CN110959015B - 双特异性重组蛋白 - Google Patents
双特异性重组蛋白 Download PDFInfo
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- CN110959015B CN110959015B CN201880031493.1A CN201880031493A CN110959015B CN 110959015 B CN110959015 B CN 110959015B CN 201880031493 A CN201880031493 A CN 201880031493A CN 110959015 B CN110959015 B CN 110959015B
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Abstract
本发明涉及生物医药领域,特别是一种双特异性重组蛋白,编码它们的核酸分子,制备它们的方法,包含它们的药物组合物所述重组蛋白在制备药物组合物中的用途,以及所述重组蛋白在治疗炎性疾病或自身免疫性疾病中的应用。
Description
技术领域
本发明涉及生物医药领域,特别是预防和/或治疗与过度的TNFα和/或IL-6活性相关的疾病的领域。具体而言,本发明涉及特异性结合TNFα和IL-6R,或TNFα和IL-6的重组蛋白。
背景技术
自身免疫性疾病作为继心血管疾病、癌症后威胁人类健康的第三大杀手,也被列入我国十类重大疾病。自身免疫是指机体免疫***对自身组织细胞所发生的免疫应答的现象。当机体免疫***对自身组织细胞发生免疫应答而造成细胞的破坏或组织的损伤并出现临床症状时,则称为自身免疫性疾病。目前发现的自身免疫性疾病有30多种,包括类风湿性关节炎(RA)、胰岛素依赖型糖尿病、多发性硬化症、红斑狼疮、银屑病、炎症性肠病、溃疡性结肠炎、重症肌无力、多发性肌炎、皮肌炎、Crohn病、自身免疫性血细胞减少、血管炎、***性红斑狼疮等。
类风湿性关节炎的治疗涉及多种遗传和环境因素,治疗效果因此不同,导致对所有患者完全缓解的治疗有效是非常困难。很多用于治疗RA的新药物特别是生物制剂有助于带来治疗革命性进步。
类风湿性关节的发病涉及许多促炎细胞因子,特别是肿瘤坏死因子α(TNFα)和白细胞介素-6(IL-6)。
TNFα活化T细胞并诱导T细胞浸润和新血管生成,通过增加成纤维细胞样滑膜细胞(FLS)的增殖导致关节破坏破骨细胞的形成。IL-6引起B细胞增殖并产生抗体,并诱导分化的T细胞分泌成IL-17分泌性T辅助细胞(Th17),从而抑制调节性T细胞分化。
IL-6能刺激血管生成和破骨细胞生成。IL-6可与IL-6R特异结合。IL-6受体有2种形式:膜结合受体(mIL-6R)和可溶性受体(sIL-6R)。IL-6与IL-6R(包括mIL-6R和sIL-6R)结合后,形成IL-6/IL-6R复合体,与gp130结合,启动下游包括JAK/STAT、ERK和PI3K在内的IL-6信号通路,因此,TNFα和IL-6可能共同引起许多致病性信号从而导致RA。
当类风湿关节炎病人接受IL-6受体(IL-6R)的单克隆抗体药物tocilizumab(ACTEMRA,Roche)治疗后,病情得到明显缓解,更进一步证明了IL-6在类风湿性节炎中的重要作用。
对现有临床结果进行综合比较发现,IL-6通路抑制剂,包括已上市的tocilizumab和在研品种,无论其靶点是IL-6,还是IL-6R,其临床效果相当,且不良反应率也没有明显差异。许多病人对TNF抑制药物响应不足或长期使用后效果下降,tocilizumab的多项III期临床试验表明TNF抑制药物响应不足或治疗效果下降的病人使用tocilizumab可得到良好的治疗效果。
双特异性抗体(BsAb)是一类具有双亲嗜性的组合抗体,通常是双价的(也有四价和六价的),即有两条抗原结合臂,具有结合两种不同特异性抗原的功能。中国专利申请CN102112495A公开了一种特异性结合TNFα和IL-6R的双特异性抗体DVD279和DVD280,其在抗体CH1和CL的N端依次连接针对TNFα和IL-6R,或针对IL-6R和TNFα的可变结构域,但其与抗TNFα亲本抗体和抗IL-6R亲本抗体对相同抗原的EC50的比值分别高达149.2倍(亲本抗体对IL-6R的EC50为1.42nM,DVD279对IL-6R的EC50为211.9nM)和9.13倍(亲本抗体对TNFα的EC50为0.44nM,DVD280对TNFα的EC50为4.02nM),也即该双特异性抗体的结合力明显差于亲本抗体,表明该双特异性抗体对一种抗原(TNFα或IL-6R)的结合显著抑制了其对另一种抗原(IL-6R或TNFα)的结合力,无法同时高效抑制TNFα和IL-6R,难以保证治疗效果。
因此,对于自身免疫性疾病或急慢性炎性疾病等疾病仍有未满足的需求,发展创新的、能更为有效、且副作用更小的治疗方法和药物是迫切而必要的。
发明内容
在本申请中,发明人通过大量的研究开发了一种双特异性结合TNFα和IL-6R,或TNFα和IL-6的重组蛋白,编码重组蛋白的核酸分子,包含核酸分子的载体,制备重组蛋白的方法,包含重组蛋白的药物组合物,药物组合物的在制备药物中的用途,重组蛋白在诊断/治疗/预防与过度的TNFα和IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)中的用途或方法,以及包含重组蛋白的试剂盒。
重组蛋白
因此,在一个方面,本发明提供了一种重组蛋白,其包含:
1)特异性结合第一抗原的第一抗体,所述第一抗体包括重链(HC)和轻链(LC);和
2)特异性结合第二抗原的包含重链可变区(VH)和轻链可变区(VL)的抗体片段(例如Fv,scFv,di-scFv);
其中,所述抗体片段连接于第一抗体的重链或轻链的N端或C端;
所述第一抗原为TNFα,并且所述第二抗原为IL-6R或IL-6;或者,第一抗原为IL-6R或IL-6,并且所述第二抗原为TNFα。
在某些优选的实施方案中,所述抗体片段为scFv。
在某些优选的实施方案中,所述重组蛋白包含1个所述第一抗体和2个所述scFv;并且,所述第一抗体包括两条HC和两条LC,其中所述第一抗体的一条HC的重链可变区(VH)与一条LC的轻链可变区(VL)形成抗原结合部位,另一条HC的重链可变区(VH)与另一条LC的轻链可变区(VL)形成抗原结合部位。
在某些优选的实施方案中,每个所述scFv分别连接于所述第一抗体的两条重链或两条轻链的N端或C端。
在某些优选的实施方案中,每个所述scFv分别连接于所述第一抗体的两条重链的N端。在某些优选的实施方案中,每个所述scFv分别连接于所述第一抗体的两条重链的C端。
在某些优选的实施方案中,每个所述scFv分别连接于所述第一抗体的两条轻链的N端。在某些优选的实施方案中,每个所述scFv分别连接于所述第一抗体的两条轻链的C端。
在某些优选的实施方案中,一个所述scFv连接于所述第一抗体的重链或轻链的N端,另一个所述scFv连接于所述第一抗体的重链或轻链的C端。
在某些优选的实施方案中,所述第一抗体的重链包含重链可变区(VH)和CH1结构域,并且所述轻链包含轻链可变区(VL)和轻链恒定区(CL)。在此类实施方案中,所述第一抗体可以为Fab片段、Fab’片段或F(ab’)2片段。在某些优选的实施方案中,所述第一抗体的重链包含重链可变区(VH)和重链恒定区(CH),并且所述轻链包含轻链可变区(VL)和轻链恒定区(CL)。在此类实施方案中,所述第一抗体可以为全长抗体。
在某些优选的实施方案中,所述第一抗体的重链为IgG同种型,例如IgG1、IgG2、IgG3或IgG4;优选为人IgG同种型。在某些实施方案中,所述第一抗体的重链为人IgG1同种型。在某些优选的实施方案中,所述第一抗体的轻链为Kappa同种型,优选为人Kappa同种型。
在某些优选的实施方案中,所述第一抗体的两条HC包含相同的CDR;和/或,所述第一抗体的两条LC包含相同的CDR。
在某些优选的实施方案中,所述第一抗体的两条HC包含相同的VH;和/或,所述第一抗体的两条LC包含相同的VL。
在某些优选的实施方案中,所述第一抗体的两条HC具有相同的氨基酸序列;和/或,所述第一抗体的两条LC具有相同的氨基酸序列。
在某些优选的实施方案中,两个所述scFv具有相同或不相同的氨基酸序列。在某些优选的实施方案中,两个所述scFv具有相同的氨基酸序列。
在某些优选的实施方案中,所述重组蛋白包含两条第一多肽链和两条第二多肽链,其中对于所述每条多肽链:
a)所述第一多肽链各自独立地包含所述第一抗体的重链(HC)和所述scFv;和
b)所述第二多肽链各自独立地包含所述第一抗体的轻链(LC);
其中,所述scFv通过接头S1与所述第一抗体的HC的N端或C端相连。
在某些优选的实施方案中,所述重组蛋白包含两条第一多肽链和两条第二多肽链,其中对于所述每条多肽链:
i)所述第一多肽链各自独立地包含所述第一抗体的轻链(LC)和所述scFv;和
ii)所述第二多肽链各自独立地包含所述第一抗体的重链(HC);
其中,所述scFv通过接头S1与所述第一抗体的LC的N端或C端相连。
在某些优选的实施方案中,所述重组蛋白包含两条第一多肽链和两条第二多肽链,其中对于所述每条多肽链:
a)所述第一多肽链各自独立地包含所述第一抗体的重链(HC)和所述scFv;和
b)所述第二多肽链各自独立地包含所述第一抗体的轻链(LC);
其中,所述scFv通过接头S1与所述第一抗体的HC的N端相连。
在某些优选的实施方案中,所述scFv的N端或C端与接头S1的C端或N端连接。
在某些优选的实施方案中,所述scFv具有结构:NH2-VH-S2-VL-COOH或NH2-VL-S2-VH-COOH,其中所述S2为接头。
在某些优选的实施方案中,所述接头S1和/或S2为肽接头,例如具有如(GmSn)x所示的氨基酸序列,其中m、n各自独立地选自1~8的整数(例如,1、2、3、4、5、6、7或8),x独立地选自1~20的整数(例如,1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20)。在某些优选的实施方案中,所述接头S1和/或S2具有如(G4S)x所示的氨基酸序列,x独立地选自1-6的整数。
在某些优选的实施方案中,所述接头S1和/或S2具有选自下列的氨基酸序列:SEQID NO:33、SEQ ID NO:34和SEQ ID NO:35。
在某些优选的实施方案中,所述接头S2具有如(G4S)4所示的氨基酸序列,即GGGGSGGGGSGGGGSGGGGS(SEQ ID NO:33)。在某些优选的实施方案中,当所述scFv与所述第一抗体的重链或轻链的N端连接时,所述接头S1具有如(G4S)3所示的氨基酸序列,即GGGGSGGGGSGGGGS(SEQ ID NO:34);当所述scFv与所述第一抗体的重链或轻链的C端连接时,所述接头S1具有如(G4S)2所示的氨基酸序列,即GGGGSGGGGS(SEQ ID NO:35)。
在某些优选的实施方案中,所述scFv的VH与VL之间存在二硫键。在抗体的VH和VL之间引入二硫键的方法是本领域熟知的,例如可参见美国专利申请US5,747,654;Rajagopal等人,Prot.Engin.10(1997)1453-1459;Reiter等人,Nature Biotechnology 14(1996)1239-1245;Reiter等人,Protein Engineering 8(1995)1323-1331;Webber等人,Molecular Immunology 32(1995)249-258;Reiter等人,Immunity 2(1995)281-287;Reiter等人,JBC 269(1994)18327-18331;Reiter等人,Inter.J.of Cancer 58(1994)142-149;或,Reiter等人,Cancer Res.54(1994)2714-2718;其通过引用并入本文。
在某些优选的实施方案中,所述scFv的位于VH第44位的氨基酸和位于VL第100位的氨基酸分别为半胱氨酸,其中提及的氨基酸位置是根据Kabat编号***的位置;并且,所述scFv的VH与VL通过分别位于VH第44位和VL第100位的2个半胱氨酸残基之间所形成的二硫键连接。
在某些优选的实施方案中,所述第一抗体特异性结合TNFα,并且所述scFv特异性结合IL-6R,其中:
所述第一抗体包含:
(a)如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ IDNO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQID NO:4所示的LCDR3;或,
(b)如SEQ ID NO:14所示的HCDR1;如SEQ ID NO:15所示的HCDR2;以及,如SEQ IDNO:16所示的HCDR3;如SEQ ID NO:10所示的LCDR1;如SEQ ID NO:11所示的LCDR2;以及,如SEQ ID NO:12所示的LCDR3;
和/或,
所述scFv包含:
(i)如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ IDNO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3;或,
(ii)如SEQ ID NO:30所示的HCDR1;如SEQ ID NO:31所示的HCDR2;以及,如SEQ IDNO:32所示的HCDR3;如SEQ ID NO:26所示的LCDR1;如SEQ ID NO:27所示的LCDR2;以及,如SEQ ID NO:28所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ ID NO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:14所示的HCDR1;如SEQ ID NO:15所示的HCDR2;以及,如SEQ ID NO:16所示的HCDR3;如SEQ ID NO:10所示的LCDR1;如SEQ ID NO:11所示的LCDR2;以及,如SEQ ID NO:12所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:30所示的HCDR1;如SEQ ID NO:31所示的HCDR2;以及,如SEQ ID NO:32所示的HCDR3;如SEQ ID NO:26所示的LCDR1;如SEQ ID NO:27所示的LCDR2;以及,如SEQ ID NO:28所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:30所示的HCDR1;如SEQ ID NO:31所示的HCDR2;以及,如SEQ ID NO:32所示的HCDR3;如SEQ ID NO:26所示的LCDR1;如SEQ ID NO:27所示的LCDR2;以及,如SEQ ID NO:28所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:14所示的HCDR1;如SEQ ID NO:15所示的HCDR2;以及,如SEQ ID NO:16所示的HCDR3;如SEQ ID NO:10所示的LCDR1;如SEQ ID NO:11所示的LCDR2;以及,如SEQ ID NO:12所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ ID NO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3。
在某些优选的实施方案中,所述重组蛋白包含1个所述第一抗体和2个所述scFv;并且,所述第一抗体包括两条HC和两条LC,其中所述第一抗体的一条HC的VH与一条LC的VL形成抗原结合部位,另一条HC的VH与另一条LC的VL形成抗原结合部位;每个所述scFv分别连接于所述第一抗体的两条重链的N端;且,所述第一抗体包含:如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3;并且,所述scFv包含:如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ IDNO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3。优选的,所述每个scFv通过接头S1与所述第一抗体的每条重链的N端连接。更优选的,所述scFv的结构为NH2-VL-S2-VH-COOH,其中所述S2为接头。
在某些优选的实施方案中,所述第一抗体的重链可变区(VH)的氨基酸序列与SEQID NO:5所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性;并且,所述第一抗体的轻链可变区(VL)的氨基酸序列与SEQ ID NO:1所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性;和,
所述scFv的重链可变区(VH)的氨基酸序列与SEQ ID NO:21或SEQ ID NO:91所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性;并且,所述scFv的的轻链可变区(VL)的氨基酸序列与SEQ ID NO:17或SEQ ID NO:90所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:5所示的重链可变区;并且,所述第一抗体的轻链可变区选自SEQ ID NO:1所示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:21或SEQ ID NO:91所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:17或SEQ ID NO:90所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:13所示的重链可变区;并且,所述第一抗体的的轻链可变区选自SEQ ID NO:9所示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:29或SEQ ID NO:93所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:25或SEQ ID NO:92所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:5所示的重链可变区;并且,所述第一抗体的的轻链可变区选自SEQ ID NO:1所示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:29或SEQ ID NO:93所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:25或SEQ ID NO:92所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:13所示的重链可变区;并且,所述第一抗体的的轻链可变区选自SEQ ID NO:9所示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:21或SEQ ID NO:91所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:17或SEQ ID NO:90所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:5所示的VH和如SEQID NO:1所示的VL;
并且,所述scFv包含:
(1)如SEQ ID NO:21所示的VH和如SEQ ID NO:17所示的VL;或,
(2)如SEQ ID NO:91所示的VH和如SEQ ID NO:90所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:5所示的VH和如SEQID NO:1所示的VL;并且,所述scFv包含如SEQ ID NO:91所示的VH和如SEQ ID NO:90所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:13所示的VH和如SEQID NO:9所示的VL;
并且,所述scFv包含:
(1)如SEQ ID NO:29所示的VH和如SEQ ID NO:25所示的VL;或,
(2)如SEQ ID NO:93所示的VH和如SEQ ID NO:92所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:5所示的VH和如SEQID NO:1所示的VL;并且,所述scFv包含:
(1)如SEQ ID NO:29所示的VH和如SEQ ID NO:25所示的VL;或,
(2)如SEQ ID NO:93所示的VH和如SEQ ID NO:92所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:13所示的VH和如SEQID NO:9所示的VL;并且,所述scFv包含:
(1)如SEQ ID NO:21所示的VH和如SEQ ID NO:17所示的VL;或,
(2)如SEQ ID NO:91所示的VH和如SEQ ID NO:90所示的VL。
在某些优选的实施方案中,所述第一抗体特异性结合IL-6R,并且所述scFv特异性结合TNFα,其中:
所述第一抗体包含:
(a)如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ IDNO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3;或,
(b)如SEQ ID NO:30所示的HCDR1;如SEQ ID NO:31所示的HCDR2;以及,如SEQ IDNO:32所示的HCDR3;如SEQ ID NO:26所示的LCDR1;如SEQ ID NO:27所示的LCDR2;以及,如SEQ ID NO:28所示的LCDR3;
和/或,
所述scFv包含:
(i)如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ IDNO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQID NO:4所示的LCDR3;或,
(ii)如SEQ ID NO:14所示的HCDR1;如SEQ ID NO:15所示的HCDR2;以及,如SEQ IDNO:16所示的HCDR3;如SEQ ID NO:10所示的LCDR1;如SEQ ID NO:11所示的LCDR2;以及,如SEQ ID NO:12所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ ID NO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:30所示的HCDR1;如SEQ ID NO:31所示的HCDR2;以及,如SEQ ID NO:32所示的HCDR3;如SEQ ID NO:26所示的LCDR1;如SEQ ID NO:27所示的LCDR2;以及,如SEQ ID NO:28所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:14所示的HCDR1;如SEQ ID NO:15所示的HCDR2;以及,如SEQ ID NO:16所示的HCDR3;如SEQ ID NO:10所示的LCDR1;如SEQ ID NO:11所示的LCDR2;以及,如SEQ ID NO:12所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ ID NO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:14所示的HCDR1;如SEQ ID NO:15所示的HCDR2;以及,如SEQ ID NO:16所示的HCDR3;如SEQ ID NO:10所示的LCDR1;如SEQ ID NO:11所示的LCDR2;以及,如SEQ ID NO:12所示的LCDR3。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:30所示的HCDR1;如SEQ ID NO:31所示的HCDR2;以及,如SEQ ID NO:32所示的HCDR3;如SEQ ID NO:26所示的LCDR1;如SEQ ID NO:27所示的LCDR2;以及,如SEQ ID NO:28所示的LCDR3;并且,
所述scFv包含:如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3。
在某些优选的实施方案中,所述第一抗体的重链可变区(VH)的氨基酸序列与SEQID NO:21所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性;并且,所述第一抗体的的轻链可变区(VL)的氨基酸序列与SEQ ID NO:17所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性;和,
所述scFv的重链可变区(VH)的氨基酸序列与SEQ ID NO:5或SEQ ID NO:87所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性;并且,所述scFv的的轻链可变区(VL)的氨基酸序列与SEQ ID NO:1或SEQ ID NO:86所示的重链可变区的氨基酸序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:21所示的重链可变区;并且,所述第一抗体的的轻链可变区选自SEQ ID NO:17示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:5或SEQ ID NO:87所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:1或SEQ ID NO:86所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:29所示的重链可变区;并且,所述第一抗体的的轻链可变区选自SEQ ID NO:25所示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:13或SEQ ID NO:89所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:9或SEQ ID NO:88所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:29所示的重链可变区;并且,所述第一抗体的的轻链可变区选自SEQ ID NO:25所示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:5或SEQ ID NO:87所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:1或SEQ ID NO:86所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体的重链可变区选自SEQ ID NO:21所示的重链可变区;并且,所述第一抗体的的轻链可变区选自SEQ ID NO:17所示的轻链可变区;和,
所述scFv的重链可变区选自SEQ ID NO:13或SEQ ID NO:89所示的重链可变区;并且,所述scFv的的轻链可变区选自SEQ ID NO:9或SEQ ID NO:88所示的轻链可变区。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:21所示的VH和如SEQID NO:17所示的VL;
并且,所述scFv包含:
(1)如SEQ ID NO:5所示的VH和如SEQ ID NO:1所示的VL;或,
(2)如SEQ ID NO:87所示的VH和如SEQ ID NO:86所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:21所示的VH和如SEQID NO:17所示的VL;并且,所述scFv包含如SEQ ID NO:87所示的VH和如SEQ ID NO:86所示的VL。
在某些优选的实施方案中,所述第一抗体包含:如SEQ ID NO:29所示的VH和如SEQID NO:25所示的VL;并且,所述scFv包含:
(1)如SEQ ID NO:13所示的VH和如SEQ ID NO:9所示的VL;或,
(2)如SEQ ID NO:89所示的VH和如SEQ ID NO:88所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:21所示的VH和如SEQID NO:17所示的VL;并且,所述scFv包含如SEQ ID NO:87所示的VH和如SEQ ID NO:86所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:29所示的VH和如SEQID NO:25所示的VL;
并且,所述scFv包含:
(1)如SEQ ID NO:5所示的VH和如SEQ ID NO:1所示的VL;或,
(2)如SEQ ID NO:87所示的VH和如SEQ ID NO:86所示的VL。
在某些优选的实施方案中,所述第一抗体包含如SEQ ID NO:21所示的VH和如SEQID NO:17所示的VL;
并且,所述scFv包含:
(1)如SEQ ID NO:13所示的VH和如SEQ ID NO:9所示的VL;或,
(2)如SEQ ID NO:89所示的VH和如SEQ ID NO:88所示的VL。
在某些优选的实施方案中,所述第一抗体包含:
(1)如SEQ ID NO:101所示的CH;和/或,
(2)如SEQ ID NO:100所示的CL。
在某些优选的实施方案中,所述重组蛋白包含两条相同的第一多肽链和两条相同的第二多肽链。
在某些优选的实施方案中,所述第一多肽链具有选自下列的氨基酸序列:SEQ IDNOs:36,38,44,46,50,52,58,60,64,66,70,76,94,95,96,97,98和99任一项所示的氨基酸序列;和/或,所述第二多肽链具有选自下列的氨基酸序列:SEQ ID NOs:42,48,56,68,74和80任一项所示的氨基酸序列。
在某些优选的实施方案中,所述重组蛋白包含:
(1)如SEQ ID NO:36所示的第一多肽链和如SEQ ID NO:42所示的第二多肽链;
(2)如SEQ ID NO:38所示的第一多肽链和如SEQ ID NO:42所示的第二多肽链;
(3)如SEQ ID NO:44所示的第一多肽链和如SEQ ID NO:48所示的第二多肽链;
(4)如SEQ ID NO:46所示的第一多肽链和如SEQ ID NO:48所示的第二多肽链;
(5)如SEQ ID NO:50所示的第一多肽链和如SEQ ID NO:56所示的第二多肽链;
(6)如SEQ ID NO:52所示的第一多肽链和如SEQ ID NO:56所示的第二多肽链;
(7)如SEQ ID NO:58所示的第一多肽链和如SEQ ID NO:56所示的第二多肽链;
(8)如SEQ ID NO:60所示的第一多肽链和如SEQ ID NO:56所示的第二多肽链;
(9)如SEQ ID NO:64所示的第一多肽链和如SEQ ID NO:68所示的第二多肽链;
(10)如SEQ ID NO:66所示的第一多肽链和如SEQ ID NO:68所示的第二多肽链;
(11)如SEQ ID NO:94所示的第一多肽链和如SEQ ID NO:68所示的第二多肽链;
(12)如SEQ ID NO:95所示的第一多肽链和如SEQ ID NO:68所示的第二多肽链;
(13)如SEQ ID NO:96所示的第一多肽链和如SEQ ID NO:42所示的第二多肽链;
(14)如SEQ ID NO:97所示的第一多肽链和如SEQ ID NO:42所示的第二多肽链;
(15)如SEQ ID NO:98所示的第一多肽链和如SEQ ID NO:48所示的第二多肽链;
(16)如SEQ ID NO:99所示的第一多肽链和如SEQ ID NO:48所示的第二多肽链;
(17)如SEQ ID NO:70所示的第一多肽链和如SEQ ID NO:74所示的第二多肽链;或
(18)如SEQ ID NO:76所示的第一多肽链和如SEQ ID NO:80所示的第二多肽链。
在某些实施方案中,本发明的重组蛋白具有与所述第一抗体的亲本抗体相比同等的抗体依赖性细胞介导的细胞毒性(ADCC)活性。在某些实施方案中,本发明的重组蛋白具有与所述第一抗体的亲本抗体相比同等的抗体依赖性细胞介导的细胞毒性(ADCC)活性,并且还具有与所述第一抗体的亲本抗体相比同等的补体依赖的细胞毒性(CDC)活性。
另一方面,本发明的重组蛋白对TNFα和IL-6R具有亲和力。在某些优选的实施方案中,本发明的重组蛋白对TNFα和IL-6R具有与其各自的亲本抗体相比同等或者更高的亲和力。在某些优选的实施方案中,本发明的重组蛋白对细胞表面的TNFα和IL-6R具有与其各自的亲本抗体相比更高的亲和力。
另一方面,本发明的重组蛋白具有良好的热稳定性。在某些优选的实施方案中,本发明的重组蛋白具有与亲本抗体相比基本相同的热稳定性。
重组蛋白的表达
在另一个方面,本发明提供了一种分离的核酸分子,其包含编码本发明的重组蛋白的核苷酸序列。在某些优选的实施方案中,所述分离的核酸分子编码本发明的重组蛋白。
在某些优选的实施方案中,所述分离的核酸分子包含编码本发明的第一多肽链的核苷酸序列。在某些优选的实施方案中,所述分离的核酸分子包含编码本发明的第二多肽链的核苷酸序列。在某些优选的实施方案中,所述分离的核酸分子包含编码本发明的第一多肽链的核苷酸序列和编码本发明的第二多肽链的核苷酸序列。
在另一个方面,本发明提供了一种载体(例如克隆载体或表达载体),其包含本发明的分离的核酸分子。
在某些优选的实施方案中,所述载体包含编码本发明的第一多肽链的核苷酸序列。在某些优选的实施方案中,所述载体包含编码本发明的第二多肽链的核苷酸序列。在某些优选的实施方案中,所述载体包含编码本发明的第一多肽链的核苷酸序列和编码本发明的第二多肽链的核苷酸序列。
在某些优选的实施方案中,本发明的载体是例如质粒,粘粒,噬菌体等。在某些优选的实施方案中,所述载体能够在受试者(例如哺乳动物,例如人)体内表达本发明的重组蛋白、第一多肽链或第二多肽链。
