CN113677704B - Psma抗体及其应用 - Google Patents

Psma抗体及其应用 Download PDF

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CN113677704B
CN113677704B CN202080009706.8A CN202080009706A CN113677704B CN 113677704 B CN113677704 B CN 113677704B CN 202080009706 A CN202080009706 A CN 202080009706A CN 113677704 B CN113677704 B CN 113677704B
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王峰
郑花鸯
张雨菡
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Nantong Yichen Biomedical Technology Co ltd
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Abstract

本发明涉及特异性结合PSMA的抗体片段，尤其是单链Fv(scfv)，包含所述scFv的双特异性抗体和嵌合抗原受体(CAR)及其制备与应用。

Description

PSMA抗体及其应用
技术领域
本发明提供了特异性结合PSMA的抗体片段，具体涉及特异性结合PSMA的单链Fv(scfv)、包含所述单链Fv的双抗、CAR及其组合物和应用。
背景技术
前列腺癌是导致男性死亡的第二大主要病因，仅次于肺癌。然而，目前的方法，例如手术、放射疗法、化学疗法和雄激素剥夺疗法，对那些晚期癌症具有有限的效果。迄今为止，根治性手术仍是前列腺癌的主要治疗方法。因此，新兴的精准医学，特别是基于肿瘤靶向抗体的精确医学，有望改善前列腺治疗的结果。
前列腺特异性膜抗原(PSMA)主要由前列腺上皮细胞表达。在前列腺癌中，特别是在低分化的、转移的和激素难以治疗的癌中，PSMA的表达增加(Gregorakis AK等(1998)Seminars in Urologic Oncology 16：2-12；Silver，DA(1997)Clinical Cancer Research3：85-515)。在前列腺外组织例知小肠、唾液腺、十二指肠粘膜、近端肾小管和脑中发现低水平PSMA表达(Silver，DA(1997)Clinical Cancer Research 3：85-515)。在一些恶性肿瘤(包括肾细胞癌和结肠癌)的肿瘤外周和肿瘤内区域中的毛细血管的内皮细胞中也表达PSMA，但是在正常组织的血管中不表达。另外，据报道PSMA与肿瘤血管生成相关(Silver，D.A.(1997)Clinical Cancer Research 3：81-85)。最近，已经证明PSMA在结肠癌、乳腺癌、膀胱癌、胰腺癌、肾癌和黑素瘤中的肿瘤相关新血管系统的内皮细胞中表达(Chang，S.S.(2004)Curr Opin Investig Drugs 5：611-5)，为前列腺癌靶向精准医学的发展奠定了基础。
发明内容
本发明利用噬菌体展示技术筛选获得一系列针对PSMA的高亲和力抗体。发明人进一步发现在这些抗体序列呈现为scFv的形式中，轻链VL的第42位氨基酸残基种类对亲和力有显著的影响；进一步的，含有特定类型第42位氨基酸的VL的双特异性抗体，其蛋白产率有大幅度提高。利用本发明中的aPSMA scfv抗体片段可用于构建双特异性抗体、嵌合抗原受体等，可满足肿瘤靶向治疗领域内对aPSMA scfv亲和力的要求。
本发明的一个方面，提供了一种特异性结合PSMA的抗体片段，其包括：
A)具有如SEQ ID NO:2所示氨基酸序列的重链可变区(VH)；
B)选自具有如下氨基酸序列的轻链可变区(VL)：SEQ ID NO:6、SEQ ID NO:8、SEQID NO:10、SEQ ID NO:12、SEQ ID NO:14或SEQ ID NO:52。
在一些实施方案中，所述特异性结合PSMA的抗体片段为单链Fv(scfv)。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:2所示氨基酸序列的VH和SEQ ID NO:6所示氨基酸序列的VL。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:2所示氨基酸序列的VH和SEQ ID NO:8所示氨基酸序列的VL。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:2所示氨基酸序列的VH和SEQ ID NO:10所示氨基酸序列的VL。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:2所示氨基酸序列的VH和SEQ ID NO:12所示氨基酸序列的VL。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:2所示氨基酸序列的VH和SEQ ID NO:14所示氨基酸序列的VL。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:2所示氨基酸序列的VH和SEQ ID NO:52所示氨基酸序列的VL。
在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:20所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:22所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:24所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:26所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:28所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:30所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:32所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:34所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:36所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ IDNO:38所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:54所示的氨基酸序列。在一些实施方案中，所述靶向PSMA的scfv具有如SEQ ID NO:56所示的氨基酸序列。
本发明的一个方面，提供了一种双特异性抗体，所述双特异性抗体包括：
1)特异性结合PSMA的第一抗原结合结构域，其包括：
A)具有如SEQ ID NO:2所示的氨基酸序列的重链可变区(VH)；和
B)具有选自如下氨基酸序列的轻链可变区(VL)：SEQ ID NO:6、SEQ ID NO:8、
SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14或SEQ ID NO:52，和
2)第二抗原结合结构域。
在一些实施方案中，所述双特异性抗体的第一抗原结合结构域为特异性结合PSMA的单链Fv(scfv)。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQID NO:20所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:22所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:24所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:26所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:28所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:30所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ IDNO:32所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:34所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:36所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:38所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:54所示的氨基酸序列。在一些实施方案中，所述双特异性抗体的第一抗原结合结构域具有如SEQ ID NO:56所示的氨基酸序列。
在一些实施方案中，所述双特异性抗体的第二抗原结合结构域结合至T细胞的特异性受体分子，其中所述T细胞的特异性受体分子优选为CD3。在一些实施方案中，所述特异性结合CD3的第二抗原结合结构域具有如SEQ ID NO:40所示的VH和SEQ ID NO:42所示的VL。
在一些实施方案中，所述双特异性抗体具有如SEQ ID NO:44和SEQ ID NO:46所示的序列。在一些实施方案中，所述双特异性抗体具有如SEQ ID NO:58和SEQ ID NO:60所示的序列。在一些实施方案中，所述双特异性抗体具有如SEQ ID NO:62和SEQ ID NO:64所示的序列。在一些实施方案中，所述双特异性抗体具有如SEQ ID NO:58和SEQ ID NO:66所示的序列。在一些实施方案中，所述双特异性抗体具有如SEQ ID NO:68和SEQ ID NO:64所示的序列。
本发明的一个方面，提供了一种嵌合抗原受体(CAR)，其中所述CAR包含特异性结合PSMA的scfv、跨膜结构域和胞内结构域。
在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:2所示的VH和SEQ ID NO:6所示的VL。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:2所示的VH和SEQ ID NO:8所示的VL。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:2所示的VH和SEQ ID NO:10所示的VL。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:2所示的VH和SEQ ID NO:12所示的VL。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:2所示的VH和SEQ IDNO:14所示的VL。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:2所示的VH和SEQ ID NO:52所示的VL。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:20所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:22所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:24所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:26所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:28所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:32所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:34所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:36所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:38所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:54所示的氨基酸序列。在一些实施方案中，所述CAR的特异性结合PSMA的scfv具有如SEQ ID NO:56所示的氨基酸序列。在一些实施方案中，所述CAR具有如SEQ ID NO:50所示的氨基酸序列。
本发明的一个方面，提供了一种多核苷酸，所述多核苷酸编码前述实施方案中任一项特异性结合PSMA的抗体片段、双特异性抗体或CAR。在一些实施方案中，所述多核苷酸包含选自下组的核苷酸序列：SEQ ID NO:5、7、9、11、13、19、21、23、25、27、29、31、33、35、37、39、41、43、44、45、47、49、51、53、55、57、59、61、63、65、67。
本发明的一个方面，提供了一种载体，其包含前述的多核苷酸。
本发明的一个方面，提供了一种细胞，其包含前述的载体。
本发明的一个方面，提供了包含前述任一项的抗体片段、双特异性抗体、CAR、多核苷酸、载体或细胞的组合物，所述组合物还包括药学可接受的载体。
本发明的一个方面，提供了治疗患有与PSMA表达相关的疾病的受试者的方法，其包括对所述受试者施用有效量的前述的组合物。
在一个方面，本发明提供了诊断哺乳动物中与PSMA表达相关的疾病的方法，所述方法包括：使用所述的抗体片段在从所述哺乳动物分离的组织样品中检测与人PSMA的结合，由此所述抗体片段对所述组织样品中人PSMA的特异性结合指示所述哺乳动物中与PSMA表达相关的疾病。
附图说明
构成本申请的附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定，在附图中：
图1为aPSMA LH RM和RM2单克隆噬菌体ELISA检测结果，其中RM为第一轮淘选、RM2为第二轮淘选。
图2为aPSMA HL单克隆噬菌体ELISA检测结果。
图3 A为VL第42位氨基酸突变的aPSMA scfv抗体与PSMA-his ELISA检测结果；图3B为靶向PSMA的scfv-Fc抗体(其中VL第42位氨基酸突变)与LnCap细胞结合流式检测结果。
图4为双特异性抗体与JurkatT细胞结合流式检测结果。
图5为双特异性抗体与LnCap细胞结合流式检测结果。
图6为双特异性抗体召集PBMC对LnCap细胞的细胞毒作用。
图7为双特性抗体在小鼠体内的PK曲线。
实施例
需要说明的是，在不冲突的情况下，本申请中的实施例仅为举例说明，不旨在对本发明造成任何方式上的限制。
实施例
实施例1噬菌体文库筛选
合成aPSMA HL(SEQ ID NO:37)和aPSMA LH(SEQ ID NO:39)，将其分别克隆进phagemid载体中，采用GeneMorph II random mutagenesis(Agilent)进行随机突变后，转化XL1-blue感受态细胞，待OD600＝0.6-0.8时，用辅助性噬菌体M13K07感染，12小时后收集噬菌体并测定噬菌体滴度(库容)。
