CN114853892B - 一种特异性抗体及其制备方法和应用 - Google Patents
一种特异性抗体及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种特异性抗体及其制备方法和应用。所述特异性抗体的重链的CDR1、CDR2和CDR3的氨基酸序列分别包括SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示的序列,所述特异性抗体的轻链的CDR1、CDR2和CDR3的氨基酸序列分别包括SEQ ID NO.4、SEQ ID NO.5和SEQ ID NO.6所示的序列。本发明筛选得到具备高亲和力的特异性抗体,所述抗体能够高效结合BCMA,并进一步利用所述抗体构建双特异性抗体和三特异性抗体,均具备高效结合活性,能够针对肿瘤细胞上多个靶点,具有高效诱导杀伤肿瘤细胞活性,对于治疗肿瘤药物开发领域具有重要意义。
Description
技术领域
本发明属于生物技术领域,涉及一种特异性抗体及其制备方法和应用。
背景技术
B-细胞成熟抗原(BCMA,TNFRSF17,CD269)是一种属于TNF受体超家族的跨膜蛋白,BCMA是一种非糖基化跨膜蛋白,其参与B细胞成熟、生长和存活,是TNF超家族的两种配体的受体:高亲和力配体APRIL(增殖诱导配体)以及低亲和力配体BAFF(B细胞活化因子),BCMA是一种高度分化的浆细胞选择性蛋白,其表达限于B-细胞谱系且主要存在于浆细胞和浆母细胞上,并在一定程度上存在于记忆B-细胞上,但是不存在于外周B-细胞上,在多发性骨髓瘤(MM)患者的恶性浆细胞中表达,支持多发性骨髓瘤细胞的生长和存活。
CD38在多种恶性血液性疾病中表达,包括但不限定于多发性骨髓瘤、B细胞慢性淋巴细胞白血病、B细胞急性淋巴细胞白血病、原发性系统性淀粉样变病、套细胞淋巴瘤、急性粒细胞白血病、慢性粒细胞白血病、滤泡淋巴瘤、NK细胞白血病和浆细胞白血病。CD38在MM患者恶性浆细胞中高表达,而在正常淋巴细胞、骨髓细胞及其它一些非造血组织细胞中的表达相对较低,因此CD38是治疗MM理想的靶点。
多发性骨髓瘤是继非霍奇金淋巴瘤的血液系统第二大恶性肿瘤,有研究表明(Bejnijamin和Stein,TherAdv Hematol7(3):142-146,2016),与任一单独的试剂相比,将双特异性咬合分子与一种或多种单克隆抗体组合可显著增加临床活性,因此,研发更加安全有效的靶向BCMA和CD38的特异性抗体,对于治疗肿瘤药物开发领域具有重要意义。
发明内容
针对现有技术的不足和实际需求,本发明提供一种特异性抗体及其制备方法和应用,所述特异性抗体具备高亲和力,能够高效结合B-细胞成熟抗原,对于治疗肿瘤药物开发领域具有重要意义。
为达上述目的,本发明采用以下技术方案:
第一方面,本发明提供一种特异性抗体,所述特异性抗体的重链的CDR1、CDR2和CDR3的氨基酸序列分别包括SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示的序列,所述特异性抗体的轻链的CDR1、CDR2和CDR3的氨基酸序列分别包括SEQ ID NO.4、SEQ ID NO.5和SEQ ID NO.6所示的序列。
本发明设计独特筛选策略,筛选到一种具备高亲和力的特异性抗体,所述抗体能够高效结合B-细胞成熟抗原。
SEQ ID NO.1:NYYMH。
SEQ ID NO.2:IIYRGHSDTSYNQKFKG。
SEQ ID NO.3:GAIYNAYDVLDY。
SEQ ID NO.4:QASQDISNYLN。
SEQ ID NO.5:YTSNLET。
SEQ ID NO.6:QQYDNLPLT。
优选地,所述特异性抗体的重链的可变区的氨基酸序列包括SEQ ID NO.7所示的序列。
优选地,所述特异性抗体的轻链的可变区的氨基酸序列包括SEQ ID NO.8所示的序列。
优选地,所述特异性抗体的重链的恒定区的氨基酸序列包括SEQ ID NO.9所示的序列。
优选地,所述特异性抗体的轻链的恒定区的氨基酸序列包括SEQ ID NO.10所示的序列。
第二方面,本发明提供一种核酸分子,所述核酸分子含有编码第一方面所述特异性抗体的核酸序列。
第三方面,本发明提供一种如第一方面所述的特异性抗体的制备方法,所述制备方法包括:
将编码如第一方面所述的特异性抗体的核酸序列插入表达载体,得到重组载体,将所述重组载体导入宿主细胞,进行培养,分离纯化,得到所述特异性抗体。
第四方面,本发明提供一种双特异性抗体,所述双特异性抗体含有第一方面所述的特异性抗体的Fab和scfv、结合CD3的scfv以及由第一Fc多肽和第二Fc多肽形成二聚结构的Fc,其中,第一方面所述特异性抗体的scfv在其C端与结合CD3的scfv的N端融合,结合CD3的scfv在其C端与第一Fc多肽的N端融合,第二方面所述特异性抗体的Fab在其C端与第二Fc多肽的N端融合。
优选地,所述第一方面所述特异性抗体的Fab的重链的可变区的氨基酸序列包括SEQ ID NO.7所示的序列,轻链的可变区的氨基酸序列包括SEQ ID NO.8所示的序列。
优选地,所述第一方面所述特异性抗体的scfv的重链的可变区的氨基酸序列包括SEQ ID NO.7所示的序列,轻链的可变区的氨基酸序列包括SEQ ID NO.8所示的序列。
优选地,所述结合CD3的scfv的重链的可变区的氨基酸序列包括SEQ ID NO.11所示的序列,轻链的可变区的氨基酸序列包括SEQ ID NO.12所示的序列。
优选地,所述第一Fc多肽的氨基酸序列包括SEQ ID NO.13所示的序列,所述第二Fc多肽的氨基酸序列包括SEQ ID NO.14所示的序列。
优选地,所述双特异性抗体含有三条多肽链,三条多肽链的氨基酸序列分别如SEQID NO.17、SEQ ID NO.18和SEQ ID NO.19所示。
