具体实施方式

以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。

下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。其中：

人单克隆抗体IgG1亚类的重链恒定区序列见SEQ ID NO:106和SEQ ID NO:126，人单克隆抗体κ亚类的轻链恒定区序列见SEQ ID NO:107和SEQ ID NO:127。

重组人CD38蛋白，购自ACRO biosystem，Cat No:CD8-H5224。

实施例1对照抗体的合成与表达

将全合成的Daratumumab、Isatuximab和Mor202抗体轻链可变区和重链可变区基因分别克隆至装有人-kappa轻链恒定区和人IgG1重链恒定区编码基因上游的真核表达载体中，分别获得Daratumumab、Isatuximab和Mor202轻、重链表达质粒。将获得的质粒转入大肠杆菌扩增，分离获得大量含Daratumumab、Isatuximab或Mor202抗体轻链和重链的质粒，将二者与PEI混合后共转染入HEK293细胞中。

细胞转染5-6天，取培养上清，利用Mabselect亲和层析柱对表达上清进行纯化，获得Daratumumab、Isatuximab和Mor202抗体重组蛋白。

Daratumumab：序列参见SEQ ID NO:128至SEQ ID NO:129。

Isatuximab：序列参见SEQ ID NO:130至SEQ ID NO:131。

Mor202：序列参见SEQ ID NO:132至SEQ ID NO:133。

实施例2CD38抗原表达细胞株的制备

制备了人CD38高表达CHO细胞株1-T-14和人CD38低表达CHO细胞株1-T-12。

通过PCR的方法，从含有CD38 cDNA的载体(北京义翘神州，Cat:HG10818-UT)中克隆出CD38基因的阅读框，并将CD38基因的阅读框(已经测序验证正确序列)通过酶切的方法克隆入含有谷氨酰氨合成酶(GS)筛选基因的稳定表达载体中，电转染(Nucleofector IIb，Lonza)悬浮培养的CHO-K1细胞，将转染后的细胞置于含有50μM MSX(Sigma，Cat:M5379)的CD CHO AGTTM培养基(Gibco，Cat:12490-025)中，接种于96孔细胞培养板，37℃，5％CO₂静置培养2-3周，通过MSX加压筛选，从镜下预筛、放大培养，最终通过流式细胞分析(FACS)挑选出2个克隆(1-T-12和1-T-14)，进行放大培养和冻存。

两个细胞株与阴性对照CHO细胞株(CHO-blank)的流式细胞术鉴定结果见图1，平均荧光强度(MFI)数值见表1。

表1 CD38抗原表达细胞株的表达(FACS)

实施例3杂交瘤细胞的筛选和鉴定

1.小鼠免疫

8-10周龄Balb/c小鼠，采用弗氏佐剂和水溶佐剂两种免疫方法，弗氏佐剂在第0天和第14天给小鼠进行两次腹腔免疫注射，水溶佐剂在第0天和第21天给8-10周龄Balb/c小鼠进行两次肌肉免疫注射小鼠，免疫抗原为：人CD38重组蛋白，由Acro biosytem生物科技有限公司在HEK293细胞中重组表达。第一次免疫剂量为50μg，第二次免疫剂量为25μg。免疫前取小鼠血清作为检测时的阴性对照，弗氏佐剂在初次免疫后第28天，水溶佐剂在初次免疫后第35天尾静脉取血，用包被重组人CD38蛋白的96孔酶标板以ELISA法检测血清滴度；血清滴度达到融合要求的小鼠加强免疫，将25μg抗原用D-PBS稀释成500μl，腹腔注射。初次免疫后第18-38天取血清滴度高的小鼠的脾细胞用于下一步的细胞融合。

2.细胞融合及杂交瘤制备

2.1骨髓瘤细胞准备

培养融合所需骨髓瘤细胞P3X63Ag8.653在500ml三角培养瓶至细胞密度0.8-1.0E+6密度时，换液至完全杂交瘤培养基中备用。

2.2淋巴结和B淋巴细胞制备

选取滴度达到要求的小鼠，摘除眼球采血，并分离血清作为抗体检测时的阳性对照血清；并无菌取小鼠脾脏，按照常规方法制备B淋巴细胞悬液。

2.3电融合(Electro Cell Fusion，ECF)