微孔板包被抗原Fc-PSMA并使用蛋白BSA封闭，300ng/孔，对前述两个噬菌体文库进行2-3轮淘选并进行亲和力检测，从淘选的板子上分别随机挑选单克隆送去测序，并对测序结果进行分析。将有序列富集和在CDR区有突变的单克隆进行了噬菌体包装和亲和力检测。检测结果如图1所示。
图1是突变库aPSMA LH RM和aPSMA LH RM2的单克隆的亲和力检测结果，从图中可以看出，除了aPSMA LH RM-R13和aPSMA LH RM2-R15外，其余单克隆的亲和力都远远高出原序列；图2是突变库aPSMA HL RM的单克隆的亲和力检测结果，仅aPSMA HL RM-R1/R10/R15的亲和力较高。
对上述亲和力较高的序列分析后发现，在突变库aPSMA LH RM、aPSMA LH RM2和aPSMA HL RM中，亲和力较高的单克隆都在VL的第42位氨基酸发生了突变。
表1序列表
实施例2靶向PSMA的抗体与细胞的亲和力检测
2.1靶向PSMA的scfv-Fc抗体克隆及表达
将aPSMA HL(SEQ ID NO:15)、aPSMA LH(SEQ ID NO:17)、aPSMA HL(L42)(SEQ IDNO:19)、aPSMA HL(H42)(SEQ ID NO:21)、aPSMA HL(T42)(SEQ ID NO:23)、aPSMA HL(S42)(SEQ ID NO:25)、aPSMA HL(Q42)(SEQ ID NO:27)及aPSMA LH(Q42)(SEQ ID NO:29)通过传统酶切连接方法分别克隆至pFuse-hIgG1-Fc2的N端，测序验证。
将构建好的真核表达载体的分别瞬时转染FreeStyle HEK293细胞(ThermoFisher)：将28ml FreeStyle HEK 293(3×107细胞/ml)接种至125ml细胞培养瓶，质粒用1ml Opti-MEM(Invitrogen)稀释后加至1ml含60μl 293Fectin(Invitrogen,Inc)的Opti-MEM中，室温静置30min，将质粒-293fectin mixture加至细胞培养液中125rpm，372，5％CO2培养。分别于转染后48h和96h收集细胞培养上清，并根据制造商的说明书，使用Protein A Resin(Genscript)纯化后经SDS-PAGE检测。
2.2靶向PSMA的scfv-Fc抗体与PSMA-His的亲和力检测
包被PSMA-His(Acro)(100ng/孔)于96孔板，4℃孵育过夜；含2％脱脂奶粉的PBST(0.5％Tween-20in PBS)室温封闭1小时，分别加入梯度稀释的scfv-Fc抗体室温孵育2h，含2％脱脂奶粉的PBST洗4-5次后，加入anti-human Fc-HRP二抗室温孵育1h，含2％脱脂奶粉的PBST洗4-5次后，采用TMB显色试剂(BioLegend,Cat.421101)显色后于650nm(未终止)或450nm(终止)处读数。Prizm Graphpad软件用specific binding model对数据进行非线性回归。
结果如图3A所示，VL野生型的aPSMA LH-Fc或aPSMA LH-Fc抗体与PSMA-his的亲和力弱，VL第42位氨基酸突变的aPMSA HL(Q42)-Fc或aPSMA LH(Q42)-Fc抗体与PSMA-his的亲和力大大增强。
2.3靶向PSMA的scfv-Fc抗体与LnCap细胞的亲和力检测
LnCap细胞饲养于含10％FBS的RPMI 1640的培养基，置于5％CO2的培养箱。2*105个细胞用预冷的PBS洗3次。PBS稀释的2％FBS封闭，与梯度稀释的抗体(100nM依次3倍梯度稀释)4℃共孵育1h。未结合的抗体由2％FBS洗去。小鼠抗人IgG Fc-APC(southernbiotech)4度孵育1h，2％FBS洗涤，流式细胞计数分析。结果如图3所示，VL第42位发生氨基酸突变的aPSMA单链scfv融合到Fc后对LnCap表面的PSMA均有较高的亲和力，比野生型VL的亲和力提高190-220倍。
实施例3靶向PSMA和CD3的双特异性抗体
3.1靶向PSMA和CD3的双特异性抗体构建和表达
采用标准分子生物学方法构建含有序列表1所示的不同aCD3-aPMSA双抗的chain-1和chain-2，测序验证。
将上述测序验证的真核表达载体的两条链瞬时共转染FreeStyle HEK293细胞(ThermoFisher)：将28ml FreeStyle HEK 293(3×107细胞/ml)接种至125ml细胞培养瓶，质粒用1ml Opti-MEM(Invitrogen)稀释后加至1ml含60μl 293Fectin(Invitrogen,Inc)的Opti-MEM中，室温静置30min，将质粒-293fectin mixture加至细胞培养液中125rpm，372，5％CO2培养。分别于转染后48h和96h收集细胞培养上清，并根据制造商的说明书，使用Protein A Resin(Genscript)纯化后经SDS-PAGE检测，并计算产率。结果显示：基于VL第42位突变的aCD3-aPSMA的产率(15-20mg/L)比VL第42位野生型的aCD3-aPSMA的产率(2.5-5mg/L)有明显提升。
3.2靶向PSMA和CD3的双特异性抗体体外活性检测
3.2.1与Jurkat(CD3+)细胞结合的流式细胞术分析
Jurkat细胞饲养于含10％FBS的RPMI 1640的培养基，置于5％CO2的培养箱。2х105个细胞用预冷的PBS洗3次，经含2％FBS的PBS封闭后，与浓度分别为100nM,33.3nM,11.1nM,3.7nM,1.2nM or 0.4nM的双抗于4双孵育1h。用含2％FBS的PBS洗去未结合的抗体，加二抗小鼠抗人IgG Fc-APC(southern biotech)4℃孵育1h，含2％FBS的PBS洗三次后，流式细胞计数分析。结果如图4所示，双特异性抗体能有效结合Jurkat细胞。
3.2.2与LnCap(PSMA+)细胞结合的流式细胞术分析
LnCap细胞饲养于含10％FBS的RPMI 1640的培养基，置于5％CO2的培养箱。2*105个细胞用预冷的PBS洗3次。PBS稀释的2％FBS封闭，与浓度分别为100nM,33.3nM,11.1nM,3.7nM,1.2nM or 0.4nM的融合蛋白样品4度共孵育1h。未结合的抗体由2％FBS洗去。小鼠抗人IgG Fc-APC(southern biotech)4度孵育1h，2％FBS洗涤，流式细胞计数分析。结果如图5所示，双特异性抗体能有效结合LnCap细胞。
表2双特异性抗体与Jurkat和LnCap结合的EC50
EC50(nM) aCD3-aPSMA aCD3 aPSMA
Jurkat 0.51 0.51 NA
LnCap 0.05 NA 0.01
3.2.3依赖PBMC的细胞毒性试验
采用常规Ficoll-Hypaque梯度离心法从新鲜健康供体血液中分离纯化出单个核细胞(PBMC)。洗涤分离后的PBMC，在含10％(vol/vol)FBS的RPMI培养基中孵育1h，去除贴壁细胞。用CD3和CD28活化PBMC后，加IL-2培养10天。
1х104个LnCap细胞(含5％FBS的RPMI培养基)与活化后的PBMCs按1:5的比例混合后，与不同稀释度的双抗于37℃孵育16h。上清中LDH(乳酸脱氢酶)的含量用Cytotox-96nonradioactive cytotoxicity assay kit(Promega)检测。用裂解液处理的仅含靶细胞的孔测得的值为maximum killing，用PBS(vehicle)处理的含效应细胞、靶细胞的孔测得的值为Spontaneous killing。根据产品说明书进行孵育显色，BMG LABTECH CLARIOstar酶标仪(Bio-Gene Technology Ltd.)读取490nm处的吸光度。计算细胞毒百分比：％cytotoxicity＝(absorbance experimental-absorbance spontaneous average)/(absorbance maximum killing average-absorbance spontaneous average)。
结果如图6所示，与对照aPSMA相比，aCD3-aPSMA能有效召集PBMC中的T细胞，发挥T细胞对靶细胞LnCap的特异性杀伤作用。
表3双特异性抗体召集PBMC对靶细胞LnCap的杀伤
aCD3-aPSMA aCD3 aPSMA
LDH Killing EC50(pM) 184.4 712.3 NA
LDH max killing(pM) 79.79 42.76 NA
3.3靶向PSMA和CD3的双特异性抗体PK研究
将双特异性抗体腹腔注射(I.P.)C57雌性小鼠(3只/组，剂量10mg/kg)，于注射后30min、1h、2h、4h、10h、24h、3d、5d、7d、14d采集全血。离心后取血浆，-80℃保存备用。血浆中双特异性抗体的含量检测参照实施例2.2进行。结果如图所示，双特异性抗体在小鼠体内的半衰期5天左右。
SEQUENCE LISTING
<110> 南通壹宸生物医药科技有限公司
<120> PSMA抗体及其应用
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<170> PatentIn version 3.5
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cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
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<210> 16
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<212> PRT
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Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser
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<210> 17
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<212> DNA
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gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
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ggccccagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
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acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 18
<211> 237
<212> PRT
<213> 人工序列
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Pro Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 19
<211> 711
<212> DNA
<213> 人工序列
<400> 19
gaggtgcagc tggtgcagag cggccccgag gtgaagaagc ccggcgccac cgtgaagatc 60
agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120
cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
aaccagaagt tcgaggacaa ggccaccctg accgtggaca agagcaccga caccgcctac 240
atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc cgccggctgg 300
aacttcgact actggggcca gggcacccta cttacagtaa gtagcggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacatccaga tgacccagag ccccagcagc 420
ctgagcacca gcgtgggcga ccgcgtgacc ctgacctgca aggccagcca ggacgtgggc 480
accgccgtgg actggtacca gcagaagccc ggcctcagcc ccaagctgct gatctactgg 540
gccagcaccc gccacaccgg catccccagc cgcttcagcg gcagcggcag cggcaccgac 600
ttcaccctga ccatcagcag cctgcagccc gaggacttcg ccgactacta ctgccagcag 660
tacaacagct accccctgac cttcggcccc ggcaccaagg tggacatcaa g 711
<210> 20
<211> 237
<212> PRT
<213> 人工序列
<400> 20
Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly
145 150 155 160
Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Gly Leu Ser Pro Lys Leu
165 170 175
Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Ile Pro Ser Arg Phe
180 185 190
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
195 200 205
Gln Pro Glu Asp Phe Ala Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr
210 215 220
Pro Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
225 230 235
<210> 21
<211> 711
<212> DNA
<213> 人工序列
<400> 21
gaggtgcagc tggtgcagag cggccccgag gtgaagaagc ccggcgccac cgtgaagatc 60
agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120
cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
aaccagaagt tcgaggacaa ggccaccctg accgtggaca agagcaccga caccgcctac 240
atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc cgccggctgg 300
aacttcgact actggggcca gggcacccta cttacagtaa gtagcggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacatccaga tgacccagag ccccagcagc 420