第五方面,本发明提供一种三特异性抗体,所述三特异性抗体含有第一方面所述特异性抗体的Fab、结合CD3的scfv、结合CD38的scfv以及由第一Fc多肽和第二Fc多肽形成二聚结构的Fc,其中,结合CD38的scfv在其C端与结合CD3的scfv的N端融合,结合CD3的scfv在其C端与第一Fc多肽的N端融合,第一方面所述特异性抗体的Fab在其C端与第二Fc多肽的N端融合。
优选地,所述第一方面所述特异性抗体的Fab的重链的可变区的氨基酸序列包括SEQ ID NO.7所示的序列,轻链的可变区的氨基酸序列包括SEQ ID NO.8所示的序列。
优选地,所述结合CD3的scfv的重链的可变区的氨基酸序列包括SEQ ID NO.11所示的序列,轻链的可变区的氨基酸序列包括SEQ ID NO.12所示的序列。
优选地,所述第一Fc多肽的氨基酸序列包括SEQ ID NO.13所示的序列,所述第二Fc多肽的氨基酸序列包括SEQ ID NO.14所示的序列。
优选地,所述结合CD38的scfv的重链的可变区的氨基酸序列包括SEQ ID NO.15所示的序列,轻链的可变区的氨基酸序列包括SEQ ID NO.16所示的序列。
优选地,所述三特异性抗体含有三条多肽链,三条多肽链的氨基酸序列分别如SEQID NO.17、SEQ ID NO.18和SEQ ID NO.20所示。
第六方面,本发明提供一种药物组合物,所述药物组合物含有第一方面所述的特异性抗体、第二方面所述的核酸分子、第四方面所述的双特异性抗体或第五方面所述的三特异性抗体中的任意一种或至少两种的组合。
第七方面,本发明提供如第一方面所述的特异性抗体、第二方面所述的核酸分子、第四方面所述的双特异性抗体、第五方面所述的三特异性抗体或第六方面所述的药物组合物在制备治疗肿瘤药物中的应用。
优选地,所述肿瘤包括多发性骨髓瘤。
与现有技术相比,本发明具备以下有益效果:
本发明筛选得到具备高亲和力的特异性抗体,所述抗体能够高效结合BCMA,并进一步利用所述抗体构建双特异性抗体和三特异性抗体,均具备高效结合活性,能够针对肿瘤细胞上多个靶点,具有高效诱导杀伤肿瘤细胞活性,对于治疗肿瘤药物开发领域具有重要意义。
附图说明
图1为本发明特异性抗体3C5B6与293T-BCMA细胞的结合活性图;
图2为本发明特异性抗体Chi-3C5B6与293T-BCMA细胞的结合活性图;
图3为本发明人源化特异性抗体h3C5B6与293T-BCMA细胞的结合活性图;
图4为本发明双特异性抗体结构示意图;
图5为本发明三特异性抗体结构示意图;
图6为本发明双特异性抗体和三特异性抗体与293T-BCMA细胞的结合活性图;
图7为本发明双特异性抗体和三特异性抗体诱导PBMC杀伤BCMA阳性细胞结果图;
图8为本发明双特异性抗体和三特异性抗体诱导PBMC杀伤肿瘤细胞RPMI 8226结果图。
具体实施方式
为进一步阐述本发明所采取的技术手段及其效果,以下结合实施例和附图对本发明作进一步地说明。可以理解的是,此处所描述的具体实施方式仅仅用于解释本发明,而非对本发明的限定。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道商购获得的常规产品。
实施例1
本实施例进行免疫与融合。
用BCMA-hFc重组融合蛋白(氨基酸序列为:MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK)与弗氏佐剂乳化后免疫Balb/C小鼠,首免使用弗氏完全佐剂,二免至三免使用弗氏不完全佐剂,本次共免疫15只小鼠(北京华阜康生物,BALB/C,6-8周,雌性),选取血清滴度较高的小鼠加强免疫,3天后处死小鼠取出脾脏用于后续实验。检测血清滴度主要采用ELISA法,包被BCMA-his重组融合蛋白(氨基酸序列为:MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAHHHHHH),浓度为1μg/mL,50μL/孔4℃过夜;用2%BSA,37℃封闭1h;用PBST将血清稀释,每孔加50μL,37℃孵育1h;然后加入二抗anti-mfc HRP(Sigma,A0168),37℃孵育1h,显色10min后,用2M(mol/L)浓硫酸终止,酶标仪上读取OD450,通过电融合技术将小鼠脾淋巴细胞与骨髓瘤细胞Sp2/0细胞进行融合得到杂交瘤细胞。
实施例2
本实施例进行抗体ELISA结合与筛选。
包板蛋白为hBCMA-his,1μg/mL,50μL/孔,4℃包板过夜;150μL/孔2%BSA25℃孵育1h;200μL/孔PBST洗三遍;样品或阳性抗体(Belantamab)配制300μL 10μg/mL的母液;稀释倍数为3.16(100μL母液+216μL封闭液),共11个梯度;50μL/孔样品或阳性抗体,H12列加入等体积mIgG1作为阴性对照,25℃孵育1h,200μL/孔PBST洗三遍;杂交瘤样品用anti-mfcHRP(1:5000)(Sigma,A0168)稀释,50μL/孔,25℃孵育1h,200μL/孔PBST洗三遍;拍干后,加入50μLTMB显色液,显色约15min,然后用硫酸终止反应,酶标仪读数OD450,筛选高亲和力抗体。
对照抗体BCMA(Belantamab)氨基酸序列:
重链:
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK;
轻链:
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC。
实施例3
本实施例进行抗体流式细胞术结合与筛选。