骨髓瘤细胞P3X63Ag8.653和B淋巴细胞以4:1的比例混合后进行电击融合。电击后，将细胞放入37℃CO₂培养箱内，静止30分钟，1000RPM，室温离心10分钟，用360ml杂交瘤选择培养基重悬细胞后，铺板至384孔板内，确保铺板密度为8000～20000细胞/孔。第2-3天后换液一次，第7-10天进行阳性杂交瘤筛选。

2.4阳性杂交瘤筛选(FACS)

将融合后的杂交瘤细胞培养于384孔板中，取上清用FACS分析杂交瘤细胞分泌的抗体，筛选得到若干克隆，该克隆能够结合人CD38高表达株1-T-14而不能够结合CHO-blank细胞。通过有限稀释的方法将筛选到的克隆单细胞化，3轮之后得到的每个杂交瘤细胞克隆只分泌一个抗体。

第一轮和第二轮融合筛选结果见图2。

实施例4鼠源单克隆抗体的可变区序列鉴定、抗人CD38嵌合抗体的制备以及抗体筛选

将分泌抗人CD38抗体的杂交瘤细胞扩大培养后，按照RNAfast200试剂盒(上海飞捷生物技术有限公司)说明书步骤提取细胞总RNA；利用5×PrimeScript RT Master Mix(Takara)将杂交瘤细胞总RNA反转录成cDNA；使用简并引物(Anke Krebber.1997)和ExtaqPCR试剂(Takara)扩增抗体轻链可变区IgVL(κ)和重链可变区VH序列；利用PCR clean-upGel extraction试剂盒(Macherey-Nagel公司)纯化PCR扩增产物；按照pClone007 SimpleVector Kit试剂盒(擎科生物科技有限公司)说明书将扩增PCR产物连接至T载体并转化大肠杆菌感受态细胞，菌株扩增、抽提质粒后进行DNA测序获得单克隆抗体可变区序列。

将鼠源抗人CD38单克隆抗体的重链可变区序列和公开发表的人单克隆抗体IgG1亚类的重链恒定区序列拼接在一起，构建到哺乳动物细胞表达载体pCDNA3.4中；将鼠源抗人CD38单克隆抗体的轻链可变区序列和公开发表的人单克隆抗体κ亚类的轻链恒定区序列拼接在一起，构建到哺乳动物细胞表达载体pCDNA3.1中。将构建好的抗人CD38嵌合抗体的重链载体和轻链载体配对混合，使用聚乙烯亚胺(PEI)转染HEK293细胞，约7天后收集细胞上清，使用Mabselect纯化得到抗人CD38嵌合抗体蛋白。

得到的嵌合抗体在本文以“鼠源抗体命名-xiIgG”表示。

对获取的鼠源抗体和嵌合抗体进行杂交瘤细胞培养上清或纯化得到的抗体的抗原ELISA结合实验、Octet结合实验、体外细胞结合实验、体外细胞学实验(补体依赖性细胞毒性(CDC)和抗体依赖性细胞毒性(ADCC))等单克隆抗体的筛选(实验操作见下文)，将鼠源抗体与相应的嵌合抗体彼此验证，综合各个实验的结合，筛选得到部分鼠源抗体及其嵌合抗体。

来自部分鼠源抗体的轻重链可变区(VH和VL)序列如下所示，其中重链和轻链的抗原互补决定簇(CDR)以下划线示出。

鼠源抗体2H17：

>2H17_VH(SEQ ID NO:50)

QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWRGGSTDYNAAFMSRLSITKDNSKSQVFFKMNSLQADDTAIYYCAKGMITTGYAMDYWGQGTSVTVSS

>2H17_VL(SEQ ID NO:51)

DIQMTQSSSSFSVSLGDRVTITCKASEDIYNRLAWYQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQYWSTPTFGGGTKLEIK

鼠源抗体4J1：

>4J1_VH(SEQ ID NO:52)

QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSFGIHWVRQSPGKGLEWLGVIWRGGSTDYNAAFLSRLSITKDNSKSQVFFKINSLRADDTAIYFCAKSMITTGYAMDYWGQGTSVTVSS

>4J1_VL(SEQ ID NO:53)

DIQMTQSSSSFSVSLGDRVTITCKASEDIYNRLAWYQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKDYILSITSLQTEDVATYYCQQYWSTPWTFGGGTKLEIK

鼠源抗体5E19：

>5E19_VH(SEQ ID NO:54)

QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWLRQSPGKGLEWLGVIWRGGSTDYSAAFMSRLNITKDNSKSQVFFKMNSLQADDTAIYYCAKTTLTRVWYCDVWGAGTTVTVSS

>5E19_VL(SEQ ID NO:55)

DIQMTQSSSSFSVSLGDRVTITCKSSEDIYNRLAWYQQKPGNAPRLLISGATSLETGVPSRFSGSGSGKDYTLSITSLQTEDVVTYYCQQYWNTPLTFGAGTKLELK

鼠源抗体8B7：

>8B7_VH(SEQ ID NO:56)

QVQLKQSGPGLVQPSQSLSITCTVSGFSLLSYGVHWVRQSPGKGLEWLGVIWRGGSADYNAAFMSRLSITKDNSKSQVFFKMNSLQADDTAIYYCAKSMITTGFTLDYWGQGTSVTVSS

>8B7_VL(SEQ ID NO:57)

DIQMTQSSSSFSVSLGDRVTITCKASEDIYNRLAWYQQKPGHAPRLLISGATSLETGVPSRFSGSGSGKDYTLSITSLQTEDVATYYCQQFWNTPWTFGGGTKLEIK

鼠源抗体13D15：

>13D15_VH(SEQ ID NO:58)

QIQLVQSGPELKKPGETVKISCKASGYTFTNFGMNWVKQAPGKGLKWMGWINTYTGEPTNADDFKGRFAFSLETSASTAYLQINNLKNEDMATYFCARKGFAYWGQGTLVTVSA

>13D15_VL(SEQ ID NO:59)

DIVLTQSPASLAVSLGQRTTISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQINEDPFTFGSGTKLEIK

鼠源抗体15A10：

>15A10_VH(SEQ ID NO:60)

QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTYTAEPTYADDFKGRFAFSLEASASTAYLQINNLKNEDMATYFCARKYGGYWGQGTTLTVSS

>15A10_VL(SEQ ID NO:61)

DIVLTQSPPSLAVSLGQRATISCRASESVDSYGNSFIHWYQQKPGQSPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQVNEDPLTFGAGTKLELK

鼠源抗体17H13：

>17H13_VH(SEQ ID NO:62)

QVQLQQSGAELAKPGASVKMSCKASGYTFTNYWMNWIKQRPGQGLEWIGYIIPSTDYTEYNQKFKDKATLTADKSSGTAYMQLSSLTSEDSAVYYCSRYPYRGYAMDYWGQGTSVTVSS

>17H13_VL(SEQ ID NO:63)

QIVLTQSPALMSASPGEKVTMTCSASSSVSYMYWYQQKPRSSPKPWIYLTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSTNPWTFGGGTKLELK

鼠源抗体20M19：

>20M19_VH(SEQ ID NO:64)

QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTYTGEPTVADDFKGRFAFSLDTSASTAYLQINNLKNEDTATYFCARNPGWFAYWGQGTLVTVSA

>20M19_VL(SEQ ID NO:65)

DIVLTQSPVFLAVSLGQRATISCRASESVDNYGNSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSHEAPWTFGGGTRLEIK

鼠源抗体32A7：

>32A7_VH(SEQ ID NO:66)

QIQLVQSGPELKKPGETVKISCKASGYNLTNYGMNWVKQAPGKGLKWMGWINTYTGEPTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARYPGWFAYWGQGTLVTVSA

>32A7_VL(SEQ ID NO:67)

DIVLTQSPASLAVSLGQRATISCRTSESVDSYGNSFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADDVATYYCQQSNEDPWTFGGGTKLEIK

结果显示，具有上述轻重链的所有鼠源抗体相对于其他鼠源抗体，具有更为良好的与人CD38重组蛋白的结合作用，细胞结合实验效果明显，并具有较强的补体依赖性细胞毒性和抗体依赖性细胞毒性；并且，在转为嵌合抗体以后，均保留了鼠源抗体的作用，并且结合活性与对照抗体Daratumumab或Isatuximab相近或更高。

实施例5抗人CD38鼠源抗体的人源化与人源化抗体制备

综合Kabat、Chothia的抗体编码方案，确定鼠源抗体的重链和轻链的6个抗原互补决定簇(CDR)的氨基酸序列区域及支撑抗体保守三维构象的框架区域(frameworkregion)。