ctgagcacca gcgtgggcga ccgcgtgacc ctgacctgca aggccagcca ggacgtgggc 480
accgccgtgg actggtacca gcagaagccc ggcctcagcc ccaagctgct gatctactgg 540
gccagcaccc gccacaccgg catccccagc cgcttcagcg gcagcggcag cggcaccgac 600
ttcaccctga ccatcagcag cctgcagccc gaggacttcg ccgactacta ctgccagcag 660
tacaacagct accccctgac cttcggcccc ggcaccaagg tggacatcaa g 711
<210> 22
<211> 237
<212> PRT
<213> 人工序列
<400> 22
Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly
145 150 155 160
Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Gly Leu Ser Pro Lys Leu
165 170 175
Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Ile Pro Ser Arg Phe
180 185 190
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
195 200 205
Gln Pro Glu Asp Phe Ala Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr
210 215 220
Pro Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
225 230 235
<210> 23
<211> 711
<212> DNA
<213> 人工序列
<400> 23
gaggtgcagc tggtgcagag cggccccgag gtgaagaagc ccggcgccac cgtgaagatc 60
agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120
cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
aaccagaagt tcgaggacaa ggccaccctg accgtggaca agagcaccga caccgcctac 240
atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc cgccggctgg 300
aacttcgact actggggcca gggcacccta cttacagtaa gtagcggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacatccaga tgacccagag ccccagcagc 420
ctgagcacca gcgtgggcga ccgcgtgacc ctgacctgca aggccagcca ggacgtgggc 480
accgccgtgg actggtacca gcagaagccc ggcaccagcc ccaagctgct gatctactgg 540
gccagcaccc gccacaccgg catccccagc cgcttcagcg gcagcggcag cggcaccgac 600
ttcaccctga ccatcagcag cctgcagccc gaggacttcg ccgactacta ctgccagcag 660
tacaacagct accccctgac cttcggcccc ggcaccaagg tggacatcaa g 711
<210> 24
<211> 237
<212> PRT
<213> 人工序列
<400> 24
Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly
145 150 155 160
Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu
165 170 175
Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Ile Pro Ser Arg Phe
180 185 190
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
195 200 205
Gln Pro Glu Asp Phe Ala Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr
210 215 220
Pro Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
225 230 235
<210> 25
<211> 711
<212> DNA
<213> 人工序列
<400> 25
gaggtgcagc tggtgcagag cggccccgag gtgaagaagc ccggcgccac cgtgaagatc 60
agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120
cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
aaccagaagt tcgaggacaa ggccaccctg accgtggaca agagcaccga caccgcctac 240
atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc cgccggctgg 300
aacttcgact actggggcca gggcacccta cttacagtaa gtagcggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacatccaga tgacccagag ccccagcagc 420
ctgagcacca gcgtgggcga ccgcgtgacc ctgacctgca aggccagcca ggacgtgggc 480
accgccgtgg actggtacca gcagaagccc ggctccagcc ccaagctgct gatctactgg 540
gccagcaccc gccacaccgg catccccagc cgcttcagcg gcagcggcag cggcaccgac 600
ttcaccctga ccatcagcag cctgcagccc gaggacttcg ccgactacta ctgccagcag 660
tacaacagct accccctgac cttcggcccc ggcaccaagg tggacatcaa g 711
<210> 26
<211> 237
<212> PRT
<213> 人工序列
<400> 26
Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly
145 150 155 160
Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu
165 170 175
Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Ile Pro Ser Arg Phe
180 185 190
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
195 200 205
Gln Pro Glu Asp Phe Ala Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr
210 215 220
Pro Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
225 230 235
<210> 27
<211> 711
<212> DNA
<213> 人工序列
<400> 27
gaggtgcagc tggtgcagag cggccccgag gtgaagaagc ccggcgccac cgtgaagatc 60
agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120
cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
aaccagaagt tcgaggacaa ggccaccctg accgtggaca agagcaccga caccgcctac 240
atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc cgccggctgg 300
aacttcgact actggggcca gggcacccta cttacagtaa gtagcggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacatccaga tgacccagag ccccagcagc 420
ctgagcacca gcgtgggcga ccgcgtgacc ctgacctgca aggccagcca ggacgtgggc 480
accgccgtgg actggtacca gcagaagccc ggccagagcc ccaagctgct gatctactgg 540
gccagcaccc gccacaccgg catccccagc cgcttcagcg gcagcggcag cggcaccgac 600
ttcaccctga ccatcagcag cctgcagccc gaggacttcg ccgactacta ctgccagcag 660
tacaacagct accccctgac cttcggcccc ggcaccaagg tggacatcaa g 711
<210> 28
<211> 237
<212> PRT
<213> 人工序列
<400> 28
Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly
145 150 155 160
Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu
165 170 175
Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Ile Pro Ser Arg Phe
180 185 190
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
195 200 205
Gln Pro Glu Asp Phe Ala Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr
210 215 220
Pro Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
225 230 235
<210> 29
<211> 711
<212> DNA
<213> 人工序列
<400> 29
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggccagagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 30
<211> 237
<212> PRT
<213> 人工序列
<400> 30
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 31
<211> 711
<212> DNA
<213> 人工序列
<400> 31
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggctccagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 32
<211> 237
<212> PRT
<213> 人工序列
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 33
<211> 711
<212> DNA
<213> 人工序列
<400> 33
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggcaccagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 34
<211> 237
<212> PRT
<213> 人工序列
<400> 34
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 35
<211> 711
<212> DNA
<213> 人工序列
<400> 35
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggccacagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 36
<211> 237
<212> PRT
<213> 人工序列
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly His Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 37
<211> 711
<212> DNA
<213> 人工序列
<400> 37
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggcctcagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 38
<211> 237
<212> PRT
<213> 人工序列
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Leu Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 39
<211> 375
<212> DNA
<213> 人工序列
<400> 39
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctctggatt caccttcaat acctacgcca tgaactgggt ccgccaggct 120
ccgggaaagg gtttggaatg ggttgctcgc attcgcagta aatataataa ttatgcaaca 180
tattatgccg attcagtgaa agaccgtttc accatctccc gcgatgattc aaagaacacg 240
ctctatctgc aaatgaacag cctgcgcgct gaggacacgg ccgtgtatta ctgcgtgcgt 300
catggcaact ttggtaattc ttatgtgagc tggttcgcct actggggcca gggaaccctg 360
gtcaccgtca gctct 375
<210> 40
<211> 125
<212> PRT