利用293T细胞(ATCC来源),进行慢病毒转染,构建293T过表达BCMA细胞株。收集293T-BCMA细胞,使用FACS buffer重悬,计数,调整细胞浓度为3×106个/mL;将50μL293T-BCMA细胞悬液加入96孔U底板中;配制抗体,250μL的40μg/mL实施例2筛选的样品/阳性对照(Belantamab)或阴性对照(IgG1 isotype),稀释倍数为3.16,共11个梯度;50μL样品加入到细胞中,4℃孵育1h;FACS buffer洗两遍;加入100μLAF647 anti-mIgG(H+L)(1:500稀释),4℃孵育40min;FACSbuffer洗三遍;用200μLFACS buffe重悬样品,流式仪上机检测样品的中位荧光强度,结果如图1所示,筛选到具备高结合活性的抗体(编号为3C5B6)。
实施例4
本实施例进行抗体分子构建与生产。
将实施例3筛选到克隆进行测序,将细胞溶于Trizol(Invitrogen,15596-018)提取RNA,按照试剂盒(PrimeScriptTMII 1st Strand cDNA Synthesis Kit,takara,6210B(Ax4))使用说明书进行操作,将反转录得到的cDNA进行PCR扩增,然后送往测序,确定具有结合活性克隆3C5B6的氨基酸序列,重连可变区氨基酸序列如SEQ ID NO.7所示,轻链可变区氨基酸序列如SEQ ID NO.8所示。
将获得的可变区序列连接至人的恒定区序列,得到人-鼠嵌合的抗体序列,重链的恒定区的氨基酸序列如SEQ ID NO.9所示,轻链的恒定区的氨基酸序列如SEQ ID NO.10所示,然后共转染进入Expi293细胞,在37℃、8%CO2、120rpm摇床中培养,7天后的瞬时表达上清通过ProteinA亲和层析,纯化获得嵌合抗体(编号chi-3C5B6)。
实施例5
本实施例进行嵌合抗体结合活性验证。
收集293T-BCMA细胞,使用FACS buffer重悬,计数,调整细胞浓度为3×106个/mL;将50μL 293T-BCMA细胞悬液加入96孔U底板中;配置抗体,250μL的40μg/mL样品/阳性对照(Belantamab),稀释倍数为3.16,共11个梯度;50μL样品加入到细胞中,4℃孵育1h;FACSbuffer洗两遍;加入100μL AF647 anti-hIgG(H+L)(1:500稀释),4℃孵育40min,FACSbuffer洗三遍;用200μLFACS buffe重悬样品,流式仪上机检测样品的中位荧光强度,结果如图2所示,表明本发明筛选到的抗体具备高效结合活性。
实施例6
本实施例进行小鼠抗体人源化。
对筛选得到鼠源抗体进3C5B6行人源化,在所获得的鼠源抗体VH/VL CDR的基础上,将重、轻链可变区序列与全人源抗体Germline数据库比较,获得同源性高的人源Germline模板,其中,人类Germline轻链框架区来自人K轻链基因,优选人种系轻链模版IGKV1-33*01和IGKJ2*02,人类种系重链框架区来自人重链,优选人种系重链模版IGHV1-46*01和IGHJ1*01。
将鼠源抗体的CDR移植到选定的人源化模板上,替换成人源化框架区,然后,以鼠源抗体的三维结构为基础,对包埋残基、与CDR区有直接相互作用的残基,以及对VL和VH的构象有重要影响的残基进行回复突变,得到一系列人源化轻重链分子。
重链可变区人源化
hVH(SEQ ID NO.21):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYMHWVRQAPGQGLEWMGIIYRGHSDTSYNQKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGAIYNAYDVLDYWGQGTLVTVSS。
轻链可变区人源化
hVL(SEQ ID NO.22):
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYYTSNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLPLTFGQGTKLEIK。
最终的人源化抗体h3C5B6,完整轻重链序列如SEQ ID NO.23。
完整轻链序列如SEQ ID NO.24所示。
并对人源化抗体h3C5B6结合活性进行验证,方法参照实施例5,结果如图3所示,人源化后并未减弱抗体的亲和力。
实施例7
本实施例进行BCMA×CD3(2:1)双特异性抗体(编号为CBA)的制备,及BCMA×CD38×CD3三特异性抗体(编号为CBCD38)的制备。
一、BCMA×CD3(2:1)双特异性抗体(编号为CBA)的制备
通过同时共转染三个不同的哺乳动物表达载体产生2:1双特异性抗体,双特异性抗体的结构示意图如图4所示,分别编码(1)相应的BCMA抗体的重链,其在Fc区携带“Hole”突变以产生异源二聚体抗体,Fc的CH2携带L234A、L235A突变,序列如SEQ ID NO.17所示;编码(2)相应的CD3(scfv)及BCMA(scfv)抗体链,其在Fc区携带“knob”突变以产生异源二聚体抗体,Fc的CH2携带L234A、L235A突变,序列如SEQ ID NO.19所示;(3)相应的BCMA抗体的轻链,序列如SEQ ID NO.18所示。人IgG1Fc区的“knob”突变由以下组成:T366W,“Hole”突变由以下组成:T366S、L368A、Y407V,同时增加H435R、Y436F突变,BCMA×CD3(2:1)。
二、BCMA×CD38×CD3三特异性抗体(编号为CBCD38)的制备
通过同时共转染三个不同的哺乳动物表达载体产生BCMA×CD38×CD3双特异性抗体,BCMA×CD38×CD3三特异性抗体结构如图5所示,分别编码(1)相应的BCMA抗体的重链,其在Fc区携带“Hole”突变以产生异源二聚体抗体,Fc的CH2携带L234A、L235A突变,序列如SEQ ID NO.17所示;编码(2)相应的CD3(scfv)及CD38(scfv)抗体链,其在Fc区携带“knob”突变以产生异源二聚体抗体,Fc的CH2携带L234A、L235A突变,序列如SEQ ID NO.20所示;(3)相应的BCMA抗体的轻链,序列如SEQ ID NO.18所示。人IgG1Fc区的“knob”突变由以下组成:T366W,“Hole”突变由以下组成:T366S、L368A、Y407V,同时增加H435R、Y436F突变。