随后通过分析搜索已知人源抗体序列，选择与鼠源抗体最为相似接近的人源抗体重链可变区序列，如IGHV1|IGHJ4*01，选择其抗体框架区序列作为模板，将鼠源抗体重链CDR与人源抗体框架区结合，最终生成人源化抗体重链可变区序列。同样过程，生成人源化抗体轻链可变区序列。

上述过程中发现，鼠源抗体CDR直接移植至人框架区的抗体常出现结合活性急剧下降，因此需要将框架区个别氨基酸从人源的改回鼠源的。在确定回复突变位点时，一是对照设计好的人源化抗体序列和原始的鼠源抗体序列，检查有哪些氨基酸的不同；二是检查这些氨基酸是否对支持抗体结构起重要作用或者对与抗原的结合起重要作用。对于人源化设计后的序列，同时还需要检查是否有一些潜在的翻译后修饰位点，如N(天冬酰胺)糖基化位点、N脱酰胺化位点、D(天冬氨酸)异构化位点等。

将人源化抗体重链可变区基因构建到含人单克隆抗体IgG1亚类的重链恒定区基因的哺乳动物细胞表达载体中；轻链可变区基因构建到含人单克隆抗体κ亚类的轻链恒定区基因的哺乳动物细胞表达载体中。构建好的抗人CD38人源化抗体的重链载体和轻链载体配对混合，使用聚乙烯亚胺(PEI)转染HEK293细胞，约7天后收集细胞上清，使用Mabselect纯化得到抗人CD38人源化抗体蛋白。

人源化改造得到的部分轻重链可变区序列如下所示，其中重链和轻链的抗原互补决定簇(CDR)以下划线示出。

>5E19_VH_hz0(SEQ ID NO:68)

QVQLVESGGGVVQPGRSLRLSCAASGFSLTNYGVHWVRQAPGKGLEWVAVIWRGGSTDYSAAFMSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTTLTRVWYCDVWGQGTLVTVSS

>5E19_VH_hz1(SEQ ID NO:69)

QVQLVESGGGVVQPGRSLRLSCAASGFSLTNYGVHWVRQAPGKGLEWVAVIWRGGSTDYSAAFMSRFTISKDNSKNTVYLQMNSLRAEDTAVYYCAKTTLTRVWYCDVWGQGTLVTVSS

>5E19_VH_hz2(SEQ ID NO:70)

QVQLVESGGGVVQPGRSLRLSCAVSGFSLTNYGVHWVRQAPGKGLEWVAVIWRGGSTDYSAAFMSRFTISKDNSKNTVYLQMNSLRAEDTAVYYCAKTTLTRVWYFDVWGQGTLVTVSS

>5E19_VH_hz3(SEQ ID NO:71)

QVQLVESGGGVVQPGRSLRLSCAVSGFSLTNYGVHWVRQAPGKGLEWVAVIWRGGSTDYSAAFMSRFTISKDNSKNTVYLQMNSLRAEDTAVYYCAKTTLTRVWYVDVWGQGTLVTVSS

>5E19_VH_hz4(SEQ ID NO:72)

QVQLVESGGGVVQPGRSLRLSCAVSGFSLTNYGVHWVRQAPGKGLEWVAVIWRGGSTDYSAAFMSRFTISKDNSKNTVYLQMNSLRAEDTAVYYCAKTTLTRVWYYDVWGQGTLVTVSS

>5E19_VL_hz0(SEQ ID NO:89)

DIQMTQSPSSLSASVGDRVTITCKSSEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWNTPLTFGQGTKVEIK

>5E19_VL_hz1(SEQ ID NO:90)

DIQMTQSPSSLSASVGDRVTITCKSSEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQYWNTPLTFGQGTKVEIK

>8B7_VH_hz0(SEQ ID NO:73)

QVQLVESGGGVVQPGRSLRLSCAASGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz1(SEQ ID NO:74)

QVQLVESGGGVVQPGRSLRLSCAASGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISKDNSKNTVYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz3(SEQ ID NO:75)

QVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISKDNSKSTVYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz4(SEQ ID NO:76)

EVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISKDNSKSTVYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz5(SEQ ID NO:77)

EVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISKDNSKNTLYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz6(SEQ ID NO:78)

EVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISRDNSKSTLYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz7(SEQ ID NO:79)

EVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz8(SEQ ID NO:80)

EVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISKDNSKSTLYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz9(SEQ ID NO:81)

EVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISKDNSKNTVYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VH_hz10(SEQ ID NO:82)

EVQLVESGGGVVQPGRSLRLSCAVSGFSLLSYGVHWVRQAPGKGLEWVAVIWRGGSADYNAAFMSRFTISRDNSKSTVYLQMNSLRAEDTAVYYCAKSMITTGFTLDYWGQGTLVTVSS

>8B7_VL_hz0(SEQ ID NO:91)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQFWNTPWTFGPGTKLEIK

>8B7_VL_hz1(SEQ ID NO:92)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLISGATSLETGVPSRFSGSGSGKDYTFTISSLQPEDVATYYCQQFWNTPWTFGPGTKLEIK

>8B7_VL_hz2(SEQ ID NO:93)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQFWNTPWTFGQGTKVEIK

>8B7_VL_hz3(SEQ ID NO:94)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLISGATSLETGVPSRFSGSGSGKDYTFTISSLQPEDVATYYCQQFWNTPWTFGQGTKVEIK

>8B7_VL_hz4(SEQ ID NO:95)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGKDFTFTISSLQPEDIATYYCQQFWNTPWTFGQGTKVEIK

>8B7_VL_hz5(SEQ ID NO:96)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQFWNTPWTFGQGTKVEIK

>8B7_VL_hz6(SEQ ID NO:97)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTFTISSLQPEDVATYYCQQFWNTPWTFGQGTKVEIK

>8B7_VL_hz7(SEQ ID NO:98)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGKDYTFTISSLQPEDIATYYCQQFWNTPWTFGQGTKVEIK

>8B7_VL_hz8(SEQ ID NO:99)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGKDFTFTISSLQPEDVATYYCQQFWNTPWTFGQGTKVEIK

>8B7_VL_hz9(SEQ ID NO:100)

DIQMTQSPSSLSASVGDRVTITCKASEDIYNRLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDYTFTISSLQPEDVATYYCQQFWNTPWTFGQGTKVEIK

>17H13_VH_hz0(SEQ ID NO:83)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMNWVRQAPGQGLEWMGYIIPSTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYPYRGYAMDYWGQGTLVTVSS

>17H13_VH_hz1(SEQ ID NO:84)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMNWVRQAPGQGLEWMGYIIPSTDYTEYNQKFKDRVTMTKDNSTSTAYMELSSLRSEDTAVYYCSRYPYRGYAMDYWGQGTLVTVSS

>17H13_VH_hz2(SEQ ID NO:85)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMNWVRQAPGQRLEWMGYIIPSTDYTEYNQKFKDRVTITRDTSASTAYMELSSLRSEDTAVYYCARYPYRGYAMDYWGQGTTVTVSS

>17H13_VH_hz3(SEQ ID NO:86)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWMNWVRQAPGQRLEWMGYIIPSTDYTEYNQKFKDRVTITADKSAGTAYMELSSLRSEDTAVYYCSRYPYRGYAMDYWGQGTTVTVSS

>17H13_VL_hz0(SEQ ID NO:101)

EIVLTQSPATLSLSPGERATLSCSASSSVSYMYWYQQKPGQAPRLLIYLTSNLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWSTNPWTFGQGTKVEIK

>17H13_VL_hz1(SEQ ID NO:102)

EIVLTQSPATLSLSPGERATLSCSASSSVSYMYWYQQKPGQAPRPLIYLTSNLASGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSTNPWTFGQGTKVEIK

>17H13_VL_hz2(SEQ ID NO:134)

QIVLTQSPATLSLSPGERATLTCSASSSVSYMYWYQQKPGQAPRPWIYLTSNLASGVPARFSGSGSGTSYTLTISSLEPEDFAVYYCQQWSTNPWTFGQGTKVEIK

>17H13_VL_hz3(SEQ ID NO:135)

QIVLTQSPATLSLSPGERATLTCSASSSVSYMYWYQQKPGSSPRPWIYLTSNLASGVPARFSGSGSGTSYTLTISSLEPEDFAVYYCQQWSTNPWTFGGGTKVEIK

>20M19_VH_hz0(SEQ ID NO:87)

QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTVADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPGWFAYWGQGTLVTVSS

>20M19_VH_hz1(SEQ ID NO:88)

QIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTVADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPGWFAYWGQGTLVTVSS

>20M19_VL_hz0(SEQ ID NO:103)