<213> 人工序列
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 41
<211> 330
<212> DNA
<213> 人工序列
<400> 41
caagctgttg tgacccaaga accgagtctg accgtgtctc cgggcggcac cgttacgctg 60
acctgtcgct cctctaccgg cgcagtcacc acgagcaact atgcaaattg ggtgcagcaa 120
aaaccggatc atctgtttcg tggcctgatt ggcggtacga acaaacgtgc gccggggacc 180
ccggcacgtt tttcgggcag cctgctgggc gataaagcag cactgaccat cagtggtgcg 240
cagccggaag atgaagcaga atattactgc gctctgtggt atagcaacct gtgggtcttt 300
ggcggtggca cgaaactgac cgttctgaaa 330
<210> 42
<211> 110
<212> PRT
<213> 人工序列
<400> 42
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Asp His Leu Phe Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Asp Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Lys
100 105 110
<210> 43
<211> 2088
<212> DNA
<213> 人工序列
<400> 43
caagctgttg tgacccaaga accgagtctg accgtgtctc cgggcggcac cgttacgctg 60
acctgtcgct cctctaccgg cgcagtcacc acgagcaact atgcaaattg ggtgcagcaa 120
aaaccggatc atctgtttcg tggcctgatt ggcggtacga acaaacgtgc gccggggacc 180
ccggcacgtt tttcgggcag cctgctgggc gataaagcag cactgaccat cagtggtgcg 240
cagccggaag atgaagcaga atattactgc gctctgtggt atagcaacct gtgggtcttt 300
ggcggtggca cgaaactgac cgttctgaaa cgcacagtgg cagcccccag cgtcttcatt 360
tttccccctt ccgatgaaca gctgaagtcc ggcactgctt ctgtggtctg tctgctgaac 420
aatttctatc ccagagaggc caaggtgcag tggaaagtgg acaacgctct gcagtccggc 480
aacagccagg agagtgtgac cgaacaggat agtaaggaca gcacatattc tctgtctagt 540
accctgacac tgagtaaggc agattacgag aagcacaaag tgtatgcctg cgaagtcact 600
catcagggac tgtcaagccc cgtgaccaag agcttcaacc ggggcgagtg tgacaaaact 660
cacacatgcc caccgtgccc agcacctcca gtcgccggac cgtcagtctt cctcttccct 720
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 780
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 960
aacaaaggcc tcccaagctc catcgagaaa accatctcca aagccaaagg gcagccccga 1020
gaaccacagg tgtgcaccct gcctccatcc cgggatgagc tgaccaagaa ccaggtcagc 1080
ctgtcctgcg cggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200
ttcctcgtca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1320
ccgggtaaag gaggcagcgg gggaagcggc ggcggagggt ctggaggagg gggcagtgac 1380
atccagatga cccagagccc cagcagcctg agcaccagcg tgggcgaccg cgtgaccctg 1440
acctgcaagg ccagccagga cgtgggcacc gccgtggact ggtaccagca gaagcccggc 1500
cagagcccca agctgctgat ctactgggcc agcacccgcc acaccggcat ccccagccgc 1560
ttcagcggca gcggcagcgg caccgacttc accctgacca tcagcagcct gcagcccgag 1620
gacttcgccg actactactg ccagcagtac aacagctacc ccctgacctt cggccccggc 1680
accaaggtgg acatcaaggg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 1740
tctgaggtgc agctggtgca gagcggcccc gaggtgaaga agcccggcgc caccgtgaag 1800
atcagctgca agaccagcgg ctacaccttc accgagtaca ccatccactg ggtgaagcag 1860
gcccccggca agggcctgga gtggatcggc aacatcaacc ccaacaacgg cggcaccacc 1920
tacaaccaga agttcgagga caaggccacc ctgaccgtgg acaagagcac cgacaccgcc 1980
tacatggagc tgagcagcct gcgcagcgag gacaccgccg tgtactactg cgccgccggc 2040
tggaacttcg actactgggg ccagggcacc ctacttacag taagtagc 2088
<210> 44
<211> 696
<212> PRT
<213> 人工序列
<400> 44
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Asp His Leu Phe Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Asp Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
340 345 350
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Ser Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
450 455 460
Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly Asp Arg Val Thr Leu
465 470 475 480
Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln
485 490 495
Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
500 505 510
Arg His Thr Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
515 520 525
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Asp
530 535 540
Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Pro Gly
545 550 555 560
Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val
580 585 590
Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr
595 600 605
Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys
610 615 620
Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr
625 630 635 640
Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser
645 650 655
Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
660 665 670
Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln
675 680 685
Gly Thr Leu Leu Thr Val Ser Ser
690 695
<210> 45
<211> 375
<212> DNA
<213> 人工序列
<400> 45
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgcgtctc 60
tcctgtgcag cctctggatt caccttcaat acctacgcca tgaactgggt ccgccaggct 120
ccgggaaagg gtttggaatg ggttgctcgc attcgcagta aatataataa ttatgcaaca 180
tattatgccg attcagtgaa agaccgtttc accatctccc gcgatgattc aaagaacacg 240
ctctatctgc aaatgaacag cctgcgcgct gaggacacgg ccgtgtatta ctgcgtgcgt 300
catggcaact ttggtaattc ttatgtgagc tggttcgcct actggggcca gggaaccctg 360
gtcaccgtca gctct 375
<210> 46
<211> 125
<212> PRT
<213> 人工序列
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 47
<211> 1329
<212> DNA
<213> 人工序列
<400> 47
caagctgttg tgacccaaga accgagtctg accgtgtctc cgggcggcac cgttacgctg 60
acctgtcgct cctctaccgg cgcagtcacc acgagcaact atgcaaattg ggtgcagcaa 120
aaaccggatc atctgtttcg tggcctgatt ggcggtacga acaaacgtgc gccggggacc 180
ccggcacgtt tttcgggcag cctgctgggc gataaagcag cactgaccat cagtggtgcg 240
cagccggaag atgaagcaga atattactgc gctctgtggt atagcaacct gtgggtcttt 300
ggcggtggca cgaaactgac cgttctgaaa cgcacagtgg cagcccccag cgtcttcatt 360
tttccccctt ccgatgaaca gctgaagtcc ggcactgctt ctgtggtctg tctgctgaac 420
aatttctatc ccagagaggc caaggtgcag tggaaagtgg acaacgctct gcagtccggc 480
aacagccagg agagtgtgac cgaacaggat agtaaggaca gcacatattc tctgtctagt 540
accctgacac tgagtaaggc agattacgag aagcacaaag tgtatgcctg cgaagtcact 600
catcagggac tgtcaagccc cgtgaccaag agcttcaacc ggggcgagtg tgacaaaact 660
cacacatgcc caccgtgccc agcacctcca gtcgccggac cgtcagtctt cctcttccct 720
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 780
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 900
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 960
aacaaaggcc tcccaagctc catcgagaaa accatctcca aagccaaagg gcagccccga 1020
gaaccacagg tgtgcaccct gcctccatcc cgggatgagc tgaccaagaa ccaggtcagc 1080
ctgtcctgcg cggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200
ttcctcgtca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1320
ccgggtaaa 1329
<210> 48
<211> 443
<212> PRT
<213> 人工序列
<400> 48
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Asp His Leu Phe Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Asp Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp
340 345 350
Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 49
<211> 1380
<212> DNA
<213> 人工序列
<400> 49
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggccagagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag caccacgacg 720
ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080
tacaagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380