在另一个方面,本发明提供了一种宿主细胞,其包含本发明的分离的核酸分子或本发明的载体。此类宿主细胞包括但不限于,原核细胞例如大肠杆菌细胞,以及真核细胞例如酵母细胞,昆虫细胞,植物细胞和动物细胞(如哺乳动物细胞,例如小鼠细胞、人细胞等)。在某些优选的实施方案中,本发明的宿主细胞是哺乳动物细胞,例如CHO(例如CHO-K1、CHO-S、CHO DG44)或HEK293。
在另一个方面,本发明提供了制备本发明的重组蛋白的方法,其包括,在允许所述重组蛋白表达的条件下,培养本发明的宿主细胞,和从培养的宿主细胞培养物中回收所述重组蛋白。
在某些优选的实施方案中,所述方法包括:
(1)构建包含编码第一多肽链的核苷酸序列和编码第二多肽链的核苷酸序列的表达载体;或,构建包含编码第一多肽链的核苷酸序列的第一表达载体和包含编码第二多肽链的核苷酸序列的第二表达载体;
(2)将步骤(1)中所述的表达载体转化至宿主细胞;或,将步骤(1)中所述的第一表达载体和第二表达载体转化至宿主细胞;
(3)在允许本发明的重组蛋白表达的条件下,培养步骤(2)中所述的宿主细胞;和
(4)从培养的宿主细胞培养物中回收所述重组蛋白。
治疗方法和药物组合物
本发明的重组蛋白可用于体外或在受试者体内中抑制TNFα和IL-6/IL-6R的活性,阻断TNFα和/或IL-6信号通路,以及用于预防和/或治疗与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)。
因此,在另一个方面,本发明提供了一种药物组合物,其含有本发明的重组蛋白,以及药学上可接受的载体和/或赋形剂。在某些优选的实施方案中,所述药物组合物还可以包含另外的药学活性剂。在某些优选的实施方案中,所述另外的药学活性剂是用于预防和/或治疗与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)的药物,例如抗炎药物或免疫抑制剂,例如非甾体抗炎药(如布洛芬、双氯芬酸、萘普生、吲哚美辛、吡罗昔康、美洛昔康、萘丁美酮或尼美舒利)、甾体抗炎药(如强的松、***或氢化考的松)、致炎性细胞因子的抗体或拮抗剂(例如,TNFα、IL-1、IL-6、IL-8、GM-CSF或PAF的抗体或受体拮抗剂)、抗炎细胞因子(如IL-10、IL-4、IL-11、IL-13或TGFβ)、抗增殖/抗代谢类药物(如环磷酰胺、甲氨蝶呤、硫唑嘌呤、莱氟米特)、钙调磷酸酶抑制剂(如环孢素、他克莫司)、天然提取物(如白芍总苷、雷公藤总苷、青藤碱)等。
在另一个方面,本发明提供了本发明的重组蛋白或本发明的药物组合物在制备药物中的用途,所述药物用于在受试者(例如人)中预防和/或治疗与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病),和/或用于体外或在受试者(例如人)体内抑制TNFα和IL-6/IL-6R的活性。
在另一个方面,本发明提供了一种用于在受试者(例如人)中预防和/或治疗与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病),和/或用于体外或在受试者(例如人)体内抑制TNFα和IL-6/IL-6R的活性的方法,其中所述方法包括,给有此需要的受试者施用有效量的本发明的重组蛋白,或者本发明的药物组合物。
在本发明中,所述与过度的TNFα和/或IL-6活性相关的疾病包括但不限于炎性疾病或自身免疫性疾病,例如,类风湿性关节炎、胰岛素依赖型糖尿病、多发性硬化症、银屑病、炎症性肠病、溃疡性结肠炎、胰腺炎、重症肌无力、多发性肌炎、皮肌炎、Crohn病、自身免疫性血细胞减少、血管炎、***性红斑狼疮或成人Still病等。
本发明的重组蛋白或者本发明的药物组合物可以配制成医学领域已知的任何剂型,例如,片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、吸入剂、喷雾剂等。优选剂型取决于预期的给药方式和治疗用途。本发明的药物组合物应当是无菌的并在生产和储存条件下稳定。一种优选的剂型是注射剂。此类注射剂可以是无菌注射溶液。例如,可通过下述方法来制备无菌注射溶液:在适当的溶剂中掺入必需剂量的本发明的重组蛋白,以及任选地,同时掺入其他期望的成分(包括但不限于,pH调节剂,表面活性剂,佐剂,离子强度增强剂,等渗剂、防腐剂、稀释剂,或其任何组合),随后过滤除菌。此外,可以将无菌注射溶液制备为无菌冻干粉剂(例如,通过真空干燥或冷冻干燥)以便于储存和使用。此类无菌冻干粉剂可在使用前分散于合适的载体中,例如无菌无热原水。
此外,本发明的重组蛋白可以以单位剂量形式存在于药物组合物中,以便于施用。在某些实施方案中,所述单位剂量为至少1mg,至少5mg,至少10mg,至少15mg,至少20mg,至少25mg,至少30mg,至少45mg,至少50mg,至少75mg,或至少100mg。在所述药物组合物为液体(例如,注射剂)剂型的情况下,其可以包含浓度至少为0.1mg/ml,如至少0.25mg/ml,至少0.5mg/ml,至少1mg/ml,至少2.5mg/ml,至少5mg/ml,至少8mg/ml,至少10mg/ml,至少15mg/ml,至少25mg/ml,至少50mg/ml,至少75mg/ml,或至少100mg/ml的本发明的重组蛋白。
本发明的重组蛋白或药物组合物可以通过本领域已知的任何合适的方法来施用,包括但不限于,口服、口腔、舌下、眼球、局部、肠胃外、直肠、叶鞘内、内胞浆网槽内、腹股沟、膀胱内、局部(如,粉剂、药膏或滴剂),或鼻腔途径。但是,对于许多治疗用途而言,优选的给药途径/方式是胃肠外给药(例如静脉注射,皮下注射,腹膜内注射,肌内注射)。技术人员应理解,给药途径和/或方式将根据预期目的而发生变化。在一个优选的实施方案中,本发明的重组蛋白或药物组合物通过静脉输注或注射给予。
本发明所提供的药物、药物组合物或重组蛋白可以单独使用或联合使用,也可以与另外的药学活性剂(例如抗炎药物或免疫抑制剂)联合使用。在某些优选的实施方案中,将本发明的重组蛋白与其它抗炎药物或免疫抑制剂联合使用,以预防和/或治疗与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)。这种另外的药学活性剂可以在施用本发明的重组蛋白或本发明的药物组合物之前、同时或之后施用。
本发明的药物组合物可以包括“治疗有效量”或“预防有效量”的本发明的重组蛋白。“预防有效量”是指,足以预防,阻止,或延迟疾病(例如与过度的TNFα和/或IL-6活性相关的疾病)的发生的量。“治疗有效量”是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。本发明的重组蛋白的治疗有效量可根据如下因素发生变化:待治疗的疾病的严重度、患者自己的免疫***的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
在本发明中,可调整给药方案以获得最佳目的反应(例如治疗或预防反应)。例如,可以单次给药,可以在一段时间内多次给药,或者可以随治疗情况的紧急程度按比例减少或增加剂量。
本发明的重组蛋白的治疗或预防有效量的典型非极限范围是0.02~50mg/kg,例如0.1~50mg/kg,0.1~25mg/kg,或1~10mg/kg。应注意的是,剂量可随需要治疗的症状的类型和严重性不同而发生变化。此外,本领域技术人员理解,对于任一特定患者,特定的给药方案应根据患者需要和医生的专业评价而随时间调整;此处给出的剂量范围只用于举例说明目的,而不限定本发明药物组合物的使用或范围。
在本发明中,所述受试者可以为哺乳动物,例如人。
检测/诊断方法和试剂盒
本发明的重组蛋白能够特异性结合TNFα/IL-6或TNFα/IL-6R,从而可用于检测TNFα/IL-6或TNFα/IL-6R在样品中的存在或其水平,以及诊断受试者是否患有与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)。
因此,在另一个方面,本发明提供了一种试剂盒,其包括本发明的重组蛋白。在某些优选的实施方案中,本发明的重组蛋白带有可检测的标记。在一个优选的实施方案中,所述试剂盒还包括第二抗体,其特异性识别本发明的重组蛋白的第一抗体或scFv。优选地,所述第二抗体还包括可检测的标记。
在本发明中,所述可检测的标记可以是可通过荧光、光谱、光化学、生物化学、免疫学、电学、光学或化学手段检测的任何物质。特别优选的是,此类标记能够适用于免疫学检测(例如,酶联免疫测定法、放射免疫测定法、荧光免疫测定法、化学发光免疫测定法等)。这类标记是本领域熟知的,包括但不限于,酶(例如,辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶、脲酶、葡萄糖氧化酶,等)、放射性核素(例如,3H、125I、35S、14C或32P)、荧光染料(例如,异硫氰酸荧光素(FITC)、荧光素、异硫氰酸四甲基罗丹明(TRITC)、藻红蛋白(PE)、德克萨斯红、罗丹明、量子点或花菁染料衍生物(例如Cy7、Alexa 750))、发光物质(例如化学发光物质,如吖啶酯类化合物)、磁珠(例如,)、测热标记物例如胶体金或有色玻璃或塑料(例如,聚苯乙烯、聚丙烯、乳胶,等)珠、以及用于结合上述标记物修饰的亲和素(例如,链霉亲和素)的生物素。教导该标记物的使用的专利包括,但不限于,美国专利3,817,837;3,850,752;3,939,350;3,996,345;4,277,437;4,275,149;及4,366,241(全部通过引用并入本文)。本发明中涵盖的标记物可通过本领域已知的方法检测。例如,放射性标记可使用摄影胶片或闪烁计算器检测,荧光标记物可使用光检测器检测,以检测发射的光。酶标记物一般通过给酶提供底物及检测通过酶对底物的作用产生的反应产物来检测,及测热标记物通过简单可视化着色标记物来检测。在某些实施方案中,可通过不同长度的接头将如上所述的可检测的标记连接至本发明的重组蛋白,以降低潜在的位阻。
在另一个方面,本发明提供了检测TNFα/IL-6或TNFα/IL-6R在样品中的存在或其水平的方法,其包括使用本发明的重组蛋白的步骤。在一个优选的实施方案中,本发明的重组蛋白还带有可检测的标记。在另一个优选的实施方案中,所述方法还包括,使用带有可检测的标记的试剂来检测本发明的重组蛋白段。所述方法可以用于诊断目的,或者非诊断目的(例如,所述样品是细胞样品,而非来自患者的样品)。
在另一个方面,本发明提供了诊断受试者是否患有与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)的方法,其包括:使用本发明的重组蛋白检测TNFα和/或IL-6在来自所述受试者的样品中的存在或其水平。在一个优选的实施方案中,本发明的重组蛋白还带有可检测的标记。在另一个优选的实施方案中,所述方法还包括,使用带有可检测的标记的试剂来检测本发明的重组蛋白的步骤。
在另一个方面,提供了本发明的重组蛋白在制备试剂盒中的用途,所述试剂盒用于检测TNFα和/或IL-6在样品中的存在或其水平,或用于诊断受试者是否患有与过度的TNFα和/或IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)。
术语定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的细胞培养、生物化学、核酸化学、免疫学实验室等操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文中所使用的,术语“抗体”是指,通常由两对多肽链(每对具有一条轻链(LC)和一条重链(HC))组成的免疫球蛋白分子。抗体轻链可分类为κ(kappa)和λ(lambda)轻链。重链可分类为μ、δ、γ、α或ε,并且分别将抗体的同种型定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链内,可变区和恒定区通过大约12或更多个氨基酸的“J”区连接,重链还包含大约3个或更多个氨基酸的“D”区。各重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由3个结构域(CH1、CH2和CH3)组成。各轻链由轻链可变区(VL)和轻链恒定区(CL)组成。轻链恒定区由一个结构域CL组成。抗体的恒定区可介导免疫球蛋白与宿主组织或因子,包括免疫***的各种细胞(例如,效应细胞)和经典补体***的第一组分(C1q)的结合。VH和VL区还可被细分为具有高变性的区域(称为互补决定区(CDR)),其间散布有较保守的称为构架区(FR)的区域。各VH和VL由按下列顺序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4从氨基末端至羧基末端排列的3个CDR和4个FR组成。各重链/轻链对的可变区(VH和VL)分别形成抗原结合部位。氨基酸至各区域或结构域的分配遵循Kabat,Sequences of Proteins ofImmunological Interest(National Institutes of Health,Bethesda,Md.(1987and1991)),或Chothia&Lesk(1987)J.Mol.Biol.196:901-917;Chothia等人(1989)Nature342:878-883的定义。
如本文中所使用的,术语“互补决定区”或“CDR”是指抗体可变区中负责抗原结合的氨基酸残基,其通常可包括,轻链可变区中的残基24-34{LCDR1}、50-56{LCDR2}、89-97{LCDR3}以及重链可变区中的残基31-35{HCDR1}、50-65{HCDR2}、95-102{HCDR3}(参见例如,Kabat等,Sequences of Proteins of lmmunological lnterest,第五版,PublicHealth Service,美国国立卫生研究院,贝塞斯达、马里兰州(1991)),或者轻链可变区中的残基26-32{Ll}、50-52{L2}、91-96{L3}以及重链可变区中的残基26-32{H1}、53-55{H2}、96-101{H3}(参见,Chothia和Lesk J.Mol.Biol.196:901-917(1987))。
如本文中所使用的,术语“构架区”或“FR”残基是指,抗体可变区中除了如上定义的CDR残基以外的那些氨基酸残基。
术语“抗体”不受任何特定的产生抗体的方法限制。例如,其包括,重组抗体、单克隆抗体和多克隆抗体。抗体可以是不同同种型的抗体,例如,IgG(例如,IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或IgM抗体。
如本文中所使用的,术语“抗原结合部位”是指,由重链以及轻链的可变区(VH和VL)的氨基酸残基所形成的、参与进行抗原结合的部分,其包含那些与抗原相互作用且决定了该抗体对抗原的特异性及亲和力的氨基酸残基。所述抗原结合部位还可以包含那些对维持上述直接结合抗原的氨基酸残基的合适构象所必需的框架区的氨基酸残基。
如本文中所使用的,术语“全长抗体”意指,由两条“全长重链”和两条“全长轻链”组成的抗体。其中,“全长重链”是指这样的多肽链,其在N端到C端的方向上由重链可变区(VH)、重链恒定区CH1结构域、铰链区(HR)、重链恒定区CH2结构域、重链恒定区CH3结构域组成;并且,当所述全长抗体为IgE同种型时,任选地还包括重链恒定区CH4结构域。优选地,“全长重链”是在N端到C端方向上由VH、CH1、HR、CH2和CH3组成的多肽链。“全长轻链”是在N端到C端方向上由轻链可变区(VL)和轻链恒定区(CL)组成的多肽链。两对全长抗体链通过在CL和CH1之间的二硫键和两条全长重链的HR之间的二硫键连接在一起。本发明的全长抗体可以来自单一物种,例如人;也可以是嵌合抗体或人源化抗体。本发明的全长抗体包含分别由VH和VL对形成的两个抗原结合部位,这两个抗原结合部位特异性识别/结合相同的抗原。
如本文中所使用的,术语“Fab片段”意指由VL、VH、CL和CH1结构域组成的抗体片段;术语“Fab'片段”意指还原连接F(ab')2片段中两个重链片段的二硫键后所获片段,由一条完整的轻链和重链的Fd片段(由VH和CH1结构域组成)组成;术语“F(ab')2片段”意指包含通过铰链区上的二硫桥连接的两个Fab片段的抗体片段。上述各个抗体片段均保持了特异性结合全长抗体所结合的相同抗原的能力,和/或与全长抗体竞争对抗原的特异性结合。
如本文中所使用的,术语“scFv”是指,包含VL和VH结构域的单个多肽链,其中所述VL和VH通过接头(linker)相连(参见,例如,Bird等人,Science 242:423-426(1988);Huston等人,Proc.Natl.Acad.Sci.USA 85:5879-5883(1988);和Pluckthun,ThePharmacology of Monoclonal Antibodies,第113卷,Roseburg和Moore编,Springer-Verlag,纽约,第269-315页(1994))。此类scFv分子可具有一般结构:NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。本发明的scFv的VH与VL之间还可以存在二硫键。在抗体的VH和VL之间引入二硫键的方法是本领域熟知的,例如可参见美国专利申请US5,747,654;Rajagopal等人,Prot.Engin.10(1997)1453-1459;Reiter等人,Nature Biotechnology 14(1996)1239-1245;Reiter等人,Protein Engineering 8(1995)1323-1331;Webber等人,Molecular Immunology 32(1995)249-258;Reiter等人,Immunity 2(1995)281-287;Reiter等人,JBC 269(1994)18327-18331;Reiter等人,Inter.J.of Cancer 58(1994)142-149;或,Reiter等人,Cancer Res.54(1994)2714-2718;其通过引用并入本文。如本文中所使用的,术语“di-scFv”是指,由两个scFv连接形成的抗体片段。
如本文中所使用的,术语“Fv片段”意指由抗体的单臂的VL和VH结构域组成的抗体片段。
如本文中所使用的,术语“亲本抗体”是指,用于制备本发明的重组蛋白的抗TNFα抗体或抗IL-6R/IL-6抗体,该抗体所具有的氨基酸序列可通过例如氨基酸置换或结构改变等方式以用于制备本发明的重组蛋白所包含的第一抗体或scFv。在本发明中,“抗TNFα亲本抗体”可以为重链和轻链可变区分别如SEQ ID NOs:1和5所示的抗体或分别如SEQ ID NOs:9和13所示的抗体;“抗IL-6R亲本抗体”可以为重链和轻链可变区分别如SEQ ID NOs:17和21所示的抗体或分别如SEQ ID NOs:25和29所示的抗体。
本发明的重组蛋白所包含的CDR、VH、VL、CH、CL、HC、LC还可以来自其他被本领域所知晓的能够特异性结合TNFα或IL-6R或IL-6的抗体或其抗体片段,或者与上述已知抗体、其抗体片段或其CDR、VH、VL、CH、CL、HC、LC具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或100%的序列同一性的抗体。作为示例,所述能够特异性结合TNFα的抗体或蛋白包括:Infliximab,Etanercept,Adalimumab,Certolizumab pegol,Golimumab,Tasonermin,TNF Kinoid,ESBA105,afelimomab,lenercept,nerelimomab,onercept,ozoralizumab,pegsunercept,placulumab,tulinercept;所述能够特异性结合IL-6R或IL-6的抗体或蛋白包括:clazakizumab,elsilimomab,olamkicept,olokizumab,siltuximab,sirukumab,Tocilizumab,olamkicept,satralizumab,sarilumab,vobarilizumab。
如本文中所使用的,术语“接头”是指,由多个氨基酸残基通过肽键连接形成的线性多肽。本发明的接头可以为人工合成的氨基酸序列,或天然存在的多肽序列,例如具有铰链区功能的多肽。此类接头多肽是本领域众所周知的(参见例如,Holliger,P.等人(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448;Poljak,R.J.等人(1994)Structure2:1121-1123)。
如本文中所使用的,术语“特异性结合”是指,两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。在某些实施方式中,特异性结合某抗原的抗体(或对某抗原具有特异性的抗体)是指,抗体以小于大约10-5M,例如小于大约10-6M、10-7M、10-8M、10-9M或10-10M或更小的亲和力(KD)结合该抗原。在本发明中,术语“KD”是指特定抗体-抗原相互作用的解离平衡常数,其用于描述抗体与抗原之间的结合亲和力。平衡解离常数越小,抗体-抗原结合越紧密,抗体与抗原之间的亲和力越高。通常,抗体(例如,本发明的抗体)以小于大约10-5M,例如小于大约10-6M、10-7M、10-8M、10-9M或10-10M或更小的解离平衡常数(KD)结合抗原(例如,HBsAg),例如,如使用表面等离子体共振术(SPR)在BIACORE仪中测定的。
如本文中所使用的,术语“载体(vector)”是指,可将多聚核苷酸***其中的一种核酸运载工具。当载体能使***的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、***瘤病毒、***多瘤空泡病毒(如SV40)。一种载体可以含有多种控制表达的元件,包括但不限于,启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外,载体还可含有复制起始位点。
如本文中所使用的,术语“宿主细胞”是指,可用于导入载体的细胞,其包括但不限于,如大肠杆菌或枯草菌等的原核细胞,如酵母细胞或曲霉菌等的真菌细胞,如S2果蝇细胞或Sf9等的昆虫细胞,或者如纤维原细胞,CHO细胞,COS细胞,NSO细胞,HeLa细胞,BHK细胞,HEK 293细胞或人细胞等的动物细胞。
如本文中所使用的,术语“同一性”用于指两个多肽之间或两个核酸之间序列的匹配情况。当两个进行比较的序列中的某个位置都被相同的碱基或氨基酸单体亚单元占据时(例如,两个DNA分子的每一个中的某个位置都被腺嘌呤占据,或两个多肽的每一个中的某个位置都被赖氨酸占据),那么各分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如,如果两个序列的10个位置中有6个匹配,那么这两个序列具有60%的同一性。例如,DNA序列CTGACT和CAGGTT共有50%的同一性(总共6个位置中有3个位置匹配)。通常,在将两个序列比对以产生最大同一性时进行比较。这样的比对可通过使用,例如,可通过计算机程序例如Align程序(DNAstar,Inc.)方便地进行的Needleman等人(1970)J.Mol.Biol.48:443-453的方法来实现。还可使用已整合入ALIGN程序(版本2.0)的E.Meyers和W.Miller(Comput.ApplBiosci.,4:11-17(1988))的算法,使用PAM120权重残基表(weight residue table)、12的缺口长度罚分和4的缺口罚分来测定两个氨基酸序列之间的百分数同一性。此外,可使用已整合入GCG软件包(可在www.gcg.com上获得)的GAP程序中的Needleman和Wunsch(J MoIBiol.48:444-453(1970))算法,使用Blossum 62矩阵或PAM250矩阵以及16、14、12、10、8、6或4的缺口权重(gap weight)和1、2、3、4、5或6的长度权重来测定两个氨基酸序列之间的百分数同一性。
本文涉及的二十个常规氨基酸的编写遵循常规用法。参见例如,Immunology-ASynthesis(2nd Edition,E.S.Golub and D.R.Gren,Eds.,Sinauer Associates,Sunderland,Mass.(1991)),其以引用的方式并入本文中。在本发明中,术语“多肽”和“蛋白质”具有相同的含义且可互换使用。并且在本发明中,氨基酸通常用本领域公知的单字母和三字母缩写来表示。例如,丙氨酸可用A或Ala表示。
如本文中所使用的,术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995),并且包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂,稀释剂,维持渗透压的试剂,延迟吸收的试剂,防腐剂。例如,pH调节剂包括但不限于磷酸盐缓冲液。表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80。离子强度增强剂包括但不限于氯化钠。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。维持渗透压的试剂包括但不限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。
如本文中使用的,术语“受试者”是指哺乳动物,例如灵长类哺乳动物,例如人。在某些实施方式中,所述受试者(例如人)患有与过度的TNFα和/或IL-6活性相关的疾病,或者,具有患有上述疾病的风险。通常而言,这类疾病或疾病状态的特征是其将受益于TNFα和/或IL-6水平的降低或TNFα和/或IL-6活性的抑制从而得到缓解或治愈。
如本文中所使用的,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如与过度的TNFα和/或IL-6活性相关的疾病)有效量是指,足以预防,阻止,或延迟疾病(例如与过度的TNFα和/或IL-6活性相关的疾病)的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫***的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
如本文中所使用的,术语“抗体依赖性细胞介导的细胞毒性(ADCC)”是指,一种细胞毒性形式,Ig通过与细胞毒性细胞(例如自然杀伤(NK)细胞、中性粒细胞或巨噬细胞)上存在的Fc受体(FcR)结合,使这些细胞毒性效应细胞特异性结合到抗原附着的靶细胞上,然后通过分泌细胞毒素杀死靶细胞。检测抗体的ADCC活性的方法是本领域已知的,例如可通过测定待测抗体与Fc受体(例如CD16a)之间的结合活性来评价。
如本文中所使用的,术语“补体依赖的细胞毒性(CDC)”是指,通过使补体成分C1q与抗体Fc结合来激活补体级联的细胞毒性形式。检测抗体的CDC活性的方法是本领域已知的,例如可通过测定待测抗体与Fc受体(例如C1q)之间的结合活性来评价。
发明的有益效果
与现有技术相比,本发明的技术方案至少具有以下有益效果:
本发明的重组蛋白不仅能够特异性识别/结合TNFα和IL-6R,而且其对TNFα和IL-6R的亲和力至少与其各自的亲本抗体相当,在体外和受试者体内能够显著且同时抑制TNFα和IL-6R的活性,阻断TNFα和IL-6信号通路。并且,本发明的重组蛋白还具有与第一抗体的亲本抗体同等优良的热稳定性。特别地,在体内实验中,本发明的重组蛋白展现出了良好的治疗活性。与亲本抗体相比,本发明双特异性重组蛋白具有更优的治疗活性。因此,本发明的重组蛋白具有用于治疗与过度的TNFα和IL-6活性相关的疾病(例如炎性疾病或自身免疫性疾病)的潜力,具有重大的临床价值。
下面将结合附图和实施例对本发明的实施方案进行详细描述,但是本领域技术人员将理解,下列附图和实施例仅用于说明本发明,而不是对本发明的范围的限定。根据附图和优选实施方案的下列详细描述,本发明的各种目的和有利方面对于本领域技术人员来说将变得可实施。
附图说明
图1显示了抗TNFα和IL-6R重组蛋白的构建体的示意图。
图2A-2B显示了ANT、ACT、TNA、TCA、ALNT、ALCT的还原与非还原SDS-PAGE电泳图。图2A,泳道:1.蛋白marker;2.AB01非还原;3.AB01还原;4.ANT非还原;5.ANT还原;6.ACT非还原;7.ACT还原;8.TNA非还原;9.TNA还原。图2B,泳道:1.蛋白marker;2.AB01非还原;3.AB01还原;4.TCA非还原;5.TCA还原;6.ALNT非还原;7.ALNT还原;8.ALCT非还原;9.ALCT还原。结果显示,各重组蛋白条带大小符合预期,且无明显聚集降解,表明各双特异性重组蛋白均能高效表达,正确装配。
图3显示了在实施例7中,抗TNFα和IL-6R重组蛋白抑制IL-6诱导的细胞增殖的检测结果。结果显示,抗TNFα和IL-6R重组蛋白可明显抑制由IL-6诱导的U266细胞增殖,且与亲本抗体的效果一致。
图4显示了实施例11中恒河猴关节炎模型的关节肿胀示意图。
图5显示了实施例11中恒河猴关节炎模型的体重变化曲线,箭头指示给药时间点。
图6显示了实施例11中恒河猴关节炎模型的临床评分变化曲线,箭头指示给药时间点。
图7显示了实施例11中恒河猴关节炎模型的血清CRP水平变化曲线,箭头指示给药时间点。
图8显示了实施例11中恒河猴关节炎模型的血液学RBC变化曲线,箭头指示给药时间点。其中,正常参考值范围为4.17-6.27。
图9显示了实施例11中恒河猴关节炎模型的血液学HGB变化曲线,箭头指示给药时间点。其中,正常参考值范围为111.7-152.5。
图10显示了实施例11中恒河猴关节炎模型的血液学HCT变化曲线,箭头指示给药时间点。其中,正常参考值范围为35.41-49.97。
序列信息
本发明涉及的部分序列的信息提供于下面的表1中。
表1:序列的描述
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具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明。
除非特别指明,本发明中所使用的分子生物学实验方法和免疫检测法,基本上参照J.Sambrook等人,分子克隆:实验室手册,第2版,冷泉港实验室出版社,1989,以及F.M.Ausubel等人,精编分子生物学实验指南,第3版,John Wiley&Sons,Inc.,1995中所述的方法进行;限制性内切酶的使用依照产品制造商推荐的条件。本领域技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本发明所要求保护的范围。
实施例1:编码抗TNFα/IL-6R双特异性重组蛋白的表达载体的构建
在本实施例中,首先获得表2中所示的抗TNFα亲本抗体(AB01、AB02)和抗IL-6R亲本抗体(AB03、AB04),然后通过DNA重组技术,分别构建包含编码第一多肽链的核苷酸序列的表达载体和编码第二多肽链的核苷酸序列的表达载体,以获得本发明的重组蛋白。
各亲本抗体(AB01、AB02、AB03、AB04)的编码核酸序列由南京金斯瑞生物技术服务公司全基因合成,各亲本抗体可变区及恒定区序列参照表2。
表2:亲本抗体的可变区及恒定区序列
按照表3中所示各重组蛋白的构建方式构建编码该重组蛋白的第一多肽链的核苷酸序列和编码第二多肽链的核苷酸序列。其中,对于各重组蛋白中的scFv,其VH、VL通过肽接头(SEQ ID NO:33,氨基酸序列为:GGGGSGGGGSGGGGSGGGGS)相连接,并且通过PCR定点突变方法将该scFv的亲本抗体的VH第44位和VL第100位氨基酸分别突变为半胱氨酸(Cys,C),从而使得该scFv的VH与VL之间形成二硫键。表3中所示各重组蛋白的构建方式例举见图1。
表3:各重组蛋白的构建方式
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注:AB01-scFv表示亲本抗体AB01来源的scFv,其可变区与AB01的区别在于:该scFv的VH第44位和VL第100位氨基酸分别为半胱氨酸;其他类似的表述具有类似的含义。
具体而言,作为示例地部分重组蛋白的核酸构建体的构建方式如下:
将编码AB01-scFv的核苷酸序列通过编码接头S1的核苷酸序列连接于编码AB03的重链的核苷酸序列的5’端或3’端,以分别构建编码TNA或TCA的第一多肽链的核苷酸序列;其中AB01-scFv从N端到C端的顺序为VL-linker-VH;编码TNA或TCA的第二多肽链的核苷酸序列为编码AB03的LC的核苷酸序列。
将编码AB01-scFv的核苷酸序列通过编码接头S1的核苷酸序列连接于编码AB03的轻链的核苷酸序列的5’端或3’端,以分别构建编码TLNA或TLCA的第一多肽链的核苷酸序列;其中AB01-scFv从N端到C端的顺序为VL-linker-VH;编码TLNA或TLCA的第二多肽链的核苷酸序列为编码AB03的HC的核苷酸序列。
将编码AB03-scFv的核苷酸序列通过编码接头S1的核苷酸序列连接于编码AB01的重链的核苷酸序列的5’端或3’端,以分别构建编码ANT或ACT的第一多肽链的核苷酸序列;其中AB03-scFv从N端到C端的顺序为VL-linker-VH;编码ANT或ACT的第二多肽链的核苷酸序列为编码AB01的LC的核苷酸序列。
将编码AB03-scFv的核苷酸序列通过编码接头S1的核苷酸序列连接于编码AB01的重链的核苷酸序列的5’端或3’端,以分别构建编码ANT-2或ACT-2的第一多肽链的核苷酸序列;其中AB03-scFv从N端到C端的顺序为VH-linker-VL;编码ANT-2或ACT-2的第二多肽链的核苷酸序列为编码AB01的LC的核苷酸序列。
将编码AB03-scFv的核苷酸序列通过编码接头S1的核苷酸序列连接于编码AB01的轻链的核苷酸序列的5’端或3’端,以分别构建编码ALNT或ALCT的第一多肽链的核苷酸序列;其中AB03-scFv从N端到C端的顺序为VL-linker-VH;编码ALNT或ALCT的第二多肽链的核苷酸序列为编码AB01的HC的核苷酸序列。
将编码AB02-scFv的核苷酸序列通过编码接头S1的核苷酸序列连接于编码AB04的重链的核苷酸序列的3’端,以构建编码SCG的第一多肽链的核苷酸序列;其中AB02-scFv从N端到C端的顺序为VL-linker-VH;编码SCG的第二多肽链的核苷酸序列为编码AB04的LC的核苷酸序列。