DIVLTQSPASLAVSPGQRATITCRASESVDNYGNSFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSGTDFTLTINPVEANDTANYYCQQSHEAPWTFGQGTKVEIK

>20M19_VL_hz1(SEQ ID NO:104)

DIVLTQSPASLAVSPGQRATITCRASESVDNYGNSFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSRTDFTLTINPVEANDTANYYCQQSHEAPWTFGQGTKVEIK

>20M19_VL_hz2(SEQ ID NO:105)

DIVLTQSPASLAVSPGQRATITCRASESVDNYGNTFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSRTDFTLTINPVEAGDTANYYCQQSHEAPWTFGQGTKVEIK

>32A7_VH_hz0(SEQ ID NO:140)

QVQLVQSGSELKKPGASVKVSCKASGYNLTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARYPGWFAYWGQGTLVTVSS

>32A7_VH_hz1(SEQ ID NO:141)

QIQLVQSGSELKKPGASVKVSCKASGYNLTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARYPGWFAYWGQGTLVTVSS

>32A7_VH_hz2(SEQ ID NO:142)

QIQLVQSGSELKKPGASVKVSCKASGYALTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARYPGWFAYWGQGTLVTVSS

>32A7_VL_hz0(SEQ ID NO:143)

DIVLTQSPASLAVSPGQRATITCRTSESVDSYGNSFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSGTDFTLTINPVEANDTANYYCQQSNEDPWTFGQGTKVEIK

>32A7_VL_hz1(SEQ ID NO:144)

DIVLTQSPASLAVSPGQRATITCRTSESVDSYGNSFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSRTDFTLTINPVEANDTANYYCQQSNEDPWTFGQGTKVEIK

>32A7_VL_hz2(SEQ ID NO:145)

DIVLTQSPASLAVSPGQRATITCRTSESVDSYGNTFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSRTDFTLTINPVEANDTANYYCQQSNEDPWTFGQGTKVEIK

>32A7_VL_hz3(SEQ ID NO:146)

DIVLTQSPASLAVSPGQRATITCRTSESVDSYGNTFMHWYQQKPGQPPKLLIYRASNLESGVPARFSGSGSRTDFTLTINPVEAQDTANYYCQQSNEDPWTFGQGTKVEIK

将人源化抗体命名为“鼠源抗体命名-HmLn”，其中m和n分别为VH和VL的人源化(hz)改造序列(VH_hz和VL_hz)编号。

实施例6抗人CD38抗体与抗原的体外结合验证与体外细胞学试验

1.Octet结合实验

进行本发明的抗体和对照抗体Daratumumab(Dara)与重组人CD38蛋白的Octet结合实验。

利用Fortebio(BLITZ pro1.1.0.28)仪器，采用抗人抗体捕获法测定抗体亲和力。测定时将抗人抗体Fc段的捕获抗体(AHC)生物探针浸泡于PBS 10min；将200μl稀释后的抗体样品(包括本发明的嵌合抗体、人源化抗体以及对照抗体Daratumumab；抗体工作浓度为15μg/mL)上样到AHC生物探针上，然后在PBS中平衡100s，进一步将AHC探针与不同稀释浓度的人CD38蛋白(ACRO biosystem，Cat No.CD8-H5224)进行结合反应，结合时间600s，之后将AHC探针转移至PBS中，进行解离反应，时间为600s。实验完毕，扣除空白对照响应值，用软件进行1:1Langmuir结合模式拟合，计算抗原抗体结合的动力学常数。

结果见表2至表5。

表2抗体与重组人CD38蛋白的体外结合活性

表3抗体与重组人CD38蛋白的体外结合活性

表4抗体与重组人CD38蛋白的体外结合活性

表5抗体与重组人CD38蛋白的体外结合活性

实验结果显示，部分人源化改造抗体保留了与人CD38重组蛋白的结合活性。

2.体外细胞结合实验

进行本发明的抗体和对照抗体Daratumumab(Dara)与CD38蛋白的体外细胞结合实验。

将抗人CD38抗体从100nM的起始浓度开始做2倍的梯度倍比稀释，共16个浓度点，各个浓度点的抗体取10μl加入384孔板。取细胞表面表达CD38的CHO细胞株1-T-14，用含0.5％BSA的PBS洗涤细胞一次，100g室温离心5分钟，重悬细胞为密度约2x10⁶个细胞/ml，取10μl加入到已加抗体的384孔板的孔中。4℃孵育1小时后，加入荧光标记的羊抗人IgG二抗。继续于4℃孵育1小时后，用流式细胞仪分析细胞群的平均荧光强度。