<210> 50
<211> 460
<212> PRT
<213> 人工序列
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser Thr Thr Thr
225 230 235 240
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
245 250 255
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
260 265 270
His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
275 280 285
Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu
290 295 300
Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro
305 310 315 320
Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys
325 330 335
Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe
340 345 350
Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu
355 360 365
Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp
370 375 380
Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys
385 390 395 400
Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala
405 410 415
Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys
420 425 430
Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr
435 440 445
Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
450 455 460
<210> 51
<211> 321
<212> DNA
<213> 人工序列
<400> 51
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggcaagagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa g 321
<210> 52
<211> 107
<212> PRT
<213> 人工序列
<400> 52
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 53
<211> 711
<212> DNA
<213> 人工序列
<400> 53
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggcaagagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 54
<211> 237
<212> PRT
<213> 人工序列
<400> 54
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 55
<211> 711
<212> DNA
<213> 人工序列
<400> 55
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggcaagagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctgagg tgcagctggt gcagagcggc cccgaggtga agaagcccgg cgccaccgtg 420
aagatcagct gcaagaccag cggctacacc ttcaccgagt acaccatcca ctgggtgaag 480
caggcccccg gcaagggcct ggagtggatc ggcaacatca accccaacaa cggcggcacc 540
acctacaacc agaagttcga ggacaaggcc accctgaccg tggacaagag caccgacacc 600
gcctacatgg agctgagcag cctgcgcagc gaggacaccg ccgtgtacta ctgcgccgcc 660
ggctggaact tcgactactg gggccagggc accctactta cagtaagtag c 711
<210> 56
<211> 237
<212> PRT
<213> 人工序列
<400> 56
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln
115 120 125
Ser Gly Pro Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys
130 135 140
Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys
145 150 155 160
Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn
165 170 175
Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu Asp Lys Ala Thr Leu
180 185 190
Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu
195 200 205
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe
210 215 220
Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser
225 230 235
<210> 57
<211> 1725
<212> DNA
<213> 人工序列
<400> 57
gaggtgcagc tggtgcagag cggccccgag gtgaagaagc ccggcgccac cgtgaagatc 60
agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120
cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
aaccagaagt tcgaggacaa ggccaccctg accgtggaca agagcaccga caccgcctac 240
atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc cgccggctgg 300
aacttcgact actggggcca gggcacccta cttacagtaa gtagcgctag tacgaaaggt 360
ccggaggtgc agctggtgga gtctggggga ggcttggtcc agcctggggg gtccctgcgt 420
ctctcctgtg cagcctctgg attcaccttc aatacctacg ccatgaactg ggtccgccag 480
gctccgggaa agggtttgga atgggttgct cgcattcgca gtaaatataa taattatgca 540
acatattatg ccgattcagt gaaagaccgt ttcaccatct cccgcgatga ttcaaagaac 600
acgctctatc tgcaaatgaa cagcctgcgc gctgaggaca cggccgtgta ttactgcgtg 660
cgtcatggca actttggtaa ttcttatgtg agctggttcg cctactgggg ccagggaacc 720
ctggtcaccg tcagctctgc ctccaccaag ggcccatcgg tcttccccct ggcaccctcc 780
tccaagagca cctctggggg cacagcggcc ctgggctgcc tggtcaagga ctacttcccc 840
gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 900
gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgactgt gccctctagc 960
agcttgggca cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg 1020
gacaagaaag ttgaacccaa atcttgcgac aaaactcaca catgcccacc gtgcccagca 1080
cctccagtcg ccggaccgtc agtcttcctc ttccctccaa aacccaagga caccctcatg 1140
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1200
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1260
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1320
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aaggcctccc aagctccatc 1380
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgcct 1440
ccatgccggg atgagctgac caagaaccag gtcagcctgt ggtgcctggt caaaggcttc 1500
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1560
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1620
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1680
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaa 1725
<210> 58
<211> 575
<212> PRT
<213> 人工序列
<400> 58
Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Glu Val Gln Leu Val Glu Ser
115 120 125
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
130 135 140
Ala Ser Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln
145 150 155 160
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
165 170 175
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
180 185 190
Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
195 200 205
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
210 215 220
Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr
225 230 235 240
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
245 250 255
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
260 265 270
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
275 280 285
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
290 295 300
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
305 310 315 320
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
325 330 335
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
340 345 350
His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
355 360 365
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
370 375 380
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
385 390 395 400
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
405 410 415
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
420 425 430
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
435 440 445
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
450 455 460
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
465 470 475 480
Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu
485 490 495
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
500 505 510
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
515 520 525
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
530 535 540
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
545 550 555 560
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