实施例8
本实施例利用FACS检测实施例7制备的双特异性抗体和三特异性抗体的结合活性。
收集293T-BCMA细胞,使用FACS buffer重悬,计数,调整细胞浓度为3×106个/mL,将50μL 293T-BCMA细胞悬液加入96孔U底板中;配置抗体,150nM起始,稀释倍数为3.16,共10个梯度;50μL样品加入到细胞中,4℃孵育1h;FACS buffer洗两遍;加入100μLAF647anti-hIgG(H+L)(1:500稀释),4℃孵育40min,FACS buffer洗三遍;用200μL FACS buffe重悬样品,流式仪上机检测样品的中位荧光强度,结果如6所示,实施例7制备的双特异性抗体和三特异性抗体均具备高效结合活性。
实施例9
本实施例利用实施例7制备的双特异性抗体(CBA)和三特异性抗体(CBCD38)进行诱导PBMC杀伤BCMA阳性细胞实验。
取新鲜分离得到的PBMC分别与处于对数生长期的靶细胞293T-BCMA细胞混合,效应/靶细胞=20:1,每孔加入50μL梯度稀释的抗体(抗体浓度从150nM(nmol/L)起,3.16倍稀释,10个梯度),5%、CO2、37℃培养24h,培养结束后,将50μL上清转移至新的黑色酶标板,加入50μL/孔LDH检测底物,10min后终止反应并检测LDH释放,结果如图7所示,在靶细胞为BCMA单阳性细胞时,CBA双抗体现了更好的杀伤活性。
实施例10
本实施例利用实施例7制备的双特异性抗体(CBA)和三特异性抗体(CBCD38)进行诱导PBMC杀伤肿瘤细胞RPMI 8226(来源ATCC)实验。
取新鲜分离得到的PBMC分别与处于对数生长期的肿瘤细胞RPMI 8226细胞混合,效应/靶细胞=10:1,每孔加入50μL梯度稀释的抗体(抗体浓度从66.7nM起,10倍稀释,8个梯度),5%、CO2、37℃培养24h,培养结束后,将50μL上清转移至新的黑色酶标板,加入50μL/孔LDH检测底物,10min后终止反应并检测LDH释放,结果如图8所示,在BCMA,CD38双阳性肿瘤细胞杀伤实验中,体现了相似的杀伤活性,但CBCD38三特异性抗体最高杀伤活性更强。
综上所述,本发明筛选得到具备高亲和力的特异性抗体,所述抗体能够高效结合BCMA,并进一步利用所述抗体构建双特异性抗体和三特异性抗体,均具备高效结合活性,能够针对肿瘤细胞上多个靶点,具有高效诱导杀伤肿瘤细胞活性,对于治疗肿瘤药物开发领域具有重要意义。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
序列表
<110> 杜坤
<120> 一种特异性抗体及其制备方法和应用
<130> 2022-0524
<160> 24
<170> PatentIn version 3.3
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<400> 1
Asn Tyr Tyr Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列
<400> 2
Ile Ile Tyr Arg Gly His Ser Asp Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 3
<211> 12
<212> PRT
<213> 人工序列
<400> 3
Gly Ala Ile Tyr Asn Ala Tyr Asp Val Leu Asp Tyr
1 5 10
<210> 4
<211> 11
<212> PRT
<213> 人工序列
<400> 4
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<400> 5
Tyr Thr Ser Asn Leu Glu Thr
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<400> 6
Gln Gln Tyr Asp Asn Leu Pro Leu Thr
1 5
<210> 7
<211> 121
<212> PRT
<213> 人工序列
<400> 7
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Tyr Arg Gly His Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asn Ala Tyr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 8
<211> 107
<212> PRT
<213> 人工序列
<400> 8
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 9
<211> 330
<212> PRT
<213> 人工序列
<400> 9
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 10
<211> 107
<212> PRT
<213> 人工序列
<400> 10
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> 11
<211> 119
<212> PRT
<213> 人工序列
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Leu Thr Arg Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 12
<211> 106
<212> PRT
<213> 人工序列
<400> 12