将编码AB04-scFv的核苷酸序列通过编码接头S1的核苷酸序列连接于编码AB02的重链的核苷酸序列的3’端,以构建编码GCS的第一多肽链的核苷酸序列;其中AB04-scFv从N端到C端的顺序为VL-linker-VH;编码GCS的第二多肽链的核苷酸序列为编码AB02的LC的核苷酸序列。
将编码上述各第一多肽链或第二多肽链的核苷酸序列与编码鼠IgG-KAPPA信号肽的核苷酸序列连接(氨基酸序列SEQ ID NO:82,核酸序列SEQ ID NO:83),并通过同源重组的方式分别导入pTT5质粒,以构建编码第一多肽链的表达载体及编码第二多肽链的表达载体。最终获得的各重组蛋白的氨基酸序列如表4所示。
表4:各重组蛋白的氨基酸序列
实施例2:抗TNFα/IL-6R双特异性重组蛋白的表达
将生长状态良好、处于对数期的CHO-S细胞,离心并按2E6cells/ml接种200ml,第二天密度长至约4E6 cells/ml。将实施例1中获得的待转染质粒通过0.22μm滤膜除菌过滤,取100μg第一多肽链重组质粒及100μg相应的第二多肽链重组质粒,加入20ml CHOgroComplex Formation Solution(购自MIRUS公司),加入1μg/ml PEIMAX(购自polysciencse公司)1.2ml,震荡混匀三次,静置10min,加入到200ml上述细胞培养物中。将培养物置于37℃、5%CO2摇床培养,24h后加入20ml 10%Sheff-CHO PF ACF(购自KERRY公司),继续培养4天后收获细胞培养物。
实施例3:抗TNFα/IL-6R双特异性重组蛋白的纯化
取实施例2中表达5天的CHO-S细胞培养物,先低速离心分离上清与细胞沉淀;再高速离心,得到澄清的料液。重组抗体通过亲和层析法(Protein A)和离子交换两步法进行纯化,纯化中使用的介质分别是GE公司生产的Mab Select SuRe和Millipore公司生产的Eshmuno CPX。各双特异性重组蛋白表达效率基本一致,均在22-45mg/L区间,且和同等条件抗IL-6R亲本抗体AB03的表达水平保持一致,说明各重组蛋白均可成功表达,且具有较高的表达效率,具体表达水平见表5,其中ANT和TCA的表达效率最高。分离纯化的重组蛋白通过超滤管浓缩并换液到PBS溶液中,SDS-PAGE电泳显示如图2A-2B所示,AB01非还原条带大小约为150kDa,还原后为50kDa(重链)及25kDa(轻链);scFv连接在重链的双特异抗体蛋白非还原条带大小约为200kDa,还原条带大小为75kDa(重链-scFv)及25kDa(轻链);scFv连接在轻链的双特异抗体蛋白非还原条带大小约为200kDa,还原条带大小为50kDa(重链)及50kDa(轻链-scFv)。条带大小符合预期,且无明显聚集降解,说明各双特异性重组蛋白均能高效表达,正确装配。
表5:双特异性重组蛋白的表达水平
抗体名称 | 获得蛋白量 | 表达效率 |
ACT | 4.4mg | 22mg/L |
ANT | 9mg | 45mg/L |
TCA | 9mg | 45mg/L |
TNA | 5.6mg | 28mg/L |
ALCT | 4.2mg | 21mg/L |
ALNT | 5.1mg | 25.5mg/L |
AB03 | 5mg | 25mg/L |
实施例4:抗TNFα/IL-6R双特异性重组蛋白的抗原结合生物学活性检测
本实施例以ELISA的方式分别检测各双特异性重组蛋白与其亲本抗体结合相同抗原的亲和力的差异,以及双特异性重组蛋白同时结合两种抗原的相对亲和力高低,以验证单独封闭一种抗原能力比亲本抗体是否有所下降;是否能同时封闭两种抗原,阻断两种信号通路,在治疗类风湿性关节炎等免疫***疾病时产生协同作用。
4.1双特异性重组蛋白对TNFα的结合活性检测
将重组TNFα蛋白(购自北京义翘神州公司)以50ng/孔加入96孔酶标板(购自thermo公司),4℃包被过夜;次日,弃孔内溶液,用洗涤缓冲液(含有0.05%Tween-20的磷酸盐缓冲液)洗1次,拍干;加入含2%BSA的PBS溶液,100μl/孔,37℃封闭2h后拍干;各双特异性重组蛋白以及亲本抗体AB01和AB03以1000ng/ml起始,做3倍稀释,共11个梯度,100μl/孔;将酶标板放入37℃孵育2h,拍干,洗涤缓冲液洗涤3次;加入HRP偶联Goat Anti-HumanIgG(H+L)溶液,100μl/孔,37℃孵育1h;100μl/孔加入TMB溶液,室温反应约5min;100μl/孔加入终止液,并放入酶标仪,读OD450吸光值。实验数据通过GraphPad prism5拟合曲线并计算EC50。
结果如表6所示,所检测的各重组蛋白结合TNFα的活性EC50与抗TNFα亲本抗体AB01的EC50相当,表明本发明的重组蛋白整体上保持了与亲本抗体同等优良的对TNFα的结合活性。
表6:重组蛋白对TNFα的结合活性
重组蛋白/亲本抗体 | EC50(pM) | 与AB01的比值 |
AB01 | 95.3 | 1 |
ACT | 124.9 | 1.31 |
ANT | 119.6 | 1.25 |
TCA | 194.2 | 2.04 |
TNA | 103.8 | 1.09 |
4.2双特异性重组蛋白对IL-6R的结合活性检测
将重组IL6R-mFC蛋白(获得自科伦研究院)以200ng/孔加入96孔酶标板,4℃包被过夜;次日,弃孔内溶液,用洗涤缓冲液洗1次,拍干;加入含2%BSA的PBS溶液,100μl/孔,37℃封闭2h后拍干;双特异性重组蛋白、抗IL-6R亲本抗体AB03及AB04以4000ng/ml起始,做4倍稀释,共11个梯度,100μl/孔;将酶标板放入37℃孵育2h,拍干,洗涤缓冲液洗涤3次;加入HRP偶联Goat Anti-Human IgG(H+L)溶液,37℃孵育1h;加入TMB溶液,室温反应约5min;加入终止液,并放入酶标仪,读OD450吸光值。实验数据通过GraphPad prism5拟合曲线并计算EC50。
结果如表7所示,所检测的各重组蛋白结合IL-6R的EC50与抗IL-6R亲本抗体AB03的EC50相当,表明本发明的重组蛋白整体上保持了与亲本抗体同等优良的对IL-6R的结合活性。
表7:重组蛋白对IL-6R的结合活性
重组蛋白/亲本抗体 | EC50(pM) | 与AB03的比值 |
AB03 | 52.76 | 1 |
ACT | 124.1 | 2.35 |
ANT | 59.3 | 1.12 |
TCA | 80.9 | 1.53 |
TNA | 60.4 | 1.14 |
4.3双特异性重组蛋白同时结合TNFα及IL-6R的活性检测
将重组TNFα蛋白以50ng/孔,4℃过夜包被于96孔酶标板;次日,弃孔内溶液,用洗涤缓冲液(含有0.05%Tween-20的磷酸盐缓冲液)洗1次,拍干;加入含2%BSA的PBS溶液,100μl/孔,37℃封闭2h后拍干;双特异性重组蛋白以2000ng/ml起始,做3倍稀释,共11个梯度,100μl/孔;将酶标板放入37℃孵育2h,拍干,洗涤缓冲液洗涤3次;每孔加IL6R-mFc抗原(科伦)0.8μg/ml,100μl/孔,37℃孵育2h,拍干,洗涤缓冲液洗涤3次;加入HRP偶联GoatAnti-Mouse FC(购自Thermo公司)溶液,37℃孵育1h;加入TMB溶液,室温反应约5min;加入终止液,并放入酶标仪,读OD450吸光值。实验数据通过GraphPad prism5拟合曲线并计算EC50。
结果如表8所示,各双特异性重组蛋白均能同时结合TNFα及IL-6R两种抗原,其中,ACT和ANT同时结合TNFα及IL-6R两种抗原活性最高,ALCT及ALNT结合活性稍弱于其他重组蛋白,但EC50都在pM级,上述结果表明本发明的双特异性重组蛋白结合一种抗原后,不影响第二种抗原结合,能同时高效的结合两种抗原,保留了与亲本抗体同等优良的结合活性,因此其可以通过同时中和在类风湿性关节炎等疾病中的起关键作用的TNFα及IL-6R炎症因子,以同时抑制两条信号通路,从而特别适用于与过度的TNFα和/或IL-6活性相关的疾病的治疗。
表8:双特异性重组蛋白同时结合TNFα及IL-6R的活性
抗体名称 | EC50(pM) |
ACT | 86.8 |
ANT | 104.6 |
TCA | 112.3 |
TNA | 161.9 |
ALCT | 250.0 |
ALNT | 284.3 |
实施例5:双特异性重组蛋白在细胞水平上对抗原的结合活性检测
本实施例中,通过流式细胞仪检测双特异性重组蛋白是否能正常结合细胞表面抗原。
5.1双特异性重组蛋白对细胞表面TNFα的结合活性检测
取状态良好的细胞表面表达TNFα的CHO细胞(所述细胞通过将TNFα表达载体导入CHO细胞构建获得),离心,PBS洗涤一次。用含0.5%BSA的PBS重悬,按50μl/孔,3E6 cells/孔加入96孔板;各双特异性重组蛋白、抗TNFα亲本抗体AB01及AB02以1μM起始,做3倍稀释,共10个梯度,50μl/孔加入含细胞的96孔板,混匀,4℃孵育1小时;PBS洗涤1次,加入50μlFITC anti-humanIgG1抗体(购自Biolegend公司),4℃孵育30分钟;PBS洗涤3次后用流式细胞仪(beckmanCyto FLEX)进行检测。
结果显示,经检测的各重组蛋白结合细胞表面TNFα的活性至少与抗TNFα亲本抗体相当,表明本发明的重组蛋白至少保持了与亲本抗体同等优良的对细胞表面TNFα的结合活性。特别地,ANT在细胞水平上结合细胞表面TNFα的EC50值甚至低于亲本抗体(如表9所示),显示出更优的对TNFα的结合活性。
表9:重组蛋白结合细胞表面TNFα活性
重组蛋白/亲本抗体 | EC50(nM) | 与AB01的比值 |
AB01 | 4.37 | 1 |
ANT | 3.06 | 0.70 |
5.2双特异性重组蛋白对细胞表面IL-6R的结合活性检测
取状态良好的细胞表面表达IL-6R的CHO细胞(所述细胞通过将IL-6R表达载体导入CHO细胞构建获得),离心,PBS洗涤一次。用含0.5%BSA的PBS重悬,按50μl/孔,3E6cells/孔加入96孔板;双特异性重组蛋白、抗IL-6R亲本抗体AB03及AB04以1μM起始,做3倍稀释,共10个梯度,50μl/孔加入含细胞的96孔板,混匀,4℃孵育1小时;PBS洗涤1次,加入50μl FITCanti-humanIgG1抗体(购自Biolegend公司),4℃孵育30分钟;PBS洗涤3次后用流式细胞仪(beckmanCyto FLEX)进行检测。
结果显示,经检测的各重组蛋白结合细胞表面IL-6R的活性至少与抗IL-6R亲本抗体相当,表明本发明的重组蛋白至少保持了与亲本抗体同等优良的对细胞表面IL-6R的结合活性。特别地,ANT在细胞水平上结合细胞表面IL-6R的EC50值甚至低于亲本抗体(如表10所示),显示出更优的对IL-6R的结合活性。
表10:重组蛋白结合细胞表面IL-6R活性
抗体名称 | EC50(nM) | 与AB03的比值 |
AB03 | 6.72 | 1 |
ANT | 4.64 | 0.69 |
实施例6:热变性温度检测
将双特异性重组蛋白及亲本抗体AB01用PBS溶液稀释至0.7mg/ml,将Orange Protein Gel Stain(thermo S6651)用蒸馏水稀释至40×。取0.2ml离心管,依次加入稀释样品12.5μl,稀释染料4.2μl,蒸馏水8.3μl。混匀后放入荧光定量PCR仪(thermo7500),设置反应参数25℃ 3min,以1%速率上升至95℃,95℃ 2min。
结果如表11所示,以AB01为第一抗体的ACT、ANT、ALCT及ALNT热稳定性优于AB03为第一抗体的TCA、TNA,与亲本抗体AB01及AB03的TM值更为相近。
表11:双特异性重组蛋白的热变性温度
实施例7:双特异性重组蛋白的细胞生物学活性实验
本实施例为验证双特异性重组蛋白功能活性,通过细胞水平实验检测双特异性重组蛋白对TNFα及IL-6R抑制活性。
7.1在L929细胞中中和TNFα诱导的细胞毒性
将重组人TNFα诱导加入L929细胞中孵育18-24h,以诱导TNFα对L929细胞的细胞毒性;加入双特异性重组蛋白中和TNFα后,细胞毒性减弱至消除。
取状态良好的L929细胞,用RPMI1640+2%FBS重悬,并调至密度为3×105cells/ml,100μl/孔铺入96孔板,37℃培养箱过夜;向RPMI1640+2%FBS中加入终浓度为0.4μg/ml的Actinomycin D,加入终浓度为6ng/ml的重组TNFα蛋白;将双特异性重组蛋白及抗TNFα亲本抗体AB01调至2μg/ml,并进行3倍连续稀释,共稀释8个梯度,L929细胞每孔加入100μl,37℃培养箱孵育48h;加入20μl CCK8试剂检测细胞活力,反应16-20小时读数。使用GrapadPrism5计算抗体中和TNFα的EC50值。
结果如表12所示,双特异性重组蛋白中和TNFα的效果与抗TNFα亲本抗体基本在同一水平,ANT和ACT活性优于ALNT和ALCT,上述结果表明本发明的重组蛋白保持了亲本抗体的生物学活性。
表12:重组蛋白中和TNFα诱导的L929细胞毒性
7.2在U266细胞中抑制IL6诱导的细胞增殖
培养U266细胞时,加入适当浓度重组IL-6蛋白,能刺激细胞生长加速;加入双特异性重组蛋白封闭细胞表面IL-6R后,细胞生长将减慢。
取状态良好的U266细胞,用RPMI1640+5%FBS重悬,调整浓度至8×104cells/ml,100μl/孔铺入96孔板;向RPMI1640+5%FBS中加入终浓度为10ng/ml的重组IL6;将双特异性重组蛋白及抗IL-6R亲本抗体AB03调至200μg/ml,并进行3倍连续稀释,共稀释8个梯度,U266细胞每孔加入100μl,37℃培养箱孵育48h;加入20μl CCK8试剂检测细胞活力,反应4小时读数。使用GraphpadPrism5计算抗体中和IL-6R的IC50值。
由于不能达到上下平台,无法推算出准确IC50值。由图3中各个重组蛋白与亲本抗体趋势对比可以看出,四种双特异性重组蛋白封闭IL-6R和抗IL-6R的能力与亲本抗体基本一致。上述结果表明本发明的重组蛋白至少保持了亲本抗体的生物学活性。
实施例8:双特异性重组蛋白的体内代谢实验
实验采用25只雄性SD大鼠,随机分为7组。分别经皮下注射给予2.5mg/kg的ANT和亲本抗体AB01。于给药前、给药后1h、4h、8h、Day1、Day3、Day5、Day8、Day11、Day15、Day22、Day29、Day36尾静脉采血,采集血样经1000-3000×g 4℃离心10min,收集上清,置于-80℃条件下保存;通过ELISA法检测血药浓度,并拟合药时曲线,计算药代动力学参数,评价双特异性重组蛋白在大鼠体内的药代动力学行为。
结果如表13所示,由于检测线未达到下平台,无法算出准确半衰期,但由AUC(药物暴露量)可知,ANT在大鼠体内代谢水平和亲本抗体AB01基本一致。
表13:双特异性重组蛋白的大鼠体内代谢结果
实施例9:双特异性重组蛋白ADCC活性的检测
细胞处理:取Jurkat-NFAT/CD16a细胞、CHO-S-TNFα细胞,CHO-S-IL6R细胞细胞(所有细胞均由四川科伦博泰生物医药股份有限公司制备),离心,用1640+1%FBS培养基重悬,计数后分别稀释调整细胞至2×106/ml、0.5×106/ml、0.5×106/ml、0.5×106/ml。靶细胞铺板:CHO-S-TNFα细胞50μl/孔,CHO-S-IL6R细胞50ul/孔,每孔总计5×104个细胞。效应细胞铺板:Jurkat-NFAT/CD16a细胞50μl/孔,每孔总计1×105个细胞。加入检测抗体:稀释AB01、ACT、ANT以及IgG对照抗体至200μg/ml,依次2倍稀释,共11个浓度点。向孔中加入50μl稀释后抗体(初始终浓度50μg/ml),最后一孔加入检测Buffer。检测:细胞孵育5小时后取出,检测区每孔加入40μl One-glo检测试剂(Promega,Cat:E6120),酶标仪上机检测。
表14:双特异性重组蛋白ADCC活性的检测
重组蛋白/亲本抗体 | EC50(nM) | 与AB01的比值 |
AB01 | 2.5 | 1 |
ACT | 18.9 | 7.56 |
ANT | 3.1 | 1.24 |
IgG对照 | N/A | N/A |
结果如表14所示。结果显示,ANT分子的ADCC的活性显著优于ACT,与AB01活性相当,这一结果表明ANT分子保留了亲本抗体完整的ADCC活性。
实施例10:双特异性重组蛋白C1q活性的检测
按下表用包被液CBS(碳酸盐缓冲溶液)包板,100μl每孔,4℃过夜。300μL PBS清洗一次,加入100μL PBS(2%BSA),37℃封闭2小时。用PBS(2%BSA)稀释C1q(PROSPEC,货号:PRO-554)至5μg/ml,100μL/孔,37℃孵育2小时。300μL PBST清洗3次,用PBS(2%BSA)稀释1:300羊抗C1q-HRP(Abcam,货号Ab46191),加入100μL对应的孔中,37℃孵育1小时。300μLPBST清洗5次,加入100μL TMB对应的孔中,室温显色3分钟,加入50μL 1M H2SO4终止,酶标仪450nm读数。
表15:双特异性重组蛋白C1q活性的检测
重组蛋白/亲本抗体 | EC50(nM) | 与AB01的比值 |
AB01 | 7.2 | 1 |
AB03 | 7.6 | -- |
ACT | 6.1 | 0.85 |
ANT | 5.3 | 0.74 |
IgG对照 | N/A | N/A |
结果如表15所示。结果显示,ANT分子的C1q的结合活性略强于ACT,ANT和ACT的结合活性均略优于亲本抗体AB01、AB03,这一结果表明ANT和ACT保留了亲本抗体完整的CDC活性。
实施例11:双特异性重组蛋白在恒河猴关节炎模型中的体内活性评价
本实施例评价本发明的双特异性重组蛋白对牛II型胶原诱导的恒河猴关节炎疾病进程的影响。具体而言,将重组蛋白以每周1次的频率静脉注射给关节炎造模成功的恒河猴,每周1次测定动物体重和采集血样,进而计算重组蛋白对恒河猴关节炎的治疗药效(抗炎疗效)。
受试药物:
药物名称、来源、配置方法:ANT,根据动物体重,按照5mg/kg,1ml/kg的剂量,稀释母液得到处理品溶液。
实验动物及饲养:
恒河猴(四川横竖生物科技股份有限公司,生产许可证号:SCXK(川)2014-029);
动物房(四川抗菌素研究所,实验动物试用许可证号:SYXK(川)2014-021)。
造模试剂:
牛II型胶原(免疫接种等级胶原)(Chondrex),弗氏完全佐剂(Sigma)。
关节炎模型的造模方法:
牛II型胶原溶解于0.1M乙酸溶液中,然后加入等体积的弗氏完全佐剂,低温高速搅拌形成均匀稳定的终浓度为2mg/ml的乳剂。在4只恒河猴背部皮下注射乳剂10个点,0.2ml/点,即胶原注射量为4mg。胶原注射当天记为D1。第1次胶原注射后2周(第15天,D15)按上述方法完成第2次胶原注射。期间每周1次称重和血清收集。根据表16监测评分指标,造模成功的动物会出现体重降低、关节炎肿胀、CRP水平上升和贫血等多种症状,造模结果如表17,得到造模成功的恒河猴3只。
表16:恒河猴关节炎疾病进程的临床评分标准
在关节炎造模成功的动物中,16063号动物发病迅速,未能及时给予ANT治疗,在D22天死亡。对于其他两只造模成功的动物,根据其关节炎发病的进程,16066号动物选择在其关节炎病程发展的早期给药,从D28开始给药;16068号动物选择在其关节炎病程发展的晚期给药,从D42开始给药。对恒河猴给予ANT重组蛋白干预的方案为:给予5mg/kg的ANT,给药体积为1ml/kg,给药途径为单次静脉注射,给药频率为每周1次,共计4次。
表17:恒河猴造模和给药情况
每周1次测量动物体重和采集血样,通过观察动物前足、后足关节肿胀情况并予以临床评分,关节炎评分标准见表16,以及分析血清中CRP(C反应蛋白)水平和血液学RBC(红细胞),HGB(血红蛋白),HCT(红细胞压积)指标来评价ANT的治疗药效。每天观察记录动物死亡情况。恒河猴造模和给药情况见表17、图4。体重、关节炎评分、CRP和血液学指标变化情况见图5-图10。
结果显示,16067号动物造模未成功,所有监测指标在胶原注射后很快恢复正常值。而在关节炎造模成功的动物中,16063号动物发病迅速,未能及时给予发明ANT治疗,最终在D22天死亡;16066号动物在疾病早期及时给予发明ANT治疗(D28天首次给药,每周1次,给药4次),给药后关节炎肿胀缓解,体重逐渐恢复,CRP水平回归正常水平,贫血症状消失;16068号动物在疾病晚期给予发明ANT治疗(D42天首次给药,每周1次,给药5次),虽然给药后关节炎肿胀未能明显缓解、体重未明显恢复、以及血液学指标未回归正常水平,但CRP水平明显降低,而且动物未死亡。
以上结果表明在恒河猴关节炎模型中,本发明的ANT具有良好的抗炎药效。与亲本抗体相比,本发明双特异性重组蛋白具有更优的治疗活性。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人员将理解:根据已经公布的所有教导,可以对细节进行各种修改和变动,并且这些改变均在本发明的保护范围之内。本发明的全部分为由所附权利要求及其任何等同物给出。
序列表
<110> 四川科伦博泰生物医药股份有限公司
<120> 双特异性重组蛋白
<130> IDC180166
<160> 101
<170> PatentIn version 3.5
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<211> 107
<212> PRT
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<220>
<223> AB01 VL
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
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Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
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Gln Gly Ile Arg Asn Tyr
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Ala Ala Ser
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<210> 4
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Gln Arg Tyr Asn Arg Ala Pro Tyr Thr
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 6
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<212> PRT
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<223> AB01 HCDR1
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Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 7
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> AB01 HCDR2
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Ala Ile Thr Trp Asn Ser Gly His Ile Asp
1 5 10
<210> 8
<211> 14
<212> PRT
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Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr
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Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
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Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
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Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
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Gln Ser Val Tyr Ser Tyr
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<223> AB02 LCDR2
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Asp Ala Ser
1
<210> 12
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Gln Gln Arg Ser Asn Trp Pro Pro Phe Thr
1 5 10
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<212> PRT
<213> 人工序列
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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 His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Met Ser Tyr Asp Gly Ser Asn Lys Lys Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Ile Ala Ala Gly Gly Asn Tyr Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 14
<211> 8
<212> PRT
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Gly Phe Thr Phe Ser Ser Tyr Ala
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<210> 15
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Met Ser Tyr Asp Gly Ser Asn Lys
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<210> 16
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<212> PRT
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Ala Arg Asp Arg Gly Ile Ala Ala Gly Gly Asn Tyr Tyr Tyr Tyr Gly
1 5 10 15
Met Asp Val
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
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Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
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Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
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Gln Asp Ile Ser Ser Tyr
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<212> PRT
<213> 人工序列
<220>
<223> AB03 LCDR2
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Tyr Thr Ser
1
<210> 20
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> AB03 LCDR3
<400> 20
Gln Gln Gly Asn Thr Leu Pro Tyr Thr
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<210> 21
<211> 119
<212> PRT
<213> 人工序列
<220>
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<400> 21
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser
115
<210> 22
<211> 9
<212> PRT
<213> 人工序列
<220>
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Gly Tyr Ser Ile Thr Ser Asp His Ala
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<210> 23
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<212> PRT
<213> 人工序列
<220>
<223> AB03 HCDR2
<400> 23
Ile Ser Tyr Ser Gly Ile Thr
1 5
<210> 24
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> AB03 HCDR3
<400> 24
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr
1 5 10
<210> 25
<211> 107
<212> PRT
<213> 人工序列
<220>
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<400> 25
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
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Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
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Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 26
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<212> PRT
<213> 人工序列
<220>
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<400> 26
Gln Gly Ile Ser Ser Trp
1 5
<210> 27
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> AB04 LCDR2
<400> 27
Gly Ala Ser
1
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> AB04 LCDR3
<400> 28
Gln Gln Ala Asn Ser Phe Pro Tyr Thr
1 5
<210> 29
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> AB04 VH
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe
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Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
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Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser
115
<210> 30
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> AB04 HCDR1
<400> 30
Arg Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 31
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> AB04 HCDR2
<400> 31
Ile Ser Trp Asn Ser Gly Arg Ile
1 5
<210> 32
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> AB04 HCDR3
<400> 32
Ala Lys Gly Arg Asp Ser Phe Asp Ile
1 5
<210> 33
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 肽接头
<400> 33