565 570 575
<210> 59
<211> 1686
<212> DNA
<213> 人工序列
<400> 59
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggccccagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gactgttgct gcaccgtcag tgttcatctt ccctccacaa 360
gctgttgtga cccaagaacc gagtctgacc gtgtctccgg gcggcaccgt tacgctgacc 420
tgtcgctcct ctaccggcgc agtcaccacg agcaactatg caaattgggt gcagcaaaaa 480
ccggatcatc tgtttcgtgg cctgattggc ggtacgaaca aacgtgcgcc ggggaccccg 540
gcacgttttt cgggcagcct gctgggcgat aaagcagcac tgaccatcag tggtgcgcag 600
ccggaagatg aagcagaata ttactgcgct ctgtggtata gcaacctgtg ggtctttggc 660
ggtggcacga aactgaccgt tctgaaacgc acagtggcag cccccagcgt cttcattttt 720
cccccttccg atgaacagct gaagtccggc actgcttctg tggtctgtct gctgaacaat 780
ttctatccca gagaggccaa ggtgcagtgg aaagtggaca acgctctgca gtccggcaac 840
agccaggaga gtgtgaccga acaggatagt aaggacagca catattctct gtctagtacc 900
ctgacactga gtaaggcaga ttacgagaag cacaaagtgt atgcctgcga agtcactcat 960
cagggactgt caagccccgt gaccaagagc ttcaaccggg gcgagtgtga caaaactcac 1020
acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 1080
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1140
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1200
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1260
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1320
aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1380
ccacaggtgt gcaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 1440
tcctgcgcgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1500
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1560
ctcgtcagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1620
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1680
ggtaaa 1686
<210> 60
<211> 562
<212> PRT
<213> 人工序列
<400> 60
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Pro Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Gln Ala Val Val Thr Gln Glu Pro Ser
115 120 125
Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Arg Ser Ser
130 135 140
Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys
145 150 155 160
Pro Asp His Leu Phe Arg Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala
165 170 175
Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Asp Lys Ala
180 185 190
Ala Leu Thr Ile Ser Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr
195 200 205
Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys
210 215 220
Leu Thr Val Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
225 230 235 240
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
245 250 255
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
260 265 270
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
275 280 285
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
290 295 300
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
305 310 315 320
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
325 330 335
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
355 360 365
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
370 375 380
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
450 455 460
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
545 550 555 560
Gly Lys
<210> 61
<211> 1719
<212> DNA
<213> 人工序列
<400> 61
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggccccagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gactgttgct gcaccgtcag tgttcatctt ccctccagag 360
gtgcagctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gcgtctctcc 420
tgtgcagcct ctggattcac cttcaatacc tacgccatga actgggtccg ccaggctccg 480
ggaaagggtt tggaatgggt tgctcgcatt cgcagtaaat ataataatta tgcaacatat 540
tatgccgatt cagtgaaaga ccgtttcacc atctcccgcg atgattcaaa gaacacgctc 600
tatctgcaaa tgaacagcct gcgcgctgag gacacggccg tgtattactg cgtgcgtcat 660
ggcaactttg gtaattctta tgtgagctgg ttcgcctact ggggccaggg aaccctggtc 720
accgtcagct ctgcctccac caagggccca tcggtcttcc ccctggcacc ctcctccaag 780
agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 840
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 900
ctacagtcct caggactcta ctccctcagc agcgtggtga ctgtgccctc tagcagcttg 960
ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1020
aaagttgaac ccaaatcttg cgacaaaact cacacatgcc caccgtgccc agcacctcca 1080
gtcgccggac cgtcagtctt cctcttccct ccaaaaccca aggacaccct catgatctcc 1140
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1200
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1260
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1320
aatggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccaagctc catcgagaaa 1380
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcctccatgc 1440
cgggatgagc tgaccaagaa ccaggtcagc ctgtggtgcc tggtcaaagg cttctatccc 1500
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1560
cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1620
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1680
cactacacgc agaagagcct ctccctgtct ccgggtaaa 1719
<210> 62
<211> 573
<212> PRT
<213> 人工序列
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Pro Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Glu Val Gln Leu Val Glu Ser Gly Gly
115 120 125
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
130 135 140
Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
145 150 155 160
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
165 170 175
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
180 185 190
Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
195 200 205
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
210 215 220
Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
245 250 255
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
260 265 270
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
275 280 285
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
290 295 300
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
305 310 315 320
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
325 330 335
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
340 345 350
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
355 360 365
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
370 375 380
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
385 390 395 400
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
405 410 415
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
420 425 430
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
435 440 445
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
450 455 460
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys
465 470 475 480
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
485 490 495
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
500 505 510
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
515 520 525
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
530 535 540
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
545 550 555 560