结果见图3和表6。

表6抗体与抗原的结合活性

3.体外细胞学试验

3.1补体依赖性细胞毒性(CDC)

使用Quidel公司的商品化人血清全补体，分析本发明的抗体和对照抗体Daratumumab(Dara)针对稳定表达人CD38的CHO细胞株1-T-14诱导补体依赖性细胞毒性(CDC)的能力。

将细胞分别与终浓度50μg/ml至7.6ng/ml的抗体和对照抗体混匀，然后将溶于细胞培养基RPMI-1640中的6.25％人血清全补体加入细胞中，在37℃下孵育3小时。其后，通过CCK-8试剂盒进行细胞毒性检测，最终通过MD酶标仪检测450nm吸光度。通过吸光值采用softmax pro7软件进行4参数拟合曲线，计算样品的EC50。

结果见表7。

表7抗体的补体依赖性细胞毒性

3.2抗体依赖性细胞毒性(ADCC)

检测本发明的抗体和对照抗体Daratumumab(Dara)针对稳定表达人CD38的CHO细胞株1-T-14诱导抗体依赖性细胞毒性(ADCC)。

使用工程改造的Jurkat细胞作为效应细胞，该细胞稳定表达FcγRIIIa-FcεRIaγ杂合受体，由NFAT应答元件驱动表达萤火虫萤光素酶。抗体在ADCC作用机制中的生物活性通过NFAT通路活化产生的萤光素酶定量。

将1.5E5个效应细胞分别与终浓度33μg/ml至85pg/ml的本发明的抗体和对照抗体Daratumumab混匀，然后将2.5E4个靶细胞即稳定表达人CD38的CHO细胞株1-T-14(效应细胞与靶细胞E:T比例为6:1)加入其中，在37℃下孵育16小时。其后，通过Promega公司试剂盒Bio-Glo^TMLuciferase Assay System进行检测，最终通过MD酶标仪检测LUM值，并使用下式进行诱导倍数和EC50计算。

诱导倍数＝(受检孔读值–背景值)/(阴性对照孔读值–背景值)

诱导倍数采用prism7软件进行4参数拟合曲线，计算样品的EC50。

结果见图4和表8。

表8抗体的抗体依赖性细胞毒性

实施例9抗人CD38人源化抗体的体外结合亲和力和动力学实验

采用GE公司BIAcore仪器S200测定抗体抗原相互作用力。

参考GE公司Biotin CAPture Kit(货号28-9202-34，Lot.10265137)操作说明，首先在传感芯片CAP分析通道和对照样品通道都偶联His标签的人CD38蛋白抗原，然后在分析通道和对照样品通道一起流过梯度稀释的抗体样品(起始浓度20nM，1:3稀释8个浓度点，并且设定0.741nm浓度点重复)，测定抗体抗原结合后发生的光反应值。经仪器软件拟合分析，最终得到抗体的结合常数Kon和解离常数Koff，以及亲和力常数KD。

结果见表9。

表9人源化改造抗体的结合动力学

实施例10抗人CD38人源化抗体的细胞凋亡活性测定

材料：Daudi-Luc(ATCC，Cat No.CCL-213)细胞

试剂盒：Alex FluorTM 488Annexin V/Dead细胞凋亡试剂盒(invitrogen,Cat:V13245,Lot:1923636)

工具抗体：AffinipureF(ab')2Fragment Goat-anti-human IgG Fcr FragmentSpecific(Immo Research,Cat:109-006-008,Lot:129913,Conc.1.3mg/ml)

实验步骤：

用预冷的PBS洗1遍Daudi细胞，然后以1E5/孔将细胞种入96孔板内，加入0.7nM抗CD38抗体孵育30分钟。加入5μg/ml羊抗人的工具抗体至96孔板内，4℃孵育24小时。用预冷的PBS洗2遍细胞后，弃掉上清，用100μl 1x Annexin溶液重悬细胞。加入5μl Alexa488annexin V和1μL 100μg/mL PI工作溶液至96孔板内，室温避光孵育15分钟。用400μl 1X annexin结合溶液终止反应后，将96孔板放置于冰上，最后用流式细胞分析仪测量荧光激发530nM和发射488nM的读值。

