEQ ID NO:287所示的轻链可变区；
如SEQ ID NO:72所示的scFv；或
如SEQ ID NO:84所示的scFv。
11.根据权利要求1所述的融合蛋白，其特征在于，所述第一单体进一步包含特异性结合FAP的抗原结合位点。
12.根据权利要求3所述的融合蛋白，其特征在于，所述第一单体包含以下结构式(III)或(IV)：
N'-X-[接头(2)]p-Fc区片段或其变体-[接头(3)]q-(T)r-C'(III)
N'-(T)r-[接头(2)]q-Fc区片段或其变体-[接头(3)]p-X-C'(IV)
在结构式(III)和(IV)中，
N'为融合蛋白的N末端，
C'为融合蛋白的C末端，
X为结构式(I)或(II)，
T为特异性结合FAP的抗原结合位点，
接头(2)和(3)为肽接头，并且
p、q和r各自独立地为0或1。
13.根据权利要求3或12所述的融合蛋白，其特征在于，所述接头包含(G4S)n接头，其中n为1至10的整数中的任意一个。
14.根据权利要求12所述的融合蛋白，其特征在于，所述第一单体的Fc区来源于人IgG1或小鼠IgG2a。
15.根据权利要求12所述的融合蛋白，其特征在于，所述第一单体的Fc包含旋钮结构或孔结构。
16.根据权利要求1所述的融合蛋白，其特征在于，所述第二单体进一步包含特异性结合FAP的抗原结合位点。
17.根据权利要求16所述的融合蛋白，其特征在于，所述特异性结合FAP的抗原结合位点为Fab、scFv、Fv或其片段。
18.根据权利要求16所述的融合蛋白，其特征在于，所述特异性结合FAP的额外结合的抗原结合位点与所述第二单体的N末端或C末端结合。
19.根据权利要求3所述的融合蛋白，其特征在于，所述第二单体包含以下结构式(V)：
N'-(R)s-[接头(4)]t-Q-[接头(5)]u-Fc区片段或其变体-[接头(6)]v-(W)a-C'(V)在结构式(V)中，
N'为融合蛋白的N末端，
C'为融合蛋白的C末端，
R为特异性结合FAP的抗原结合位点，
Q为特异性结合FAP的抗原结合位点，
W为特异性结合FAP的scFv；或结构式(I)或(II)的IL-12或其变体，
接头(4)和(6)为肽接头，并且
s、t、u和v各自独立地为0或1。
20.根据权利要求19所述的融合蛋白，其特征在于，所述结构式(V)包含以下结构式(V')和(V”)：
N'-(R')s-[接头(4)]t-Q'-[接头(5)]u-Fc区片段或其变体-[接头(6)]p-(W)a-C'(V')
N'-(R”)s-[接头(4)]t-Q”-[接头(7)]x-(W)b-C'(V”)
在结构式(V')和(V”)中，
R'为特异性结合FAP的抗体的重链区，其包含可变区和CH1区，或抗体的轻链区；
R”为特异性结合FAP的抗体的轻链区，或抗体的重链区，其包含可变区和CH1区；
其中R'和R”相互结合形成抗体的可变区，其中所述可变区特异性结合FAP；
Q'为特异性结合FAP的抗体的重链区，其包含可变区和CH1区，或抗体的轻链区；
Q”为特异性结合FAP的抗体的轻链区，或抗体的重链区，其包含可变区和CH1区；
其中Q'和Q”相互结合形成抗体的可变区，其中所述可变区特异性结合FAP，
R'和Q'各自为抗体的重链区，其包含可变区和CH1区，或抗体的轻链区；
R”和Q”各自为抗体的轻链区，或抗体的重链区，其包含可变区和CH1区；
其中R'和R”；Q'和Q”相互结合形成抗体的可变区，其中所述可变区特异性结合FAP，
W为特异性结合FAP的scFv，
接头(4)、(5)和(7)为肽接头，并且
s、t、u、x、a和b各自独立地为0或1。
21.据权利要求1所述的融合蛋白，其特征在于，所述融合蛋白包含结构式(III)和结构式(V)；结构式(IV)和结构式(V)；结构式(III)和结构式(III)；结构式(IV)和结构式(IV)；或结构式(V)和结构式(V)。
22.根据权利要求1所述的融合蛋白，其特征在于，所述第二单体包含由如SEQ IDNO:102所示的氨基酸序列组成的重链和由如SEQ ID NO:103所示的氨基酸序列组成的轻链；或由如SEQ ID NO:110所示的氨基酸序列组成的重链和由如SEQ ID NO:111所示的氨基酸序列组成的轻链。
23.根据权利要求2所述的融合蛋白，其特征在于，所述第二单体的Fc包含旋钮结构或孔结构。
24.一种用于预防或治疗癌症的药物组合物，其包含权利要求1至23任一项所述的融合蛋白作为活性成分。
25.根据权利要求24所述的药物组合物，其特征在于，所述癌症选自由胃癌、肝癌、肺癌、结直肠癌、乳腺癌、前列腺癌、皮肤癌、骨癌、多发性骨髓瘤、神经胶质瘤、卵巢癌、胰腺癌、宫颈癌、甲状腺癌、喉癌、急性髓系白血病、慢性髓系白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、脑肿瘤、神经母细胞瘤、视网膜母细胞瘤、头颈癌、唾液腺癌和淋巴瘤组成的组中的任一种。
26.一种编码权利要求1中所述第一单体的多核苷酸。
27.一种包含权利要求26中所述多核苷酸的载体。
28.一种编码权利要求1中所述第二单体的多核苷酸。
29.一种包含权利要求28中所述多核苷酸的载体。
30.一种将权利要求27或29中所述载体引入其中的转化细胞。
31.一种产生融合蛋白的方法，其包括：
i)培养权利要求30中所述的转化细胞；和