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> 34
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 肽接头
<400> 34
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 35
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽接头
<400> 35
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 36
<211> 712
<212> PRT
<213> 人工序列
<220>
<223> TNA第一多肽链
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser
165 170 175
Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro
260 265 270
Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser
275 280 285
Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp Val Arg Gln Pro
290 295 300
Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ile
305 310 315 320
Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Leu Arg Asp
325 330 335
Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala
340 345 350
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala Arg Thr Thr Ala
355 360 365
Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser
370 375 380
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
385 390 395 400
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
405 410 415
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
420 425 430
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
435 440 445
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
450 455 460
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
465 470 475 480
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
485 490 495
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
500 505 510
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
515 520 525
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
530 535 540
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
545 550 555 560
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
565 570 575
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
580 585 590
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
595 600 605
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
610 615 620
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
625 630 635 640
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
645 650 655
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
660 665 670
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
675 680 685
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
690 695 700
Ser Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 37
<211> 2139
<212> DNA
<213> 人工序列
<220>
<223> TNA第一多肽链编码序列
<400> 37
gatattcaga tgactcagtc cccttctagt ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca gggccagcca gggcatccgg aactacctgg cttggtatca gcagaagcca 120
ggcaaggccc ccaagctgct gatctacgcc gcttccaccc tgcaaagcgg agtgccatct 180
cggttctccg gcagcggctc tggcacagac tttaccctga caatctccag cctgcagcct 240
gaggatgtgg ctacctacta ttgccagagg tacaatcggg ccccatatac cttcggctgc 300
ggcacaaagg tggagatcaa gggcggcggc ggctctggcg gcggcggctc tggtggcggc 360
ggcagtggcg gcggcggctc tgaagtccag ctggtcgaaa gcgggggggg gctggtgcag 420
cctggcaggt ctctgcggct gtcctgcgcc gctagcggct tcacctttga cgattacgcc 480
atgcactggg tgagacaggc tccaggcaag tgcctggagt gggtgagcgc catcacctgg 540
aactctggcc atatcgacta cgctgatagc gtggagggca gattcacaat ctctagggac 600
aacgccaaga actccctgta tctgcaaatg aatagcctga gggccgagga taccgccgtg 660
tactattgcg ccaaggtgtc ttacctgagc accgcttcca gcctggacta ttggggccag 720
ggcaccctgg tgacagtgtc ttccggagga ggaggatccg gaggaggagg aagcggtggc 780
ggcggctctc aggtgcagct gcaggagagc ggacctggac tggtgagacc aagccagacc 840
ctgtctctga cctgcacagt gtctggctac tccatcacaa gcgatcacgc ttggtcttgg 900
gtgagacagc cacctggaag gggactggag tggatcggct acatcagcta ttctggcatc 960
accacatata acccctctct gaagtccagg gtgaccatgc tgcgggacac atccaagaat 1020
cagttcagcc tgaggctgtc cagcgtgacc gctgctgata cagccgtgta ctattgtgcc 1080
aggtccctgg ctcggaccac agccatggac tactggggac agggatccct ggtgaccgtg 1140
tcttccgcct ctacaaaggg cccctccgtg tttccactgg ctccctcctc taagagcacc 1200
tctggcggca cagccgctct gggctgtctg gtgaaggatt acttcccaga gcccgtgaca 1260
gtgagctgga actctggcgc cctgacctct ggagtgcaca catttccagc tgtgctgcag 1320
tccagcggcc tgtactccct gtcttccgtg gtgaccgtgc ccagctcttc cctgggcacc 1380
cagacatata tctgcaacgt gaaccacaag ccatccaata caaaggtgga caagaaggtg 1440
gagcccaagt cctgtgataa gacccataca tgcccccctt gtcctgctcc agagctgctg 1500
ggaggacctt ccgtgttcct gtttccaccc aaacctaagg acaccctgat gatcagcagg 1560
acccccgagg tgacatgcgt ggtggtggac gtgtctcacg aggatcccga ggtgaagttc 1620
aactggtatg tcgatggcgt ggaggtgcat aatgctaaga ccaagcctcg ggaggagcag 1680
tacaactcca cctatagagt ggtgagcgtg ctgacagtgc tgcatcagga ctggctgaac 1740
ggcaaggagt ataagtgcaa ggtgtccaat aaggccctgc ccgctcccat cgagaagacc 1800
atcagcaagg ccaagggcca gccaagggag ccacaggtgt acacactgcc tccatcccgg 1860
gacgagctga ccaagaacca ggtgagcctg acatgtctgg tgaagggctt ctatcctagc 1920
gatatcgctg tggagtggga gtccaatggc cagccagaga acaattacaa gaccacaccc 1980
cctgtgctgg actccgatgg cagcttcttt ctgtattcta agctgaccgt ggataagtcc 2040
cggtggcagc agggcaacgt gttctcctgt agcgtgatgc acgaagccct gcataatcac 2100
tatactcaga aaagtctgtc actgtcacct ggtaaatga 2139
<210> 38
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> TCA第一多肽链
<400> 38
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
450 455 460
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
465 470 475 480
Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala Trp Tyr Gln Gln
485 490 495
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu
500 505 510
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
515 520 525
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr
530 535 540
Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr Thr Phe Gly Cys Gly Thr
545 550 555 560
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
565 570 575
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
580 585 590
Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala
595 600 605
Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln
610 615 620
Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser
625 630 635 640
Gly His Ile Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser
645 650 655
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
660 665 670
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser
675 680 685
Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
690 695 700
Ser Ser
705
<210> 39
<211> 2121
<212> DNA
<213> 人工序列
<220>
<223> TCA第一多肽链编码序列
<400> 39
caggtgcagc tgcaggagag cggacctgga ctggtgagac caagccagac cctgtctctg 60
acctgcacag tgtctggcta ctccatcaca agcgatcacg cttggtcttg ggtgagacag 120
ccacctggaa ggggactgga gtggatcggc tacatcagct attctggcat caccacatat 180
aacccctctc tgaagtccag ggtgaccatg ctgcgggaca catccaagaa tcagttcagc 240
ctgaggctgt ccagcgtgac cgctgctgat acagccgtgt actattgtgc caggtccctg 300
gctcggacca cagccatgga ctactgggga cagggatccc tggtgaccgt gtcttccgcc 360
tctacaaagg gcccctccgt gtttccactg gctccctcct ctaagagcac ctctggcggc 420
acagccgctc tgggctgtct ggtgaaggat tacttcccag agcccgtgac agtgagctgg 480
aactctggcg ccctgacctc tggagtgcac acatttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgaccgtg cccagctctt ccctgggcac ccagacatat 600
atctgcaacg tgaaccacaa gccatccaat acaaaggtgg acaagaaggt ggagcccaag 660
tcctgtgata agacccatac atgcccccct tgtcctgctc cagagctgct gggaggacct 720
tccgtgttcc tgtttccacc caaacctaag gacaccctga tgatcagcag gacccccgag 780
gtgacatgcg tggtggtgga cgtgtctcac gaggatcccg aggtgaagtt caactggtat 840
gtcgatggcg tggaggtgca taatgctaag accaagcctc gggaggagca gtacaactcc 900
acctatagag tggtgagcgt gctgacagtg ctgcatcagg actggctgaa cggcaaggag 960
tataagtgca aggtgtccaa taaggccctg cccgctccca tcgagaagac catcagcaag 1020
gccaagggcc agccaaggga gccacaggtg tacacactgc ctccatcccg ggacgagctg 1080
accaagaacc aggtgagcct gacatgtctg gtgaagggct tctatcctag cgatatcgct 1140
gtggagtggg agtccaatgg ccagccagag aacaattaca agaccacacc ccctgtgctg 1200
gactccgatg gcagcttctt tctgtattct aagctgaccg tggataagtc ccggtggcag 1260
cagggcaacg tgttctcctg tagcgtgatg cacgaagccc tgcataatca ctatactcag 1320
aaaagtctgt cactgtcacc tggtggagga ggaggatccg gaggaggagg aagcgatatt 1380
cagatgactc agtccccttc tagtctgtcc gcctctgtgg gcgacagagt gaccatcaca 1440
tgcagggcca gccagggcat ccggaactac ctggcttggt atcagcagaa gccaggcaag 1500
gcccccaagc tgctgatcta cgccgcttcc accctgcaaa gcggagtgcc atctcggttc 1560
tccggcagcg gctctggcac agactttacc ctgacaatct ccagcctgca gcctgaggat 1620
gtggctacct actattgcca gaggtacaat cgggccccat ataccttcgg ctgcggcaca 1680
aaggtggaga tcaagggcgg cggcggctct ggcggcggcg gctctggtgg cggcggcagt 1740
ggcggcggcg gctctgaagt ccagctggtc gaaagcgggg gggggctggt gcagcctggc 1800
aggtctctgc ggctgtcctg cgccgctagc ggcttcacct ttgacgatta cgccatgcac 1860
tgggtgagac aggctccagg caagtgcctg gagtgggtga gcgccatcac ctggaactct 1920
ggccatatcg actacgctga tagcgtggag ggcagattca caatctctag ggacaacgcc 1980
aagaactccc tgtatctgca aatgaatagc ctgagggccg aggataccgc cgtgtactat 2040
tgcgccaagg tgtcttacct gagcaccgct tccagcctgg actattgggg ccagggcacc 2100
ctggtgacag tgtcttcctg a 2121
<210> 40
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> TNA与TCA的scFv
<400> 40
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser
165 170 175
Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser
245
<210> 41
<211> 744
<212> DNA
<213> 人工序列
<220>
<223> TNA与TCA的scFv的编码序列
<400> 41
gatattcaga tgactcagtc cccttctagt ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca gggccagcca gggcatccgg aactacctgg cttggtatca gcagaagcca 120
ggcaaggccc ccaagctgct gatctacgcc gcttccaccc tgcaaagcgg agtgccatct 180
cggttctccg gcagcggctc tggcacagac tttaccctga caatctccag cctgcagcct 240
gaggatgtgg ctacctacta ttgccagagg tacaatcggg ccccatatac cttcggctgc 300
ggcacaaagg tggagatcaa gggcggcggc ggctctggcg gcggcggctc tggtggcggc 360
ggcagtggcg gcggcggctc tgaagtccag ctggtcgaaa gcgggggggg gctggtgcag 420
cctggcaggt ctctgcggct gtcctgcgcc gctagcggct tcacctttga cgattacgcc 480
atgcactggg tgagacaggc tccaggcaag tgcctggagt gggtgagcgc catcacctgg 540
aactctggcc atatcgacta cgctgatagc gtggagggca gattcacaat ctctagggac 600
aacgccaaga actccctgta tctgcaaatg aatagcctga gggccgagga taccgccgtg 660
tactattgcg ccaaggtgtc ttacctgagc accgcttcca gcctggacta ttggggccag 720
ggcaccctgg tgacagtgtc ttcc 744
<210> 42
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> TNA与TCA第二多肽链
<400> 42
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 43
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> TNA与TCA第二多肽链的编码序列
<400> 43
gacatccaga tgacccagtc tccaagctct ctgtccgcta gcgtgggcga cagagtgacc 60
atcacatgcc gcgcctccca ggacatctcc agctacctga actggtatca gcagaagcca 120
ggcaaggctc ccaagctgct gatctactat acctccaggc tgcatagcgg agtgccatct 180
cggttctctg gatccggaag cggaaccgac ttcaccttta caatctcttc cctgcagccc 240
gaggacatcg ccacctacta ttgtcagcag ggcaataccc tgccttatac atttggccag 300
ggcaccaagg tggagatcaa gagaacagtg gccgctccct ccgtgttcat ctttccccct 360
tccgacgagc agctgaagtc cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420
cccagggagg ctaaggtgca gtggaaggtg gataacgccc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ctgattacga gaagcacaag gtgtatgcct gtgaagtcac tcatcagggt 600
ctgtccagcc cagtcactaa gtcattcaac cgtggcgaat gctga 645
<210> 44
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> TLNA第一多肽链
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser
165 170 175
Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
260 265 270
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
275 280 285
Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
290 295 300
Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly
305 310 315 320
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe
325 330 335
Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln
340 345 350
Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
355 360 365
Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser
370 375 380
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
385 390 395 400
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
405 410 415
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
420 425 430
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
435 440 445
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
450 455 460
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
465 470 475
<210> 45
<211> 1434
<212> DNA
<213> 人工序列
<220>
<223> TLNA第一多肽链编码序列
<400> 45
gatattcaga tgactcagtc cccttctagt ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca gggccagcca gggcatccgg aactacctgg cttggtatca gcagaagcca 120
ggcaaggccc ccaagctgct gatctacgcc gcttccaccc tgcaaagcgg agtgccatct 180
cggttctccg gcagcggctc tggcacagac tttaccctga caatctccag cctgcagcct 240
gaggatgtgg ctacctacta ttgccagagg tacaatcggg ccccatatac cttcggctgc 300
ggcacaaagg tggagatcaa gggcggcggc ggctctggcg gcggcggctc tggtggcggc 360
ggcagtggcg gcggcggctc tgaagtccag ctggtcgaaa gcgggggggg gctggtgcag 420
cctggcaggt ctctgcggct gtcctgcgcc gctagcggct tcacctttga cgattacgcc 480
atgcactggg tgagacaggc tccaggcaag tgcctggagt gggtgagcgc catcacctgg 540
aactctggcc atatcgacta cgctgatagc gtggagggca gattcacaat ctctagggac 600
aacgccaaga actccctgta tctgcaaatg aatagcctga gggccgagga taccgccgtg 660
tactattgcg ccaaggtgtc ttacctgagc accgcttcca gcctggacta ttggggccag 720
ggcaccctgg tgacagtgtc ttccggagga ggaggatccg gaggaggagg aagcggtggc 780
ggcggctctg acatccagat gacccagtct ccaagctctc tgtccgctag cgtgggcgac 840
agagtgacca tcacatgccg cgcctcccag gacatctcca gctacctgaa ctggtatcag 900
cagaagccag gcaaggctcc caagctgctg atctactata cctccaggct gcatagcgga 960
gtgccatctc ggttctctgg atccggaagc ggaaccgact tcacctttac aatctcttcc 1020
ctgcagcccg aggacatcgc cacctactat tgtcagcagg gcaataccct gccttataca 1080
tttggccagg gcaccaaggt ggagatcaag agaacagtgg ccgctccctc cgtgttcatc 1140
tttccccctt ccgacgagca gctgaagtcc ggcaccgcca gcgtggtgtg cctgctgaac 1200
aacttctacc ccagggaggc taaggtgcag tggaaggtgg ataacgccct gcagtccggc 1260
aatagccagg agtctgtgac cgagcaggac tccaaggata gcacatattc tctgtcttcc 1320
accctgacac tgtctaaggc tgattacgag aagcacaagg tgtatgcctg tgaagtcact 1380
catcagggtc tgtccagccc agtcactaag tcattcaacc gtggcgaatg ctga 1434
<210> 46
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> TLCA第一多肽链
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
225 230 235 240
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
245 250 255
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
260 265 270
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
275 280 285
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
290 295 300
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
305 310 315 320
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
325 330 335
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
340 345 350
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser
355 360 365
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala
370 375 380
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser
385 390 395 400
Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu
405 410 415
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
420 425 430
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
435 440 445
Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln
450 455 460
Gly Thr Leu Val Thr Val Ser Ser
465 470
<210> 47
<211> 1419
<212> DNA
<213> 人工序列
<220>
<223> TLCA第一多肽链编码序列
<400> 47