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 Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 233
<212> PRT
<213> 人工序列
<400> 13
Ala Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
20 25 30
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
35 40 45
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
50 55 60
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
65 70 75 80
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
85 90 95
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
100 105 110
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
115 120 125
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu
130 135 140
Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
165 170 175
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
180 185 190
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
195 200 205
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
210 215 220
Lys Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 14
<211> 232
<212> PRT
<213> 人工序列
<400> 14
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 15
<211> 122
<212> PRT
<213> 人工序列
<400> 15
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asn Ser Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 16
<211> 107
<212> PRT
<213> 人工序列
<400> 16
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 Ser 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
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 17
<211> 451
<212> PRT
<213> 人工序列
<400> 17
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Arg Gly His Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asn Ala Tyr Asp Val 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 Ala Ala Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 18
<211> 214
<212> PRT
<213> 人工序列
<400> 18
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 Gln Ala Ser Gln Asp Ile Ser Asn 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 Asn Leu Glu Thr 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 Tyr Asp Asn Leu Pro Leu
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> 19
<211> 721
<212> PRT
<213> 人工序列
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Arg Gly His Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asn Ala Tyr Asp Val 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 Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Asn Leu Glu Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Asn Leu Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly
245 250 255
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala
260 265 270
Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala
275 280 285
Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Ser Arg Gly
290 295 300
Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Leu Thr Arg
305 310 315 320
Asp Lys Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser
325 330 335
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr
340 345 350
Cys Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
355 360 365
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
370 375 380
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
385 390 395 400
Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
405 410 415
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr Asp Thr
420 425 430
Ser Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
435 440 445
Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
450 455 460
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly
465 470 475 480
Gly Gly Thr Lys Val Glu Ile Lys Ala Glu Pro Lys Ser Ser Asp Lys
485 490 495
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
500 505 510
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
515 520 525
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
530 535 540
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
545 550 555 560
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
565 570 575
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
580 585 590
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
595 600 605
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
610 615 620
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
625 630 635 640
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
645 650 655
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
660 665 670
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
675 680 685
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
690 695 700
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
705 710 715 720
Lys
<210> 20
<211> 722
<212> PRT
<213> 人工序列
<400> 20
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asn Ser Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
130 135 140
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
145 150 155 160
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala
180 185 190
Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
210 215 220
Cys Gln Gln Arg Ser Asn Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys
225 230 235 240
Val Glu Ile Lys Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser
245 250 255
Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys
260 265 270
Ala Ser Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln
275 280 285
Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Ser Arg
290 295 300
Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Leu Thr
305 310 315 320
Arg Asp Lys Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg
325 330 335
Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His
340 345 350
Tyr Cys Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
370 375 380
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
385 390 395 400
Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met Asn
405 410 415
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr Asp
420 425 430
Thr Ser Lys Val Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
435 440 445
Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
450 455 460
Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe
465 470 475 480
Gly Gly Gly Thr Lys Val Glu Ile Lys Ala Glu Pro Lys Ser Ser Asp
485 490 495
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
500 505 510
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
515 520 525
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
530 535 540
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
545 550 555 560
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
565 570 575
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
580 585 590
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
595 600 605
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
610 615 620
Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
625 630 635 640
Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
645 650 655
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
660 665 670
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
675 680 685
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
690 695 700
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
705 710 715 720
Gly Lys
<210> 21
<211> 121
<212> PRT
<213> 人工序列
<400> 21
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Arg Gly His Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asn Ala Tyr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 22
<211> 107
<212> PRT
<213> 人工序列
<400> 22
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 Gln Ala Ser Gln Asp Ile Ser Asn 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 Asn Leu Glu Thr 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 Tyr Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 23
<211> 451
<212> PRT
<213> 人工序列
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Arg Gly His Ser Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Ile Tyr Asn Ala Tyr Asp Val 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> 24
<211> 214
<212> PRT
<213> 人工序列
<400> 24
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 Gln Ala Ser Gln Asp Ile Ser Asn 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 Asn Leu Glu Thr 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 Tyr Asp Asn Leu Pro Leu
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
Claims (16)
1.一种特异性抗体,其特征在于,所述特异性抗体的重链的CDR1、CDR2和CDR3的氨基酸序列分别为SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示的序列;
所述特异性抗体的轻链的CDR1、CDR2和CDR3的氨基酸序列分别为SEQ ID NO.4、SEQ IDNO.5和SEQ ID NO.6所示的序列。
2.根据权利要求1所述的特异性抗体,其特征在于,所述特异性抗体的重链的可变区的氨基酸序列为SEQ ID NO.7所示的序列。
3.根据权利要求1所述的特异性抗体,其特征在于,所述特异性抗体的轻链的可变区的氨基酸序列为SEQ ID NO.8所示的序列。
4.根据权利要求1所述的特异性抗体,其特征在于,所述特异性抗体的重链的恒定区的氨基酸序列为SEQ ID NO.9所示的序列。
5.根据权利要求1所述的特异性抗体,其特征在于,所述特异性抗体的轻链的恒定区的氨基酸序列为SEQ ID NO.10所示的序列。
6.一种核酸分子,其特征在于,所述核酸分子含有编码权利要求1-5任一项所述特异性抗体的核酸序列。
7.一种如权利要求1-5任一项所述的特异性抗体的制备方法,其特征在于,所述制备方法包括:
将编码如权利要求1-5任一项所述的特异性抗体的核酸序列插入表达载体,得到重组载体,将所述重组载体导入宿主细胞,进行培养,分离纯化,得到所述特异性抗体。
8.一种双特异性抗体,其特征在于,所述双特异性抗体含有权利要求1所述的特异性抗体的Fab和scfv、结合CD3的scfv以及由第一Fc多肽和第二Fc多肽形成二聚结构的Fc;
其中,权利要求1所述特异性抗体的scfv在其C端与结合CD3的scfv的N端融合,结合CD3的scfv在其C端与第一Fc多肽的N端融合,权利要求1或2所述特异性抗体的Fab在其C端与第二Fc多肽的N端融合;
所述结合CD3的scfv的重链的可变区的氨基酸序列为SEQ ID NO.11所示的序列,轻链的可变区的氨基酸序列为SEQ ID NO.12所示的序列。
9.根据权利要求8所述的双特异性抗体,其特征在于,所述权利要求1或2所述特异性抗体的Fab的重链的可变区的氨基酸序列为SEQ ID NO.7所示的序列,轻链的可变区的氨基酸序列为SEQ ID NO.8所示的序列。
10.根据权利要求8所述的双特异性抗体,其特征在于,所述权利要求1或2所述特异性抗体的scfv的重链的可变区的氨基酸序列为SEQ ID NO.7所示的序列,轻链的可变区的氨基酸序列为SEQ ID NO.8所示的序列。
11.根据权利要求8所述的双特异性抗体,其特征在于,所述第一Fc多肽的氨基酸序列为SEQ ID NO.13所示的序列,所述第二Fc多肽的氨基酸序列为SEQ ID NO.14所示的序列。
12.一种三特异性抗体,其特征在于,所述三特异性抗体含有权利要求1或2所述特异性抗体的Fab、结合CD3的scfv、结合CD38的scfv以及由第一Fc多肽和第二Fc多肽形成二聚结构的Fc;
其中,结合CD38的scfv在其C端与结合CD3的scfv的N端融合,结合CD3的scfv在其C端与第一Fc多肽的N端融合,权利要求1或2所述特异性抗体的Fab在其C端与第二Fc多肽的N端融合;
所述结合CD3的scfv的重链的可变区的氨基酸序列为SEQ ID NO.11所示的序列,轻链的可变区的氨基酸序列为SEQ ID NO.12所示的序列;
所述结合CD38的scfv的重链的可变区的氨基酸序列为SEQ ID NO.15所示的序列,轻链的可变区的氨基酸序列为SEQ ID NO.16所示的序列。
13.根据权利要求12所述的三特异性抗体,其特征在于,所述权利要求1或2所述特异性抗体的Fab的重链的可变区的氨基酸序列为SEQ ID NO.7所示的序列,轻链的可变区的氨基酸序列为SEQ ID NO.8所示的序列。
14.根据权利要求12所述的三特异性抗体,其特征在于,所述第一Fc多肽的氨基酸序列为SEQ ID NO.13所示的序列,所述第二Fc多肽的氨基酸序列为SEQ ID NO.14所示的序列。
15.一种药物组合物,其特征在于,所述药物组合物含有权利要求1-5任一项所述的特异性抗体、权利要求6所述的核酸分子、权利要求8-11任一项所述的双特异性抗体或权利要求12-14任一项所述的三特异性抗体中的任意一种或至少两种的组合。
16.如权利要求1-5任一项所述的特异性抗体、权利要求6所述的核酸分子、权利要求8-11任一项所述的双特异性抗体、权利要求12-14任一项所述的三特异性抗体或权利要求15所述的药物组合物在制备治疗肿瘤药物中的应用;
所述肿瘤为多发性骨髓瘤。
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