ii)回收包含所述第一单体和所述第二单体的融合蛋白。
32.一种用于治疗或预防癌症的方法，其包括：
向受试者施用一种融合蛋白，其包含含有IL-12或其变体的第一单体和包含特异性结合FAP的抗原结合位点的第二单体。
33.一种融合蛋白，其包含含有IL-12或其变体的第一单体和包含特异性结合FAP的抗原结合位点的第二单体在治疗癌症中的应用。
34.一种融合蛋白，其包含含有IL-12或其变体的第一单体和包含特异性结合FAP的抗原结合位点的第二单体在制备用于治疗癌症的药物中的应用。
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| US3924445A (en) | 1973-09-28 | 1975-12-09 | Toyota Motor Co Ltd | Flow rate measuring system with calibration means |
| WO1993005804A1 (en) | 1991-09-18 | 1993-04-01 | Sloan-Kettering Institute For Cancer Research | Activated stromal fibroblast-specific antibody, f19 and methods of using the same |
| DE69303494T2 (de) | 1992-11-13 | 1997-01-16 | Idec Pharma Corp | Therapeutische verwendung von chimerischen und markierten antikörper gegen menschlichen b lymphozyt beschränkter differenzierung antigen für die behandlung von b-zell-lymphoma |
| US6455677B1 (en) * | 1998-04-30 | 2002-09-24 | Boehringer Ingelheim International Gmbh | FAPα-specific antibody with improved producibility |
| EP2280997A2 (en) * | 2008-04-18 | 2011-02-09 | Xencor, Inc. | Human equivalent monoclonal antibodies engineered from nonhuman variable regions |
| WO2011112935A2 (en) * | 2010-03-12 | 2011-09-15 | The Regents Of The University Of California | Antibody fusion proteins with disrupted heparin-binding activity |
| WO2012020006A2 (en) | 2010-08-13 | 2012-02-16 | Roche Glycart Ag | Anti-fap antibodies and methods of use |
| EA201892619A1 (ru) * | 2011-04-29 | 2019-04-30 | Роше Гликарт Аг | Иммуноконъюгаты, содержащие мутантные полипептиды интерлейкина-2 |
| ES2848732T3 (es) * | 2012-08-07 | 2021-08-11 | Roche Glycart Ag | Inmunoterapia mejorada |
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| GB201713765D0 (en) | 2017-08-28 | 2017-10-11 | Psioxus Therapeutics Ltd | Modified adenovirus |
| JP2021509820A (ja) * | 2017-11-17 | 2021-04-08 | 科済生物医薬（上海）有限公司Ｃａｒｓｇｅｎ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｃｏ．，Ｌｔｄ． | 線維芽細胞活性化タンパク質αを標的とする結合ユニットとその応用 |
| TW202112804A (zh) | 2019-06-04 | 2021-04-01 | 瑞士商分子夥伴股份有限公司 | 多特異性蛋白質 |
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| WO2022035201A1 (ko) | 2022-02-17 |
| KR20220020229A (ko) | 2022-02-18 |
| BR112022026577A2 (pt) | 2023-02-23 |
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