gacatccaga tgacccagtc tccaagctct ctgtccgcta gcgtgggcga cagagtgacc 60
atcacatgcc gcgcctccca ggacatctcc agctacctga actggtatca gcagaagcca 120
ggcaaggctc ccaagctgct gatctactat acctccaggc tgcatagcgg agtgccatct 180
cggttctctg gatccggaag cggaaccgac ttcaccttta caatctcttc cctgcagccc 240
gaggacatcg ccacctacta ttgtcagcag ggcaataccc tgccttatac atttggccag 300
ggcaccaagg tggagatcaa gagaacagtg gccgctccct ccgtgttcat ctttccccct 360
tccgacgagc agctgaagtc cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420
cccagggagg ctaaggtgca gtggaaggtg gataacgccc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ctgattacga gaagcacaag gtgtatgcct gtgaagtcac tcatcagggt 600
ctgtccagcc cagtcactaa gtcattcaac cgtggcgaat gcggaggagg aggaagcggt 660
ggcggcggct ctgatattca gatgactcag tccccttcta gtctgtccgc ctctgtgggc 720
gacagagtga ccatcacatg cagggccagc cagggcatcc ggaactacct ggcttggtat 780
cagcagaagc caggcaaggc ccccaagctg ctgatctacg ccgcttccac cctgcaaagc 840
ggagtgccat ctcggttctc cggcagcggc tctggcacag actttaccct gacaatctcc 900
agcctgcagc ctgaggatgt ggctacctac tattgccaga ggtacaatcg ggccccatat 960
accttcggct gcggcacaaa ggtggagatc aagggcggcg gcggctctgg cggcggcggc 1020
tctggtggcg gcggcagtgg cggcggcggc tctgaagtcc agctggtcga aagcgggggg 1080
gggctggtgc agcctggcag gtctctgcgg ctgtcctgcg ccgctagcgg cttcaccttt 1140
gacgattacg ccatgcactg ggtgagacag gctccaggca agtgcctgga gtgggtgagc 1200
gccatcacct ggaactctgg ccatatcgac tacgctgata gcgtggaggg cagattcaca 1260
atctctaggg acaacgccaa gaactccctg tatctgcaaa tgaatagcct gagggccgag 1320
gataccgccg tgtactattg cgccaaggtg tcttacctga gcaccgcttc cagcctggac 1380
tattggggcc agggcaccct ggtgacagtg tcttcctga 1419
<210> 48
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> TLNA与TLCA第二多肽链
<400> 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 49
<211> 1347
<212> DNA
<213> 人工序列
<220>
<223> TLNA与TLCA第二多肽链编码序列
<400> 49
caggtgcagc tgcaggagag cggacctgga ctggtgagac caagccagac cctgtctctg 60
acctgcacag tgtctggcta ctccatcaca agcgatcacg cttggtcttg ggtgagacag 120
ccacctggaa ggggactgga gtggatcggc tacatcagct attctggcat caccacatat 180
aacccctctc tgaagtccag ggtgaccatg ctgcgggaca catccaagaa tcagttcagc 240
ctgaggctgt ccagcgtgac cgctgctgat acagccgtgt actattgtgc caggtccctg 300
gctcggacca cagccatgga ctactgggga cagggatccc tggtgaccgt gtcttccgcc 360
tctacaaagg gcccctccgt gtttccactg gctccctcct ctaagagcac ctctggcggc 420
acagccgctc tgggctgtct ggtgaaggat tacttcccag agcccgtgac agtgagctgg 480
aactctggcg ccctgacctc tggagtgcac acatttccag ctgtgctgca gtccagcggc 540
ctgtactccc tgtcttccgt ggtgaccgtg cccagctctt ccctgggcac ccagacatat 600
atctgcaacg tgaaccacaa gccatccaat acaaaggtgg acaagaaggt ggagcccaag 660
tcctgtgata agacccatac atgcccccct tgtcctgctc cagagctgct gggaggacct 720
tccgtgttcc tgtttccacc caaacctaag gacaccctga tgatcagcag gacccccgag 780
gtgacatgcg tggtggtgga cgtgtctcac gaggatcccg aggtgaagtt caactggtat 840
gtcgatggcg tggaggtgca taatgctaag accaagcctc gggaggagca gtacaactcc 900
acctatagag tggtgagcgt gctgacagtg ctgcatcagg actggctgaa cggcaaggag 960
tataagtgca aggtgtccaa taaggccctg cccgctccca tcgagaagac catcagcaag 1020
gccaagggcc agccaaggga gccacaggtg tacacactgc ctccatcccg ggacgagctg 1080
accaagaacc aggtgagcct gacatgtctg gtgaagggct tctatcctag cgatatcgct 1140
gtggagtggg agtccaatgg ccagccagag aacaattaca agaccacacc ccctgtgctg 1200
gactccgatg gcagcttctt tctgtattct aagctgaccg tggataagtc ccggtggcag 1260
cagggcaacg tgttctcctg tagcgtgatg cacgaagccc tgcataatca ctatactcag 1320
aaaagtctgt cactgtcacc tggtaaa 1347
<210> 50
<211> 712
<212> PRT
<213> 人工序列
<220>
<223> ANT第一多肽链
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His
145 150 155 160
Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp Ile
165 170 175
Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys
180 185 190
Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu
195 200 205
Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser
225 230 235 240
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
260 265 270
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
275 280 285
Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys
290 295 300
Gly Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp
305 310 315 320
Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
325 330 335
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
340 345 350
Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser
355 360 365
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
370 375 380
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
385 390 395 400
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
405 410 415
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
420 425 430
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
435 440 445
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
450 455 460
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
465 470 475 480
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
485 490 495
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
500 505 510
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
515 520 525
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
530 535 540
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
545 550 555 560
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
565 570 575
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
580 585 590
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
595 600 605
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
610 615 620
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
625 630 635 640
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
645 650 655
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
660 665 670
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
675 680 685
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
690 695 700
Ser Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 51
<211> 2139
<212> DNA
<213> 人工序列
<220>
<223> ANT第一多肽链编码序列
<400> 51
gacatccaga tgacccagtc tccaagctct ctgtccgcta gcgtgggcga cagagtgacc 60
atcacatgcc gcgcctccca ggacatctcc agctacctga actggtatca gcagaagcca 120
ggcaaggctc ccaagctgct gatctactat acctccaggc tgcatagcgg agtgccatct 180
cggttctctg gatccggaag cggaaccgac ttcaccttta caatctcttc cctgcagccc 240
gaggacatcg ccacctacta ttgtcagcag ggcaataccc tgccttatac atttggctgc 300
ggcaccaagg tggagatcaa gggcggcggc ggctctggcg gcggcggctc tggtggcggc 360
ggcagtggcg gcggcggctc tcaggtgcag ctgcaggaga gcggacctgg actggtgaga 420
ccaagccaga ccctgtctct gacctgcaca gtgtctggct actccatcac aagcgatcac 480
gcttggtctt gggtgagaca gccacctgga aggtgcctgg agtggatcgg ctacatcagc 540
tattctggca tcaccacata taacccctct ctgaagtcca gggtgaccat gctgcgggac 600
acatccaaga atcagttcag cctgaggctg tccagcgtga ccgctgctga tacagccgtg 660
tactattgtg ccaggtccct ggctcggacc acagccatgg actactgggg acagggatcc 720
ctggtgaccg tgtcttccgg aggaggagga tccggaggag gaggaagcgg tggcggcggc 780
tctgaagtcc agctggtcga aagcgggggg gggctggtgc agcctggcag gtctctgcgg 840
ctgtcctgcg ccgctagcgg cttcaccttt gacgattacg ccatgcactg ggtgagacag 900
gctccaggca agggcctgga gtgggtgagc gccatcacct ggaactctgg ccatatcgac 960
tacgctgata gcgtggaggg cagattcaca atctctaggg acaacgccaa gaactccctg 1020
tatctgcaaa tgaatagcct gagggccgag gataccgccg tgtactattg cgccaaggtg 1080
tcttacctga gcaccgcttc cagcctggac tattggggcc agggcaccct ggtgacagtg 1140
tcttccgcct ctacaaaggg cccctccgtg tttccactgg ctccctcctc taagagcacc 1200
tctggcggca cagccgctct gggctgtctg gtgaaggatt acttcccaga gcccgtgaca 1260
gtgagctgga actctggcgc cctgacctct ggagtgcaca catttccagc tgtgctgcag 1320
tccagcggcc tgtactccct gtcttccgtg gtgaccgtgc ccagctcttc cctgggcacc 1380
cagacatata tctgcaacgt gaaccacaag ccatccaata caaaggtgga caagaaggtg 1440
gagcccaagt cctgtgataa gacccataca tgcccccctt gtcctgctcc agagctgctg 1500
ggaggacctt ccgtgttcct gtttccaccc aaacctaagg acaccctgat gatcagcagg 1560
acccccgagg tgacatgcgt ggtggtggac gtgtctcacg aggatcccga ggtgaagttc 1620
aactggtatg tcgatggcgt ggaggtgcat aatgctaaga ccaagcctcg ggaggagcag 1680
tacaactcca cctatagagt ggtgagcgtg ctgacagtgc tgcatcagga ctggctgaac 1740
ggcaaggagt ataagtgcaa ggtgtccaat aaggccctgc ccgctcccat cgagaagacc 1800
atcagcaagg ccaagggcca gccaagggag ccacaggtgt acacactgcc tccatcccgg 1860
gacgagctga ccaagaacca ggtgagcctg acatgtctgg tgaagggctt ctatcctagc 1920
gatatcgctg tggagtggga gtccaatggc cagccagaga acaattacaa gaccacaccc 1980
cctgtgctgg actccgatgg cagcttcttt ctgtattcta agctgaccgt ggataagtcc 2040
cggtggcagc agggcaacgt gttctcctgt agcgtgatgc acgaagccct gcataatcac 2100
tatactcaga aaagtctgtc actgtcacct ggtaaatga 2139
<210> 52
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> ACT第一多肽链
<400> 52
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys 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 Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
450 455 460
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
465 470 475 480
Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr
485 490 495
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser
500 505 510
Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
515 520 525
Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala
530 535 540
Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Cys
545 550 555 560
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln
580 585 590
Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr
595 600 605
Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp
610 615 620
Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp Ile Gly Tyr Ile Ser
625 630 635 640
Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr
645 650 655
Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser
660 665 670
Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala
675 680 685
Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val
690 695 700
Ser Ser
705
<210> 53
<211> 2121
<212> DNA
<213> 人工序列
<220>
<223> ACT第一多肽链编码序列
<400> 53
gaagtccagc tggtcgaaag cggggggggg ctggtgcagc ctggcaggtc tctgcggctg 60
tcctgcgccg ctagcggctt cacctttgac gattacgcca tgcactgggt gagacaggct 120
ccaggcaagg gcctggagtg ggtgagcgcc atcacctgga actctggcca tatcgactac 180
gctgatagcg tggagggcag attcacaatc tctagggaca acgccaagaa ctccctgtat 240
ctgcaaatga atagcctgag ggccgaggat accgccgtgt actattgcgc caaggtgtct 300
tacctgagca ccgcttccag cctggactat tggggccagg gcaccctggt gacagtgtct 360
tccgcctcta caaagggccc ctccgtgttt ccactggctc cctcctctaa gagcacctct 420
ggcggcacag ccgctctggg ctgtctggtg aaggattact tcccagagcc cgtgacagtg 480
agctggaact ctggcgccct gacctctgga gtgcacacat ttccagctgt gctgcagtcc 540
agcggcctgt actccctgtc ttccgtggtg accgtgccca gctcttccct gggcacccag 600
acatatatct gcaacgtgaa ccacaagcca tccaatacaa aggtggacaa gaaggtggag 660
cccaagtcct gtgataagac ccatacatgc cccccttgtc ctgctccaga gctgctggga 720
ggaccttccg tgttcctgtt tccacccaaa cctaaggaca ccctgatgat cagcaggacc 780
cccgaggtga catgcgtggt ggtggacgtg tctcacgagg atcccgaggt gaagttcaac 840
tggtatgtcg atggcgtgga ggtgcataat gctaagacca agcctcggga ggagcagtac 900
aactccacct atagagtggt gagcgtgctg acagtgctgc atcaggactg gctgaacggc 960
aaggagtata agtgcaaggt gtccaataag gccctgcccg ctcccatcga gaagaccatc 1020
agcaaggcca agggccagcc aagggagcca caggtgtaca cactgcctcc atcccgggac 1080
gagctgacca agaaccaggt gagcctgaca tgtctggtga agggcttcta tcctagcgat 1140
atcgctgtgg agtgggagtc caatggccag ccagagaaca attacaagac cacaccccct 1200
gtgctggact ccgatggcag cttctttctg tattctaagc tgaccgtgga taagtcccgg 1260
tggcagcagg gcaacgtgtt ctcctgtagc gtgatgcacg aagccctgca taatcactat 1320
actcagaaaa gtctgtcact gtcacctggt ggaggaggag gatccggagg aggaggaagc 1380
gacatccaga tgacccagtc tccaagctct ctgtccgcta gcgtgggcga cagagtgacc 1440
atcacatgcc gcgcctccca ggacatctcc agctacctga actggtatca gcagaagcca 1500
ggcaaggctc ccaagctgct gatctactat acctccaggc tgcatagcgg agtgccatct 1560
cggttctctg gatccggaag cggaaccgac ttcaccttta caatctcttc cctgcagccc 1620
gaggacatcg ccacctacta ttgtcagcag ggcaataccc tgccttatac atttggctgc 1680
ggcaccaagg tggagatcaa gggcggcggc ggctctggcg gcggcggctc tggtggcggc 1740
ggcagtggcg gcggcggctc tcaggtgcag ctgcaggaga gcggacctgg actggtgaga 1800
ccaagccaga ccctgtctct gacctgcaca gtgtctggct actccatcac aagcgatcac 1860
gcttggtctt gggtgagaca gccacctgga aggtgcctgg agtggatcgg ctacatcagc 1920
tattctggca tcaccacata taacccctct ctgaagtcca gggtgaccat gctgcgggac 1980
acatccaaga atcagttcag cctgaggctg tccagcgtga ccgctgctga tacagccgtg 2040
tactattgtg ccaggtccct ggctcggacc acagccatgg actactgggg acagggatcc 2100
ctggtgaccg tgtcttcctg a 2121
<210> 54
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> ANT与ACT的scFv
<400> 54
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His
145 150 155 160
Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp Ile
165 170 175
Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys
180 185 190
Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu
195 200 205
Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser
225 230 235 240
Leu Val Thr Val Ser Ser
245
<210> 55
<211> 744
<212> DNA
<213> 人工序列
<220>
<223> ANT与ACT的scFv的编码序列
<400> 55
gatattcaga tgactcagtc cccttctagt ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca gggccagcca gggcatccgg aactacctgg cttggtatca gcagaagcca 120
ggcaaggccc ccaagctgct gatctacgcc gcttccaccc tgcaaagcgg agtgccatct 180
cggttctccg gcagcggctc tggcacagac tttaccctga caatctccag cctgcagcct 240
gaggatgtgg ctacctacta ttgccagagg tacaatcggg ccccatatac cttcggctgc 300
ggcacaaagg tggagatcaa gggcggcggc ggctctggcg gcggcggctc tggtggcggc 360
ggcagtggcg gcggcggctc tgaagtccag ctggtcgaaa gcgggggggg gctggtgcag 420
cctggcaggt ctctgcggct gtcctgcgcc gctagcggct tcacctttga cgattacgcc 480
atgcactggg tgagacaggc tccaggcaag tgcctggagt gggtgagcgc catcacctgg 540
aactctggcc atatcgacta cgctgatagc gtggagggca gattcacaat ctctagggac 600
aacgccaaga actccctgta tctgcaaatg aatagcctga gggccgagga taccgccgtg 660
tactattgcg ccaaggtgtc ttacctgagc accgcttcca gcctggacta ttggggccag 720
ggcaccctgg tgacagtgtc ttcc 744
<210> 56
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> ANT与ACT第二多肽链
<400> 56
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 57
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> ANT与ACT第二多肽链编码序列
<400> 57
gatattcaga tgactcagtc cccttctagt ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca gggccagcca gggcatccgg aactacctgg cttggtatca gcagaagcca 120
ggcaaggccc ccaagctgct gatctacgcc gcttccaccc tgcaaagcgg agtgccatct 180
cggttctccg gcagcggctc tggcacagac tttaccctga caatctccag cctgcagcct 240
gaggatgtgg ctacctacta ttgccagagg tacaatcggg ccccatatac cttcggccaa 300
ggcacaaagg tggagatcaa gagaacagtg gccgctccct ccgtgttcat ctttccccct 360
tccgacgagc agctgaagtc cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420
cccagggagg ctaaggtgca gtggaaggtg gataacgccc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ctgattacga gaagcacaag gtgtatgcct gtgaagtcac tcatcagggt 600
ctgtccagcc cagtcactaa gtcattcaac cgtggcgaat gctga 645
<210> 58
<211> 712
<212> PRT
<213> 人工序列
<220>
<223> ANT-2第一多肽链
<400> 58
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg
180 185 190
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
260 265 270
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
275 280 285
Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys
290 295 300
Gly Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp
305 310 315 320
Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