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
565 570
<210> 63
<211> 1692
<212> DNA
<213> 人工序列
<400> 63
gaggtgcagc tggtgcagag cggccccgag gtgaagaagc ccggcgccac cgtgaagatc 60
agctgcaaga ccagcggcta caccttcacc gagtacacca tccactgggt gaagcaggcc 120
cccggcaagg gcctggagtg gatcggcaac atcaacccca acaacggcgg caccacctac 180
aaccagaagt tcgaggacaa ggccaccctg accgtggaca agagcaccga caccgcctac 240
atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc cgccggctgg 300
aacttcgact actggggcca gggcacccta cttacagtaa gtagcgctag tacgaaaggt 360
ccgcaagctg ttgtgaccca agaaccgagt ctgaccgtgt ctccgggcgg caccgttacg 420
ctgacctgtc gctcctctac cggcgcagtc accacgagca actatgcaaa ttgggtgcag 480
caaaaaccgg atcatctgtt tcgtggcctg attggcggta cgaacaaacg tgcgccgggg 540
accccggcac gtttttcggg cagcctgctg ggcgataaag cagcactgac catcagtggt 600
gcgcagccgg aagatgaagc agaatattac tgcgctctgt ggtatagcaa cctgtgggtc 660
tttggcggtg gcacgaaact gaccgttctg aaacgcacag tggcagcccc cagcgtcttc 720
atttttcccc cttccgatga acagctgaag tccggcactg cttctgtggt ctgtctgctg 780
aacaatttct atcccagaga ggccaaggtg cagtggaaag tggacaacgc tctgcagtcc 840
ggcaacagcc aggagagtgt gaccgaacag gatagtaagg acagcacata ttctctgtct 900
agtaccctga cactgagtaa ggcagattac gagaagcaca aagtgtatgc ctgcgaagtc 960
actcatcagg gactgtcaag ccccgtgacc aagagcttca accggggcga gtgtgacaaa 1020
actcacacat gcccaccgtg cccagcacct ccagtcgccg gaccgtcagt cttcctcttc 1080
cctccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1140
gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1200
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc 1260
agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1320
tccaacaaag gcctcccaag ctccatcgag aaaaccatct ccaaagccaa agggcagccc 1380
cgagaaccac aggtgtgcac cctgcctcca tcccgggatg agctgaccaa gaaccaggtc 1440
agcctgtcct gcgcggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1500
aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1560
ttcttcctcg tcagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1620
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 1680
tctccgggta aa 1692
<210> 64
<211> 564
<212> PRT
<213> 人工序列
<400> 64
Glu Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu Leu Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Gln Ala Val Val Thr Gln Glu
115 120 125
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Arg
130 135 140
Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln
145 150 155 160
Gln Lys Pro Asp His Leu Phe Arg Gly Leu Ile Gly Gly Thr Asn Lys
165 170 175
Arg Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Asp
180 185 190
Lys Ala Ala Leu Thr Ile Ser Gly Ala Gln Pro Glu Asp Glu Ala Glu
195 200 205
Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly
210 215 220
Thr Lys Leu Thr Val Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe
225 230 235 240
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
245 250 255
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
260 265 270
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
275 280 285
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
290 295 300
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
305 310 315 320
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
325 330 335
Glu Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val
340 345 350
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
355 360 365
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
370 375 380
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
385 390 395 400
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
405 410 415
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
420 425 430
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
435 440 445
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
450 455 460
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
465 470 475 480
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
485 490 495
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
500 505 510
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
515 520 525
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
530 535 540
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
545 550 555 560
Ser Pro Gly Lys
<210> 65
<211> 1686
<212> DNA
<213> 人工序列
<400> 65
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggccagagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gactgttgct gcaccgtcag tgttcatctt ccctccacaa 360
gctgttgtga cccaagaacc gagtctgacc gtgtctccgg gcggcaccgt tacgctgacc 420
tgtcgctcct ctaccggcgc agtcaccacg agcaactatg caaattgggt gcagcaaaaa 480
ccggatcatc tgtttcgtgg cctgattggc ggtacgaaca aacgtgcgcc ggggaccccg 540
gcacgttttt cgggcagcct gctgggcgat aaagcagcac tgaccatcag tggtgcgcag 600
ccggaagatg aagcagaata ttactgcgct ctgtggtata gcaacctgtg ggtctttggc 660
ggtggcacga aactgaccgt tctgaaacgc acagtggcag cccccagcgt cttcattttt 720
cccccttccg atgaacagct gaagtccggc actgcttctg tggtctgtct gctgaacaat 780
ttctatccca gagaggccaa ggtgcagtgg aaagtggaca acgctctgca gtccggcaac 840
agccaggaga gtgtgaccga acaggatagt aaggacagca catattctct gtctagtacc 900
ctgacactga gtaaggcaga ttacgagaag cacaaagtgt atgcctgcga agtcactcat 960
cagggactgt caagccccgt gaccaagagc ttcaaccggg gcgagtgtga caaaactcac 1020
acatgcccac cgtgcccagc acctccagtc gccggaccgt cagtcttcct cttccctcca 1080
aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 1140
gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 1200
aatgccaaga caaagccgcg ggaggagcag tacaacagca cgtaccgtgt ggtcagcgtc 1260
ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 1320
aaaggcctcc caagctccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1380
ccacaggtgt gcaccctgcc tccatcccgg gatgagctga ccaagaacca ggtcagcctg 1440
tcctgcgcgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1500
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1560
ctcgtcagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1620
tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1680
ggtaaa 1686
<210> 66
<211> 562
<212> PRT
<213> 人工序列
<400> 66
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Gln Ala Val Val Thr Gln Glu Pro Ser
115 120 125
Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Arg Ser Ser
130 135 140
Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Gln Lys
145 150 155 160
Pro Asp His Leu Phe Arg Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala
165 170 175
Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Asp Lys Ala
180 185 190
Ala Leu Thr Ile Ser Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr
195 200 205
Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys
210 215 220
Leu Thr Val Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
225 230 235 240
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
245 250 255
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
260 265 270
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
275 280 285
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