325 330 335
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
340 345 350
Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser
355 360 365
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
370 375 380
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
385 390 395 400
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
405 410 415
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
420 425 430
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
435 440 445
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
450 455 460
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
465 470 475 480
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
485 490 495
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
500 505 510
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
515 520 525
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
530 535 540
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
545 550 555 560
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
565 570 575
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
580 585 590
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
595 600 605
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
610 615 620
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
625 630 635 640
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
645 650 655
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
660 665 670
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
675 680 685
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
690 695 700
Ser Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 59
<211> 2139
<212> DNA
<213> 人工序列
<220>
<223> ANT-2第一多肽链编码序列
<400> 59
caggtgcagc tgcaggagag cggacctgga ctggtgagac caagccagac cctgtctctg 60
acctgcacag tgtctggcta ctccatcaca agcgatcacg cttggtcttg ggtgagacag 120
ccacctggaa ggtgcctgga gtggatcggc tacatcagct attctggcat caccacatat 180
aacccctctc tgaagtccag ggtgaccatg ctgcgggaca catccaagaa tcagttcagc 240
ctgaggctgt ccagcgtgac cgctgctgat acagccgtgt actattgtgc caggtccctg 300
gctcggacca cagccatgga ctactgggga cagggatccc tggtgaccgt gtcttccggc 360
ggcggcggct ctggcggcgg cggctctggt ggcggcggca gtggcggcgg cggctctgac 420
atccagatga cccagtctcc aagctctctg tccgctagcg tgggcgacag agtgaccatc 480
acatgccgcg cctcccagga catctccagc tacctgaact ggtatcagca gaagccaggc 540
aaggctccca agctgctgat ctactatacc tccaggctgc atagcggagt gccatctcgg 600
ttctctggat ccggaagcgg aaccgacttc acctttacaa tctcttccct gcagcccgag 660
gacatcgcca cctactattg tcagcagggc aataccctgc cttatacatt tggctgcggc 720
accaaggtgg agatcaaggg aggaggagga tccggaggag gaggaagcgg tggcggcggc 780
tctgaagtcc agctggtcga aagcgggggg gggctggtgc agcctggcag gtctctgcgg 840
ctgtcctgcg ccgctagcgg cttcaccttt gacgattacg ccatgcactg ggtgagacag 900
gctccaggca agggcctgga gtgggtgagc gccatcacct ggaactctgg ccatatcgac 960
tacgctgata gcgtggaggg cagattcaca atctctaggg acaacgccaa gaactccctg 1020
tatctgcaaa tgaatagcct gagggccgag gataccgccg tgtactattg cgccaaggtg 1080
tcttacctga gcaccgcttc cagcctggac tattggggcc agggcaccct ggtgacagtg 1140
tcttccgcct ctacaaaggg cccctccgtg tttccactgg ctccctcctc taagagcacc 1200
tctggcggca cagccgctct gggctgtctg gtgaaggatt acttcccaga gcccgtgaca 1260
gtgagctgga actctggcgc cctgacctct ggagtgcaca catttccagc tgtgctgcag 1320
tccagcggcc tgtactccct gtcttccgtg gtgaccgtgc ccagctcttc cctgggcacc 1380
cagacatata tctgcaacgt gaaccacaag ccatccaata caaaggtgga caagaaggtg 1440
gagcccaagt cctgtgataa gacccataca tgcccccctt gtcctgctcc agagctgctg 1500
ggaggacctt ccgtgttcct gtttccaccc aaacctaagg acaccctgat gatcagcagg 1560
acccccgagg tgacatgcgt ggtggtggac gtgtctcacg aggatcccga ggtgaagttc 1620
aactggtatg tcgatggcgt ggaggtgcat aatgctaaga ccaagcctcg ggaggagcag 1680
tacaactcca cctatagagt ggtgagcgtg ctgacagtgc tgcatcagga ctggctgaac 1740
ggcaaggagt ataagtgcaa ggtgtccaat aaggccctgc ccgctcccat cgagaagacc 1800
atcagcaagg ccaagggcca gccaagggag ccacaggtgt acacactgcc tccatcccgg 1860
gacgagctga ccaagaacca ggtgagcctg acatgtctgg tgaagggctt ctatcctagc 1920
gatatcgctg tggagtggga gtccaatggc cagccagaga acaattacaa gaccacaccc 1980
cctgtgctgg actccgatgg cagcttcttt ctgtattcta agctgaccgt ggataagtcc 2040
cggtggcagc agggcaacgt gttctcctgt agcgtgatgc acgaagccct gcataatcac 2100
tatactcaga aaagtctgtc actgtcacct ggtaaatga 2139
<210> 60
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> ACT-2第一多肽链
<400> 60
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys 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 Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr 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 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu
450 455 460
Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu
465 470 475 480
Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser
485 490 495
Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp Ile Gly Tyr Ile
500 505 510
Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val
515 520 525
Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser
530 535 540
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu
545 550 555 560
Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr
565 570 575
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
595 600 605
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
610 615 620
Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
625 630 635 640
Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly
645 650 655
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe
660 665 670
Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln
675 680 685
Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Cys Gly Thr Lys Val Glu
690 695 700
Ile Lys
705
<210> 61
<211> 2121
<212> DNA
<213> 人工序列
<220>
<223> ACT-2第一多肽链编码序列
<400> 61
gaagtccagc tggtcgaaag cggggggggg ctggtgcagc ctggcaggtc tctgcggctg 60
tcctgcgccg ctagcggctt cacctttgac gattacgcca tgcactgggt gagacaggct 120
ccaggcaagg gcctggagtg ggtgagcgcc atcacctgga actctggcca tatcgactac 180
gctgatagcg tggagggcag attcacaatc tctagggaca acgccaagaa ctccctgtat 240
ctgcaaatga atagcctgag ggccgaggat accgccgtgt actattgcgc caaggtgtct 300
tacctgagca ccgcttccag cctggactat tggggccagg gcaccctggt gacagtgtct 360
tccgcctcta caaagggccc ctccgtgttt ccactggctc cctcctctaa gagcacctct 420
ggcggcacag ccgctctggg ctgtctggtg aaggattact tcccagagcc cgtgacagtg 480
agctggaact ctggcgccct gacctctgga gtgcacacat ttccagctgt gctgcagtcc 540
agcggcctgt actccctgtc ttccgtggtg accgtgccca gctcttccct gggcacccag 600
acatatatct gcaacgtgaa ccacaagcca tccaatacaa aggtggacaa gaaggtggag 660
cccaagtcct gtgataagac ccatacatgc cccccttgtc ctgctccaga gctgctggga 720
ggaccttccg tgttcctgtt tccacccaaa cctaaggaca ccctgatgat cagcaggacc 780
cccgaggtga catgcgtggt ggtggacgtg tctcacgagg atcccgaggt gaagttcaac 840
tggtatgtcg atggcgtgga ggtgcataat gctaagacca agcctcggga ggagcagtac 900
aactccacct atagagtggt gagcgtgctg acagtgctgc atcaggactg gctgaacggc 960
aaggagtata agtgcaaggt gtccaataag gccctgcccg ctcccatcga gaagaccatc 1020
agcaaggcca agggccagcc aagggagcca caggtgtaca cactgcctcc atcccgggac 1080
gagctgacca agaaccaggt gagcctgaca tgtctggtga agggcttcta tcctagcgat 1140
atcgctgtgg agtgggagtc caatggccag ccagagaaca attacaagac cacaccccct 1200
gtgctggact ccgatggcag cttctttctg tattctaagc tgaccgtgga taagtcccgg 1260
tggcagcagg gcaacgtgtt ctcctgtagc gtgatgcacg aagccctgca taatcactat 1320
actcagaaaa gtctgtcact gtcacctggt ggaggaggag gatccggagg aggaggaagc 1380
caggtgcagc tgcaggagag cggacctgga ctggtgagac caagccagac cctgtctctg 1440
acctgcacag tgtctggcta ctccatcaca agcgatcacg cttggtcttg ggtgagacag 1500
ccacctggaa ggtgcctgga gtggatcggc tacatcagct attctggcat caccacatat 1560
aacccctctc tgaagtccag ggtgaccatg ctgcgggaca catccaagaa tcagttcagc 1620
ctgaggctgt ccagcgtgac cgctgctgat acagccgtgt actattgtgc caggtccctg 1680
gctcggacca cagccatgga ctactgggga cagggatccc tggtgaccgt gtcttccggc 1740
ggcggcggct ctggcggcgg cggctctggt ggcggcggca gtggcggcgg cggctctgac 1800
atccagatga cccagtctcc aagctctctg tccgctagcg tgggcgacag agtgaccatc 1860
acatgccgcg cctcccagga catctccagc tacctgaact ggtatcagca gaagccaggc 1920
aaggctccca agctgctgat ctactatacc tccaggctgc atagcggagt gccatctcgg 1980
ttctctggat ccggaagcgg aaccgacttc acctttacaa tctcttccct gcagcccgag 2040
gacatcgcca cctactattg tcagcagggc aataccctgc cttatacatt tggctgcggc 2100
accaaggtgg agatcaagtg a 2121
<210> 62
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> ANT-2与ACT-2的scFv
<400> 62
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg
180 185 190
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys
245
<210> 63
<211> 738
<212> DNA
<213> 人工序列
<220>
<223> ANT-2与ACT-2的scFv的编码序列
<400> 63
caggtgcagc tgcaggagag cggacctgga ctggtgagac caagccagac cctgtctctg 60
acctgcacag tgtctggcta ctccatcaca agcgatcacg cttggtcttg ggtgagacag 120
ccacctggaa ggtgcctgga gtggatcggc tacatcagct attctggcat caccacatat 180
aacccctctc tgaagtccag ggtgaccatg ctgcgggaca catccaagaa tcagttcagc 240
ctgaggctgt ccagcgtgac cgctgctgat acagccgtgt actattgtgc caggtccctg 300
gctcggacca cagccatgga ctactgggga cagggatccc tggtgaccgt gtcttccggc 360
ggcggcggct ctggcggcgg cggctctggt ggcggcggca gtggcggcgg cggctctgac 420
atccagatga cccagtctcc aagctctctg tccgctagcg tgggcgacag agtgaccatc 480
acatgccgcg cctcccagga catctccagc tacctgaact ggtatcagca gaagccaggc 540
aaggctccca agctgctgat ctactatacc tccaggctgc atagcggagt gccatctcgg 600
ttctctggat ccggaagcgg aaccgacttc acctttacaa tctcttccct gcagcccgag 660
gacatcgcca cctactattg tcagcagggc aataccctgc cttatacatt tggctgcggc 720
accaaggtgg agatcaag 738
<210> 64
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> ALNT第一多肽链
<400> 64
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
115 120 125
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr
130 135 140
Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His
145 150 155 160
Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp Ile
165 170 175
Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys
180 185 190
Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu
195 200 205
Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser
225 230 235 240
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
260 265 270
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
275 280 285
Gly Ile Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
290 295 300
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
305 310 315 320
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
325 330 335
Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr
340 345 350
Asn Arg Ala Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
355 360 365
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
370 375 380
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
385 390 395 400
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
405 410 415
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
420 425 430
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
435 440 445
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
450 455 460
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
465 470 475
<210> 65
<211> 1428
<212> DNA
<213> 人工序列
<220>
<223> ALNT第一多肽链编码序列
<400> 65
gacatccaga tgacccagtc tccaagctct ctgtccgcta gcgtgggcga cagagtgacc 60
atcacatgcc gcgcctccca ggacatctcc agctacctga actggtatca gcagaagcca 120
ggcaaggctc ccaagctgct gatctactat acctccaggc tgcatagcgg agtgccatct 180
cggttctctg gatccggaag cggaaccgac ttcaccttta caatctcttc cctgcagccc 240
gaggacatcg ccacctacta ttgtcagcag ggcaataccc tgccttatac atttggctgc 300
ggcaccaagg tggagatcaa gggcggcggc ggctctggcg gcggcggctc tggtggcggc 360
ggcagtggcg gcggcggctc tcaggtgcag ctgcaggaga gcggacctgg actggtgaga 420
ccaagccaga ccctgtctct gacctgcaca gtgtctggct actccatcac aagcgatcac 480
gcttggtctt gggtgagaca gccacctgga aggtgcctgg agtggatcgg ctacatcagc 540
tattctggca tcaccacata taacccctct ctgaagtcca gggtgaccat gctgcgggac 600
acatccaaga atcagttcag cctgaggctg tccagcgtga ccgctgctga tacagccgtg 660
tactattgtg ccaggtccct ggctcggacc acagccatgg actactgggg acagggatcc 720
ctggtgaccg tgtcttccgg aggaggagga tccggaggag gaggaagcgg tggcggcggc 780
tctgatattc agatgactca gtccccttct agtctgtccg cctctgtggg cgacagagtg 840
accatcacat gcagggccag ccagggcatc cggaactacc tggcttggta tcagcagaag 900
ccaggcaagg cccccaagct gctgatctac gccgcttcca ccctgcaaag cggagtgcca 960
tctcggttct ccggcagcgg ctctggcaca gactttaccc tgacaatctc cagcctgcag 1020
cctgaggatg tggctaccta ctattgccag aggtacaatc gggccccata taccttcggc 1080
caaggcacaa aggtggagat caagagaaca gtggccgctc cctccgtgtt catctttccc 1140
ccttccgacg agcagctgaa gtccggcacc gccagcgtgg tgtgcctgct gaacaacttc 1200
taccccaggg aggctaaggt gcagtggaag gtggataacg ccctgcagtc cggcaatagc 1260
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 1320
acactgtcta aggctgatta cgagaagcac aaggtgtatg cctgtgaagt cactcatcag 1380
ggtctgtcca gcccagtcac taagtcattc aaccgtggcg aatgctga 1428
<210> 66
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> ALCT第一多肽链
<400> 66
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
225 230 235 240
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
245 250 255
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
260 265 270
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
275 280 285
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
290 295 300
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
305 310 315 320
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser
325 330 335
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
340 345 350
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln Thr
355 360 365
Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp His
370 375 380
Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp Ile
385 390 395 400
Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu Lys
405 410 415
Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser Leu
420 425 430
Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
435 440 445
Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly Ser
450 455 460
Leu Val Thr Val Ser Ser
465 470
<210> 67
<211> 1413
<212> DNA
<213> 人工序列
<220>
<223> ALCT第一多肽链编码序列
<400> 67
gatattcaga tgactcagtc cccttctagt ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca gggccagcca gggcatccgg aactacctgg cttggtatca gcagaagcca 120
ggcaaggccc ccaagctgct gatctacgcc gcttccaccc tgcaaagcgg agtgccatct 180
cggttctccg gcagcggctc tggcacagac tttaccctga caatctccag cctgcagcct 240
gaggatgtgg ctacctacta ttgccagagg tacaatcggg ccccatatac cttcggccaa 300
ggcacaaagg tggagatcaa gagaacagtg gccgctccct ccgtgttcat ctttccccct 360
tccgacgagc agctgaagtc cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420
cccagggagg ctaaggtgca gtggaaggtg gataacgccc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ctgattacga gaagcacaag gtgtatgcct gtgaagtcac tcatcagggt 600
ctgtccagcc cagtcactaa gtcattcaac cgtggcgaat gcggaggagg aggatccgga 660
ggaggaggaa gcgacatcca gatgacccag tctccaagct ctctgtccgc tagcgtgggc 720
gacagagtga ccatcacatg ccgcgcctcc caggacatct ccagctacct gaactggtat 780
cagcagaagc caggcaaggc tcccaagctg ctgatctact atacctccag gctgcatagc 840
ggagtgccat ctcggttctc tggatccgga agcggaaccg acttcacctt tacaatctct 900
tccctgcagc ccgaggacat cgccacctac tattgtcagc agggcaatac cctgccttat 960
acatttggct gcggcaccaa ggtggagatc aagggcggcg gcggctctgg cggcggcggc 1020
tctggtggcg gcggcagtgg cggcggcggc tctcaggtgc agctgcagga gagcggacct 1080
ggactggtga gaccaagcca gaccctgtct ctgacctgca cagtgtctgg ctactccatc 1140
acaagcgatc acgcttggtc ttgggtgaga cagccacctg gaaggtgcct ggagtggatc 1200
ggctacatca gctattctgg catcaccaca tataacccct ctctgaagtc cagggtgacc 1260
atgctgcggg acacatccaa gaatcagttc agcctgaggc tgtccagcgt gaccgctgct 1320
gatacagccg tgtactattg tgccaggtcc ctggctcgga ccacagccat ggactactgg 1380
ggacagggat ccctggtgac cgtgtcttcc tga 1413
<210> 68
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> ALNT与ALCT的第二多肽链
<400> 68
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys 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 Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr 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> 69
<211> 1356
<212> DNA
<213> 人工序列
<220>
<223> ALNT与ALCT的第二多肽链编码序列
<400> 69
gaagtccagc tggtcgaaag cggggggggg ctggtgcagc ctggcaggtc tctgcggctg 60
tcctgcgccg ctagcggctt cacctttgac gattacgcca tgcactgggt gagacaggct 120
ccaggcaagg gcctggagtg ggtgagcgcc atcacctgga actctggcca tatcgactac 180
gctgatagcg tggagggcag attcacaatc tctagggaca acgccaagaa ctccctgtat 240
ctgcaaatga atagcctgag ggccgaggat accgccgtgt actattgcgc caaggtgtct 300
tacctgagca ccgcttccag cctggactat tggggccagg gcaccctggt gacagtgtct 360
tccgcctcta caaagggccc ctccgtgttt ccactggctc cctcctctaa gagcacctct 420
ggcggcacag ccgctctggg ctgtctggtg aaggattact tcccagagcc cgtgacagtg 480
agctggaact ctggcgccct gacctctgga gtgcacacat ttccagctgt gctgcagtcc 540
agcggcctgt actccctgtc ttccgtggtg accgtgccca gctcttccct gggcacccag 600
acatatatct gcaacgtgaa ccacaagcca tccaatacaa aggtggacaa gaaggtggag 660
cccaagtcct gtgataagac ccatacatgc cccccttgtc ctgctccaga gctgctggga 720
ggaccttccg tgttcctgtt tccacccaaa cctaaggaca ccctgatgat cagcaggacc 780
cccgaggtga catgcgtggt ggtggacgtg tctcacgagg atcccgaggt gaagttcaac 840
tggtatgtcg atggcgtgga ggtgcataat gctaagacca agcctcggga ggagcagtac 900
aactccacct atagagtggt gagcgtgctg acagtgctgc atcaggactg gctgaacggc 960
aaggagtata agtgcaaggt gtccaataag gccctgcccg ctcccatcga gaagaccatc 1020
agcaaggcca agggccagcc tagggagcca caggtgtaca cactgcctcc atcccgggac 1080
gagctgacca agaaccaggt gagcctgaca tgtctggtga agggcttcta tcctagcgat 1140
atcgctgtgg agtgggagtc caatggccag ccagagaaca attacaagac cacaccccct 1200
gtgctggact ccgatggcag cttctttctg tattctaagc tgaccgtgga taagtcccgg 1260
tggcagcagg gcaacgtgtt ctcctgtagc gtgatgcacg aagccctgca taatcactat 1320
actcagaaaa gtctgtcact gtcacctggt aaatga 1356
<210> 70
<211> 709
<212> PRT
<213> 人工序列
<220>
<223> SCG第一多肽链
<400> 70
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala
450 455 460
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
465 470 475 480
Ser Gln Ser Val Tyr Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
485 490 495
Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly
500 505 510
Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
515 520 525
Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
530 535 540
Gln Arg Ser Asn Trp Pro Pro Phe Thr Phe Gly Pro Gly Thr Lys Val
545 550 555 560
Asp Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly
580 585 590
Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser
595 600 605
Gly Phe Thr Phe Ser Ser Tyr Ala Met His Trp Val Arg Gln Ala Pro
610 615 620
Gly Lys Gly Leu Glu Trp Val Ala Phe Met Ser Tyr Asp Gly Ser Asn
625 630 635 640
Lys Lys Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
645 650 655
Asn Pro Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
660 665 670
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Ile Ala Ala Gly
675 680 685
Gly Asn Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
690 695 700
Val Thr Val Ser Ser
705
<210> 71
<211> 2130
<212> DNA
<213> 人工序列
<220>
<223> SCG第一多肽链编码序列
<400> 71
gaggtgcagc tggtggagag cggcggcggc ctggtgcagc ccggcaggag cctgaggctg 60
agctgcgccg ccagcaggtt caccttcgac gactacgcca tgcactgggt gaggcaggcc 120
cccggcaagg gcctggagtg ggtgagcggc atcagctgga acagcggcag gatcggctac 180
gccgacagcg tgaagggcag gttcaccatc agcagggaca acgccgagaa cagcctgttc 240
ctgcagatga acggcctgag ggccgaggac accgccctgt actactgcgc caagggcagg 300
gacagcttcg acatctgggg ccagggcacc atggtgaccg tgagcagcgc cagcaccaag 360
ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg caccgccgcc 420
ctgggctgcc tggtgaagga ctacttcccc gagcccgtga ccgtgagctg gaacagcggc 480
gccctgacca gcggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc 540
ctgagcagcg tggtgaccgt gcccagcagc agcctgggca cccagaccta catctgcaac 600
gtgaaccaca agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgcgac 660
aagacccaca cctgcccccc ctgccccgcc cccgagctgc tgggcggccc cagcgtgttc 720
ctgttccccc ccaagcccaa ggacaccctg atgatcagca ggacccccga ggtgacctgc 780
gtggtggtgg acgtgagcca cgaggacccc gaggtgaagt tcaactggta cgtggacggc 840
gtggaggtgc acaacgccaa gaccaagccc agggaggagc agtacaacag cacctacagg 900
gtggtgagcg tgctgaccgt gctgcaccag gactggctga acggcaagga gtacaagtgc 960
aaggtgagca acaaggccct gcccgccccc atcgagaaga ccatcagcaa ggccaagggc 1020
cagcccaggg agccccaggt gtacaccctg ccccccagca gggacgagct gaccaagaac 1080
caggtgagcc tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg 1140
gagagcaacg gccagcccga gaacaactac aagaccaccc cccccgtgct ggacagcgac 1200
ggcagcttct tcctgtacag caagctgacc gtggacaaga gcaggtggca gcagggcaac 1260
gtgttcagct gcagcgtgat gcacgaggcc ctgcacaacc actacaccca gaagagcctg 1320
agcctgagcc ccggcggcgg cggcggcagc ggcggcggcg gcagcgagat cgtgctgacc 1380
cagagccccg ccaccctgag cctgagcccc ggcgagaggg ccaccctgag ctgcagggcc 1440
agccagagcg tgtacagcta cctggcctgg taccagcaga agcccggcca ggcccccagg 1500
ctgctgatct acgacgccag caacagggcc accggcatcc ccgccaggtt cagcggcagc 1560
ggcagcggca ccgacttcac cctgaccatc agcagcctgg agcccgagga cttcgccgtg 1620
tactactgcc agcagaggag caactggccc cccttcacct tcggccccgg caccaaggtg 1680
gacatcaagg gcggcggcgg cagcggcggc ggcggcagcg gcggcggcgg cagcggcggc 1740
ggcggcagcc aggtgcagct ggtggagagc ggcggcggcg tggtgcagcc cggcaggagc 1800
ctgaggctga gctgcgccgc cagcggcttc accttcagca gctacgccat gcactgggtg 1860
aggcaggccc ccggcaaggg cctggagtgg gtggccttca tgagctacga cggcagcaac 1920
aagaagtacg ccgacagcgt gaagggcagg ttcaccatca gcagggacaa ccccaagaac 1980
accctgtacc tgcagatgaa cagcctgagg gccgaggaca ccgccgtgta ctactgcgcc 2040
agggacaggg gcatcgccgc cggcggcaac tactactact acggcatgga cgtgtggggc 2100
cagggcacca ccgtgaccgt gagcagctga 2130
<210> 72
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> SCG的scFv
<400> 72
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
145 150 155 160
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
165 170 175
Ala Phe Met Ser Tyr Asp Gly Ser Asn Lys Lys Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Asp Arg Gly Ile Ala Ala Gly Gly Asn Tyr Tyr Tyr Tyr Gly
225 230 235 240
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
245 250
<210> 73
<211> 765
<212> DNA
<213> 人工序列
<220>
<223> SCG的scFv的编码序列
<400> 73
gagatcgtgc tgacccagag ccccgccacc ctgagcctga gccccggcga gagggccacc 60
ctgagctgca gggccagcca gagcgtgtac agctacctgg cctggtacca gcagaagccc 120
ggccaggccc ccaggctgct gatctacgac gccagcaaca gggccaccgg catccccgcc 180
aggttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctggagccc 240
gaggacttcg ccgtgtacta ctgccagcag aggagcaact ggcccccctt caccttcggc 300
cccggcacca aggtggacat caagggcggc ggcggcagcg gcggcggcgg cagcggcggc 360
ggcggcagcg gcggcggcgg cagccaggtg cagctggtgg agagcggcgg cggcgtggtg 420
cagcccggca ggagcctgag gctgagctgc gccgccagcg gcttcacctt cagcagctac 480
gccatgcact gggtgaggca ggcccccggc aagggcctgg agtgggtggc cttcatgagc 540
tacgacggca gcaacaagaa gtacgccgac agcgtgaagg gcaggttcac catcagcagg 600
gacaacccca agaacaccct gtacctgcag atgaacagcc tgagggccga ggacaccgcc 660
gtgtactact gcgccaggga caggggcatc gccgccggcg gcaactacta ctactacggc 720
atggacgtgt ggggccaggg caccaccgtg accgtgagca gctga 765
<210> 74
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> SCG第二多肽链
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 75
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> SCG第二多肽链编码序列
<400> 75
gacatccaga tgacccagag ccccagcagc gtgagcgcca gcgtgggcga cagggtgacc 60
atcacctgca gggccagcca gggcatcagc agctggctgg cctggtacca gcagaagccc 120
ggcaaggccc ccaagctgct gatctacggc gccagcagcc tggagagcgg cgtgcccagc 180
aggttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccagctacta ctgccagcag gccaacagct tcccctacac cttcggccag 300
ggcaccaagc tggagatcaa gagaacagtg gccgctccct ccgtgttcat ctttccccct 360
tccgacgagc agctgaagtc cggcaccgcc agcgtggtgt gcctgctgaa caacttctac 420
cccagggagg ctaaggtgca gtggaaggtg gataacgccc tgcagtccgg caatagccag 480
gagtctgtga ccgagcagga ctccaaggat agcacatatt ctctgtcttc caccctgaca 540
ctgtctaagg ctgattacga gaagcacaag gtgtatgcct gtgaagtcac tcatcagggt 600
ctgtccagcc cagtcactaa gtcattcaac cgtggcgaat gctga 645
<210> 76
<211> 708
<212> PRT
<213> 人工序列
<220>
<223> GCS第一多肽链
<400> 76
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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 His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Met Ser Tyr Asp Gly Ser Asn Lys Lys Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Ile Ala Ala Gly Gly Asn Tyr Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
210 215 220
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly
450 455 460
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val
465 470 475 480
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser
485 490 495
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
500 505 510
Ile Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser
515 520 525
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
530 535 540
Pro Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro
545 550 555 560
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
580 585 590
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
595 600 605
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr
610 615 620
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
625 630 635 640
Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val
645 650 655
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe
660 665 670
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
675 680 685
Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val
690 695 700
Thr Val Ser Ser
705
<210> 77
<211> 2127
<212> DNA
<213> 人工序列
<220>
<223> GCS第一多肽链编码序列
<400> 77
caggtgcagc tggtggagag cggcggcggc gtggtgcagc ccggcaggag cctgaggctg 60
agctgcgccg ccagcggctt caccttcagc agctacgcca tgcactgggt gaggcaggcc 120
cccggcaagg gcctggagtg ggtggccttc atgagctacg acggcagcaa caagaagtac 180
gccgacagcg tgaagggcag gttcaccatc agcagggaca accccaagaa caccctgtac 240
ctgcagatga acagcctgag ggccgaggac accgccgtgt actactgcgc cagggacagg 300
ggcatcgccg ccggcggcaa ctactactac tacggcatgg acgtgtgggg ccagggcacc 360
accgtgaccg tgagcagcgc cagcaccaag ggccccagcg tgttccccct ggcccccagc 420
agcaagagca ccagcggcgg caccgccgcc ctgggctgcc tggtgaagga ctacttcccc 480
gagcccgtga ccgtgagctg gaacagcggc gccctgacca gcggcgtgca caccttcccc 540
gccgtgctgc agagcagcgg cctgtacagc ctgagcagcg tggtgaccgt gcccagcagc 600
agcctgggca cccagaccta catctgcaac gtgaaccaca agcccagcaa caccaaggtg 660
gacaagaagg tggagcccaa gagctgcgac aagacccaca cctgcccccc ctgccccgcc 720
cccgagctgc tgggcggccc cagcgtgttc ctgttccccc ccaagcccaa ggacaccctg 780
atgatcagca ggacccccga ggtgacctgc gtggtggtgg acgtgagcca cgaggacccc 840
gaggtgaagt tcaactggta cgtggacggc gtggaggtgc acaacgccaa gaccaagccc 900
agggaggagc agtacaacag cacctacagg gtggtgagcg tgctgaccgt gctgcaccag 960
gactggctga acggcaagga gtacaagtgc aaggtgagca acaaggccct gcccgccccc 1020
atcgagaaga ccatcagcaa ggccaagggc cagcccaggg agccccaggt gtacaccctg 1080
ccccccagca gggacgagct gaccaagaac caggtgagcc tgacctgcct ggtgaagggc 1140
ttctacccca gcgacatcgc cgtggagtgg gagagcaacg gccagcccga gaacaactac 1200
aagaccaccc cccccgtgct ggacagcgac ggcagcttct tcctgtacag caagctgacc 1260
gtggacaaga gcaggtggca gcagggcaac gtgttcagct gcagcgtgat gcacgaggcc 1320
ctgcacaacc actacaccca gaagagcctg agcctgagcc ccggcggcgg cggcggcagc 1380
ggcggcggcg gcagcgacat ccagatgacc cagagcccca gcagcgtgag cgccagcgtg 1440
ggcgacaggg tgaccatcac ctgcagggcc agccagggca tcagcagctg gctggcctgg 1500
taccagcaga agcccggcaa ggcccccaag ctgctgatct acggcgccag cagcctggag 1560
agcggcgtgc ccagcaggtt cagcggcagc ggcagcggca ccgacttcac cctgaccatc 1620
agcagcctgc agcccgagga cttcgccagc tactactgcc agcaggccaa cagcttcccc 1680
tacaccttcg gccagggcac caagctggag atcaagggcg gcggcggcag cggcggcggc 1740
ggcagcggcg gcggcggcag cggcggcggc ggcagcgagg tgcagctggt ggagagcggc 1800
ggcggcctgg tgcagcccgg caggagcctg aggctgagct gcgccgccag caggttcacc 1860
ttcgacgact acgccatgca ctgggtgagg caggcccccg gcaagggcct ggagtgggtg 1920
agcggcatca gctggaacag cggcaggatc ggctacgccg acagcgtgaa gggcaggttc 1980
accatcagca gggacaacgc cgagaacagc ctgttcctgc agatgaacgg cctgagggcc 2040
gaggacaccg ccctgtacta ctgcgccaag ggcagggaca gcttcgacat ctggggccag 2100
ggcaccatgg tgaccgtgag cagctga 2127
<210> 78
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> GCS的scFv
<400> 78
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr Ala
145 150 155 160
Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser
165 170 175
Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe Leu
195 200 205
Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala
210 215 220
Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr
225 230 235 240
Val Ser Ser
<210> 79
<211> 729
<212> DNA
<213> 人工序列
<220>
<223> GCS的scFv的编码序列
<400> 79
gacatccaga tgacccagag ccccagcagc gtgagcgcca gcgtgggcga cagggtgacc 60
atcacctgca gggccagcca gggcatcagc agctggctgg cctggtacca gcagaagccc 120
ggcaaggccc ccaagctgct gatctacggc gccagcagcc tggagagcgg cgtgcccagc 180
aggttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccagctacta ctgccagcag gccaacagct tcccctacac cttcggccag 300
ggcaccaagc tggagatcaa gggcggcggc ggcagcggcg gcggcggcag cggcggcggc 360
ggcagcggcg gcggcggcag cgaggtgcag ctggtggaga gcggcggcgg cctggtgcag 420
cccggcagga gcctgaggct gagctgcgcc gccagcaggt tcaccttcga cgactacgcc 480
atgcactggg tgaggcaggc ccccggcaag ggcctggagt gggtgagcgg catcagctgg 540
aacagcggca ggatcggcta cgccgacagc gtgaagggca ggttcaccat cagcagggac 600
aacgccgaga acagcctgtt cctgcagatg aacggcctga gggccgagga caccgccctg 660
tactactgcg ccaagggcag ggacagcttc gacatctggg gccagggcac catggtgacc 720
gtgagcagc 729
<210> 80
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> GCS第二多肽链
<400> 80
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 81
<211> 648
<212> DNA
<213> 人工序列
<220>
<223> GCS第二多肽链编码序列
<400> 81
gagatcgtgc tgacccagag ccccgccacc ctgagcctga gccccggcga gagggccacc 60
ctgagctgca gggccagcca gagcgtgtac agctacctgg cctggtacca gcagaagccc 120
ggccaggccc ccaggctgct gatctacgac gccagcaaca gggccaccgg catccccgcc 180
aggttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctggagccc 240
gaggacttcg ccgtgtacta ctgccagcag aggagcaact ggcccccctt caccttcggc 300
cccggcacca aggtggacat caagagaaca gtggccgctc cctccgtgtt catctttccc 360
ccttccgacg agcagctgaa gtccggcacc gccagcgtgg tgtgcctgct gaacaacttc 420
taccccaggg aggctaaggt gcagtggaag gtggataacg ccctgcagtc cggcaatagc 480
caggagtctg tgaccgagca ggactccaag gatagcacat attctctgtc ttccaccctg 540
acactgtcta aggctgatta cgagaagcac aaggtgtatg cctgtgaagt cactcatcag 600
ggtctgtcca gcccagtcac taagtcattc aaccgtggcg aatgctga 648
<210> 82