290 295 300
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
305 310 315 320
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
325 330 335
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
340 345 350
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
355 360 365
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
370 375 380
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
385 390 395 400
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
405 410 415
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
420 425 430
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
435 440 445
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys
450 455 460
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
465 470 475 480
Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
485 490 495
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
500 505 510
Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp
515 520 525
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
530 535 540
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
545 550 555 560
Gly Lys
<210> 67
<211> 1719
<212> DNA
<213> 人工序列
<400> 67
gacatccaga tgacccagag ccccagcagc ctgagcacca gcgtgggcga ccgcgtgacc 60
ctgacctgca aggccagcca ggacgtgggc accgccgtgg actggtacca gcagaagccc 120
ggccagagcc ccaagctgct gatctactgg gccagcaccc gccacaccgg catccccagc 180
cgcttcagcg gcagcggcag cggcaccgac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgactacta ctgccagcag tacaacagct accccctgac cttcggcccc 300
ggcaccaagg tggacatcaa gactgttgct gcaccgtcag tgttcatctt ccctccagag 360
gtgcagctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gcgtctctcc 420
tgtgcagcct ctggattcac cttcaatacc tacgccatga actgggtccg ccaggctccg 480
ggaaagggtt tggaatgggt tgctcgcatt cgcagtaaat ataataatta tgcaacatat 540
tatgccgatt cagtgaaaga ccgtttcacc atctcccgcg atgattcaaa gaacacgctc 600
tatctgcaaa tgaacagcct gcgcgctgag gacacggccg tgtattactg cgtgcgtcat 660
ggcaactttg gtaattctta tgtgagctgg ttcgcctact ggggccaggg aaccctggtc 720
accgtcagct ctgcctccac caagggccca tcggtcttcc ccctggcacc ctcctccaag 780
agcacctctg ggggcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 840
gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 900
ctacagtcct caggactcta ctccctcagc agcgtggtga ctgtgccctc tagcagcttg 960
ggcacccaga cctacatctg caacgtgaat cacaagccca gcaacaccaa ggtggacaag 1020
aaagttgaac ccaaatcttg cgacaaaact cacacatgcc caccgtgccc agcacctcca 1080
gtcgccggac cgtcagtctt cctcttccct ccaaaaccca aggacaccct catgatctcc 1140
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1200
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1260
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1320
aatggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccaagctc catcgagaaa 1380
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcctccatgc 1440
cgggatgagc tgaccaagaa ccaggtcagc ctgtggtgcc tggtcaaagg cttctatccc 1500
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1560
cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1620
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1680
cactacacgc agaagagcct ctccctgtct ccgggtaaa 1719
<210> 68
<211> 573
<212> PRT
<213> 人工序列
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Ile 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 Asp Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Glu Val Gln Leu Val Glu Ser Gly Gly
115 120 125
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
130 135 140
Gly Phe Thr Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
145 150 155 160
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
165 170 175
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
180 185 190
Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
195 200 205
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
210 215 220
Asn Ser Tyr Val Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
245 250 255
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
260 265 270
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
275 280 285
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
290 295 300
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
305 310 315 320
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
325 330 335
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
340 345 350
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu
355 360 365
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
370 375 380
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
385 390 395 400
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
405 410 415
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
420 425 430
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
435 440 445
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
450 455 460
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys
465 470 475 480
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys
485 490 495
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
500 505 510
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
515 520 525
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
530 535 540
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
545 550 555 560
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
565 570

Claims (16)

1.一种特异性结合人PSMA的抗体片段，其包括：
A) 氨基酸序列如SEQ ID NO:2所示的重链可变区(VH)；和
B) 选自如下氨基酸序列的轻链可变区(VL)：SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12或SEQ ID NO:14。
2. 根据权利要求1所述的抗体片段，其为单链Fv (scfv)。
3. 根据权利要求2所述的抗体片段，其中所述scfv的氨基酸序列如SEQ ID NO:20、SEQID NO:22、SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:28、SEQ ID NO:30、SEQ ID NO:32、SEQID NO:34、SEQ ID NO:36、SEQ ID NO:38、SEQ ID NO:54或SEQ ID NO:56所示。
4.一种双特异性抗体，所述双特异性抗体包括：
1) 特异性结合PSMA的第一抗原结合结构域，其包括：
A) 氨基酸序列如SEQ ID NO:2所示的重链可变区(VH)；和
B) 氨基酸序列如下所示的轻链可变区(VL)：SEQ ID NO:6、SEQ ID NO:8、SEQ ID NO:10、SEQ ID NO:12、SEQ ID NO:14或SEQ ID NO:52，和
2) 第二抗原结合结构域。
5.根据权利要求4所述的双特异性抗体，其中所述第一抗原结合域是scfv，所述scfv具有如权利要求3所述的氨基酸序列。
6.根据权利要求4所述的双特异性抗体，其中所述第二抗原结合结构域结合T细胞的特异性受体分子，其中所述T细胞的特异性受体分子为CD3。
7. 根据权利要求6所述的双特异性抗体，其中所述特异性结合CD3的第二抗原结合结构域的重链可变区（VH）和轻链可变区（VL）氨基酸分别如SEQ ID NO:40和SEQ ID NO:42所示。
8. 根据权利要求4-7任一项所述的双特异性抗体包括可结合CD3和PMSA的两条多肽链组成的组：SEQ ID NO:44和SEQ ID NO:46；SEQ ID NO:58和SEQ ID NO:60；SEQ ID NO:62和SEQ ID NO:64；SEQ ID NO:58和SEQ ID NO:66；SEQ ID NO:68和SEQ ID NO:64。
9.一种多核苷酸，其编码根据权利要求1-3中任一项所述的抗体片段、或根据权利要求4-8中任一项所述的双特异性抗体。
10. 根据权利要求9所述的多核苷酸，其具有SEQ ID NO: 19、21、23、25、27、29、31、33、35、37、43、45、49、51、53、55、57、59、61、63、65或67所示的核苷酸序列。
11.一种载体，其包含根据权利要求9或10所述的多核苷酸。
12.一种细胞，其包含根据权利要求9-10任一项所述的多核苷酸或根据权利要求11所述的载体。
13.根据权利要求12所述的细胞，其中该细胞是T细胞。
14.组合物，其包含根据权利要求1-3中任一项所述的scfv、根据权利要求4-8中任一项所述的双特异性抗体、根据权利要求9-10中任一项所述的多核苷酸、根据权利要求11所述的载体，或根据权利要求12-13任一项所述的细胞。
15.权利要求14的组合物，其还包括药学可接受的载体。
16.根据权利要求4-8中任一项所述的双特异性抗体制备用于治疗患有与PSMA表达相关的前列腺癌的药物中的用途。
CN202080009706.8A 2019-11-22 2020-11-20 Psma抗体及其应用 Active CN113677704B (zh)

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