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> IgG-KAPPA信号肽
<400> 82
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 83
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> IgG-KAPPA信号肽编码序列
<400> 83
atgggctggt cttgtattat tctgttcctg gtcgcaactg caaccggcgt ccatagc 57
<210> 84
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> AB03 重链
<400> 84
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 85
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> AB01 轻链
<400> 85
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 86
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> AB01突变型VL
<400> 86
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105
<210> 87
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> AB01突变型VH
<400> 87
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 88
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> AB02突变型VL
<400> 88
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105
<210> 89
<211> 126
<212> PRT
<213> 人工序列
<220>
<223> AB02突变型VH
<400> 89
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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 His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Met Ser Tyr Asp Gly Ser Asn Lys Lys Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Ile Ala Ala Gly Gly Asn Tyr Tyr Tyr Tyr Gly
100 105 110
Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 90
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> AB03突变型VL
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105
<210> 91
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> AB03突变型VH
<400> 91
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser
115
<210> 92
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> AB04突变型VL
<400> 92
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Tyr
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 93
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> AB04突变型VH
<400> 93
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Arg Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Asp Ser Phe Asp Ile Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser
115
<210> 94
<211> 475
<212> PRT
<213> 人工序列
<220>
<223> ALNT-2第一多肽链
<400> 94
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg
180 185 190
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr
210 215 220
Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
260 265 270
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
275 280 285
Gly Ile Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
290 295 300
Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
305 310 315 320
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
325 330 335
Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr
340 345 350
Asn Arg Ala Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
355 360 365
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
370 375 380
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
385 390 395 400
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
405 410 415
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
420 425 430
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
435 440 445
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
450 455 460
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
465 470 475
<210> 95
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> ALCT-2第一多肽链
<400> 95
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
225 230 235 240
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
245 250 255
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Cys Leu Glu Trp
260 265 270
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
275 280 285
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
290 295 300
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
305 310 315 320
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
325 330 335
Ser Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
340 345 350
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
355 360 365
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
370 375 380
Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
385 390 395 400
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg
405 410 415
Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
420 425 430
Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr
435 440 445
Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Cys Gly
450 455 460
Thr Lys Val Glu Ile Lys
465 470
<210> 96
<211> 712
<212> PRT
<213> 人工序列
<220>
<223> TNA-2第一多肽链
<400> 96
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
180 185 190
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val
210 215 220
Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr Thr Phe Gly
225 230 235 240
Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Pro
260 265 270
Gly Leu Val Arg Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser
275 280 285
Gly Tyr Ser Ile Thr Ser Asp His Ala Trp Ser Trp Val Arg Gln Pro
290 295 300
Pro Gly Arg Gly Leu Glu Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ile
305 310 315 320
Thr Thr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Leu Arg Asp
325 330 335
Thr Ser Lys Asn Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala
340 345 350
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Leu Ala Arg Thr Thr Ala
355 360 365
Met Asp Tyr Trp Gly Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser
370 375 380
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
385 390 395 400
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
405 410 415
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
420 425 430
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
435 440 445
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
450 455 460
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
465 470 475 480
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
485 490 495
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
500 505 510
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
515 520 525
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
530 535 540
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
545 550 555 560
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
565 570 575
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
580 585 590
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
595 600 605
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
610 615 620
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
625 630 635 640
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
645 650 655
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
660 665 670
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
675 680 685
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
690 695 700
Ser Leu Ser Leu Ser Pro Gly Lys
705 710
<210> 97
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> TCA-2第一多肽链
<400> 97
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Met Leu Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Ala Arg Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
450 455 460
Ser Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys
465 470 475 480
Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg
485 490 495
Gln Ala Pro Gly Lys Cys Leu Glu Trp Val Ser Ala Ile Thr Trp Asn
500 505 510
Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile
515 520 525
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu
545 550 555 560
Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
595 600 605
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
610 615 620
Ser Gln Gly Ile Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
625 630 635 640
Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly
645 650 655
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
660 665 670
Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln
675 680 685
Arg Tyr Asn Arg Ala Pro Tyr Thr Phe Gly Cys Gly Thr Lys Val Glu
690 695 700
Ile Lys
705
<210> 98
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> TLNA-2第一多肽链
<400> 98
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
180 185 190
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val
210 215 220
Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr Thr Phe Gly
225 230 235 240
Cys Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
260 265 270
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
275 280 285
Ser Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
290 295 300
Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly
305 310 315 320
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe
325 330 335
Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln
340 345 350
Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu
355 360 365
Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser
370 375 380
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
385 390 395 400
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
405 410 415
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
420 425 430
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
435 440 445
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
450 455 460
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
465 470 475
<210> 99
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> TLCA-2第一多肽链
<400> 99
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
225 230 235 240
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
245 250 255
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
260 265 270
Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
275 280 285
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
290 295 300
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
305 310 315 320
Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly
325 330 335
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
340 345 350
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
355 360 365
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
370 375 380
Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala Trp
385 390 395 400
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
405 410 415
Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
420 425 430
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val
435 440 445
Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr Thr Phe Gly
450 455 460
Cys Gly Thr Lys Val Glu Ile Lys
465 470
<210> 100
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人轻链kappa同种型的CL
<400> 100
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 101
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 人重链IgG1同种型的CH
<400> 101
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
Claims (41)
1.一种双特异性重组蛋白,其包含:
1)特异性结合第一抗原的第一抗体,所述第一抗体包括重链HC和轻链LC;和
2)特异性结合第二抗原的scFv;
其中,所述重组蛋白具备以下特征:
(a)所述重组蛋白由1个所述第一抗体和2个所述scFv组成;并且,所述第一抗体包括两条HC和两条LC,其中所述第一抗体的一条HC的VH与一条LC的VL形成抗原结合部位,另一条HC的VH与另一条LC的VL形成抗原结合部位;
(b)(i)所述第一抗体特异性结合IL-6R,并且所述scFv特异性结合TNFα,其中:
所述第一抗体包含:
如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ ID NO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ IDNO:20所示的LCDR3;并且,
所述scFv包含:
如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3;
或者,(ii)所述第一抗体特异性结合TNFα,并且所述scFv特异性结合IL-6R,其中:
所述第一抗体包含:
如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3;并且,
所述scFv包含:
如SEQ ID NO:22所示的HCDR1;如SEQ ID NO:23所示的HCDR2;以及,如SEQ ID NO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ IDNO:20所示的LCDR3;
(c)每个所述scFv分别连接于所述第一抗体的两条重链或两条轻链的N端;或者,每个所述scFv分别连接于所述第一抗体的两条重链或两条轻链的C端;
和,
(d)所述scFv的位于VH第44位的氨基酸和位于VL第100位的氨基酸分别为半胱氨酸,其中提及的氨基酸位置是根据Kabat编号***的位置;并且,所述scFv的VH与VL通过分别位于VH第44位和VL第100位的2个半胱氨酸残基之间所形成的二硫键连接。
2.权利要求1所述的重组蛋白,其中所述第一抗体的重链包含重链可变区VH和重链恒定区CH,并且所述轻链包含轻链可变区VL和轻链恒定区CL。
3.权利要求1所述的重组蛋白,所述第一抗体为全长抗体。
4.权利要求1-3任一项所述的重组蛋白,其中所述第一抗体的重链为IgG同种型;和/或,所述第一抗体的轻链为Kappa同种型。
5.权利要求4所述的重组蛋白,其中所述第一抗体的重链为IgG1、IgG2、IgG3或IgG4。
6.权利要求4所述的重组蛋白,其中所述第一抗体的轻链为人Kappa同种型。
7.权利要求5所述的重组蛋白,其中所述第一抗体的轻链为人Kappa同种型。
8.权利要求1所述的重组蛋白,所述第一抗体的两条HC包含相同的VH;和/或,所述第一抗体的两条LC包含相同的VL。
9.权利要求1所述的重组蛋白,所述第一抗体的两条HC具有相同的氨基酸序列;和/或,所述第一抗体的两条LC具有相同的氨基酸序列。
10.权利要求9所述的重组蛋白,两个所述scFv具有相同的氨基酸序列。
11.权利要求1-3、5-10任一项所述的重组蛋白,其中所述重组蛋白包含两条第一多肽链和两条第二多肽链,其中对于所述每条多肽链:
a)所述第一多肽链各自独立地包含所述第一抗体的重链HC和所述scFv;和
b)所述第二多肽链各自独立地包含所述第一抗体的轻链LC;
其中,所述scFv通过接头S1与所述第一抗体的HC的N端或C端相连;
或者,
a)所述第一多肽链各自独立地包含所述第一抗体的轻链LC和所述scFv;和
b)所述第二多肽链各自独立地包含所述第一抗体的重链HC;
其中,所述scFv通过接头S1与所述第一抗体的LC的N端或C端相连。
12.权利要求11所述的重组蛋白,所述scFv具有结构:NH2-VH-S2-VL-COOH或NH2-VL-S2-VH-COOH,其中所述S2为接头。
13.权利要求11所述的重组蛋白,所述重组蛋白包含两条相同的第一多肽链和两条相同的第二多肽链。
14.权利要求12或13所述的重组蛋白,其中所述接头S1和/或S2为肽接头,具有如(GmSn)x所示的氨基酸序列,其中m、n各自独立地选自1~8的整数,x独立地选自1~20的整数。
15.权利要求14所述的重组蛋白,其中m、n各自独立地选自1、2、3、4、5、6、7或8,x独立地选自1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
16.权利要求15所述的重组蛋白,所述接头S1和/或S2具有如(G4S)x所示的氨基酸序列,x独立地选自1-6的整数。
17.权利要求16所述的重组蛋白,所述S1和/或S2具有选自下列的氨基酸序列:SEQ IDNO:33、SEQ ID NO:34和SEQ ID NO:35。
18.权利要求17所述的重组蛋白,所述接头S2具有如SEQ ID NO:33所示的氨基酸序列,且当所述scFv与所述第一抗体的重链或轻链的N端连接时,所述接头S1具有如SEQ ID NO:34所示的氨基酸序列,当所述scFv与所述第一抗体的重链或轻链的C端连接时,所述接头S1具有如SEQ ID NO:35所示的氨基酸序列。
19.权利要求1-3、5-10、12-13、15-18任一项所述的重组蛋白,其中,每个所述scFv分别连接于所述第一抗体的两条重链的N端;且,
所述第一抗体包含:如SEQ ID NO:6所示的HCDR1;如SEQ ID NO:7所示的HCDR2;以及,如SEQ ID NO:8所示的HCDR3;如SEQ ID NO:2所示的LCDR1;如SEQ ID NO:3所示的LCDR2;以及,如SEQ ID NO:4所示的LCDR3;并且,所述scFv包含:如SEQ ID NO:22所示的HCDR1;如SEQID NO:23所示的HCDR2;以及,如SEQ ID NO:24所示的HCDR3;如SEQ ID NO:18所示的LCDR1;如SEQ ID NO:19所示的LCDR2;以及,如SEQ ID NO:20所示的LCDR3。
20.权利要求19所述的重组蛋白,其中,所述重组蛋白包含两条第一多肽链和两条第二多肽链,其中对于所述每条多肽链:
a)所述第一多肽链各自独立地包含所述第一抗体的重链(HC)和所述scFv,所述scFv任选地通过接头S1与所述第一抗体的HC的N端连接;和
b)所述第二多肽链各自独立地包含所述第一抗体的轻链(LC)。
21.权利要求20所述的重组蛋白,其中,所述重组蛋白包含两条相同的第一多肽链和两条相同的第二多肽链。
22.权利要求1-3、5-10、12-13、15-18、21任一项所述的重组蛋白,其中:所述第一抗体包含如SEQ ID NO:5所示的VH和如SEQ ID NO:1所示的VL;并且,所述scFv包含:如SEQ IDNO:91所示的VH和如SEQ ID NO:90所示的VL。
23.权利要求1-3、5-10、12-13、15-18、21任一项所述的重组蛋白,其中:所述第一抗体包含如SEQ ID NO:21所示的VH和如SEQ ID NO:17所示的VL;并且,所述scFv包含:如SEQ IDNO:87所示的VH和如SEQ ID NO:86所示的VL。
24.权利要求1-3、5-10、12-13、15-18、21任一项所述的重组蛋白,其中所述第一抗体包含:如SEQ ID NO:101所示的CH;和/或,如SEQ ID NO:100所示的CL。
25.权利要求22所述的重组蛋白,其中所述第一抗体包含:如SEQ ID NO:101所示的CH;和/或,如SEQ ID NO:100所示的CL。
26.权利要求23所述的重组蛋白,其中所述第一抗体包含:如SEQ ID NO:101所示的CH;和/或,如SEQ ID NO:100所示的CL。
27.权利要求1-3、5-10、12-13、15-18、21、25-26任一项所述的重组蛋白,其中所述重组蛋白包含:
(1)如SEQ ID NO:36所示的第一多肽链和如SEQ ID NO:42所示的第二多肽链;
(2)如SEQ ID NO:38所示的第一多肽链和如SEQ ID NO:42所示的第二多肽链;
(3)如SEQ ID NO:50所示的第一多肽链和如SEQ ID NO:56所示的第二多肽链;
(4)如SEQ ID NO:52所示的第一多肽链和如SEQ ID NO:56所示的第二多肽链;
(5)如SEQ ID NO:64所示的第一多肽链和如SEQ ID NO:68所示的第二多肽链;或
(6)如SEQ ID NO:66所示的第一多肽链和如SEQ ID NO:68所示的第二多肽链。
28.一种分离的核酸分子,其包含编码权利要求1-27任一项所述的重组蛋白的核苷酸序列。
29.一种载体,其包含权利要求28所述的分离的核酸分子。
30.宿主细胞,其包含权利要求28所述的分离的核酸分子或权利要求29所述的载体。
31.制备权利要求1-27任一项所述的重组蛋白的方法,其包括,在允许所述重组蛋白表达的条件下,培养权利要求30所述的宿主细胞,和从培养的宿主细胞培养物中回收所述重组蛋白。
32.药物组合物,其含有权利要求1-27任一项所述的重组蛋白,以及药学上可接受的载体和/或赋形剂。
33.权利要求32所述的药物组合物,所述药物组合物还包含另外的药学活性剂。
34.权利要求33所述的药物组合物,所述的药学活性剂为用于预防和/或治疗与过度的TNFα和/或IL-6活性相关的疾病的药物。
35.权利要求34所述的药物组合物,所述的药学活性剂为抗炎药物或免疫抑制剂。
36.权利要求1-27任一项所述的重组蛋白或权利要求32-35任一项所述的药物组合物在制备药物中的用途,所述药物用于在受试者中治疗炎性疾病或自身免疫性疾病。
37.权利要求36所述的用途,其中,所述炎性疾病或自身免疫性疾病为关节炎性疾病。
38.权利要求37所述的用途,其中,所述关节炎性疾病为类风湿性关节炎。
39.权利要求36所述的用途,其中,所述炎性疾病或自身免疫性疾病为多发性硬化症、银屑病、炎症性肠病、多发性肌炎、Crohn病、***性红斑狼疮或成人Still病。
40.权利要求36所述的用途,所述受试者为哺乳动物。
41.权利要求40所述的用途,所述受试者为人。
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