结果见表10。

表10本发明抗体的细胞凋亡活性

表中的“交联”和“非交联”分别为桥接Fab和不桥接Fab的形式。

实施例11抗人CD38人源化抗体的成药性表征

1.抗体表位分析

采用Fortebio公司的In tandem方法进行本发明抗体的抗原表位分析。简言之，先用本发明的含鼠源抗体的单克隆上清液结合抗原细胞即人CD38高表达CHO细胞株1-T-14，然后加入对照抗体与鼠源抗体竞争与抗原表位的结合。检测所标记的对照抗体的结合信号，对照抗体的结合信号越低，越能证明鼠源抗体占据了对照抗体识别的抗原表位，本发明的抗体与对照抗体的抗原结合表位靠近或一致。

本发明的抗体与Daratumumab、Mor202、Isatuximab的竞争结果分别见图5。

实验证明，本发明的抗体与抗原的结合位点与对照抗体的表位是一致的。

2.抗体单体率分析

实验仪器：UPLC CLASS ACQUITYH(WATERS)

分析柱：TSKgel G3000SWXL 7.8*300(TOSHI，Cat No 003C03326C

分析溶液：DPBS(GIBCO，Cat No.14190-136，Lot#1967705)

分析方法：将50μl浓度为1mg/ml的抗体进样至预平衡好的层析柱内，室温，0.7ml/min的流速流动35min，并同时检测机器A280和A214的吸收值，进入根据出峰时间和出峰体积来判断抗体的单体含量和比例。

结果见表11。

表11本发明抗体的主峰保留时间和单体率

3.抗体疏水性质分析

实验仪器：ARC(Waters)

实验用分析柱：TSKgel Butyl-NPR(4.6mmX3.5cm，Cat No 14947)

分析溶液：a.20mM Histidine，pH6.0；b.20mM Histidine，1.6M(NH₄)₂SO₄

分析方法：根据疏水层析柱使用说明，来分析抗体的疏水性质。

结果见表12。

表12本发明抗体的疏水性质

4.抗体体外猴(cyno)血清稳定性研究

实验材料：待测抗体，FBS，抗原人CD38重组蛋白，anti-huIgG Fab单克隆抗体(Sigma,I5260-1ML)，HRP标记山羊抗人IgG二抗(Jackson,code:109-035-098)。

实验仪器：37℃培养箱，酶标仪。

实验步骤：

样品制备：

1)待测抗体调浓度至20μg/ml，过滤除菌，分装为250μl/管备用；

2)FBS等体积加入分装好的待测抗体，即终浓度为50％血清浓度，10μg/ml抗体浓度；

3)共制备7个样品，封口膜封口，放置于37℃，全程需保持无菌；

4)分别于第0天、3天、7天、10天、14天、21天取样放置于4℃保存待测，其中第21天取样应至少在4℃放置一天。

检测方法：

1)分别PBS包被结合抗原、anti-IgG Fab单克隆抗体于96孔酶联板，0.2μg/ml，100μl/孔，4℃过夜；

2)配置所需试剂：

封闭液5％BSA+PBS

抗体稀释液5％BSA+PBS+50％FBS

酶联板洗涤液0.1％Tween+PBS

3)包被好的酶联板PBS清洗三遍，300μl/孔，洗去游离的未包被抗原；

4)加入封闭液，200μl/孔，37℃封闭1h；

5)待测抗体使用抗体稀释液稀释至2μg/ml，并3倍稀释共8个梯度；

6)倒掉封闭液，两种包被方法的酶联板分别加入稀释好的抗体，100μl/孔，于37℃孵育1h；

7)PBST洗板3遍；

8)1:5000稀释二抗，加入洗涤好的酶联板中，100μl/孔，37℃孵育40min；

9)PBST洗板3遍；

10)TMB显色，100μl/孔，避光10min；

11)加入50μl 2M HCL终止，450nm读数。

结果处理：

根据ELISA显色值制定结合曲线，观察放置不同时间的结合曲线变化，评估放置后抗体结合活性稳定性。

结果见图6。

5.抗体小鼠体内药物代谢分析

实验材料：待测抗体，小鼠不同时间点采集的血清，待测抗体的结合抗原人CD38，抗体标准品Dara，anti-huIgG Fab单克隆抗体(Sigma,I5260-1ML)，HRP标记山羊抗人IgG二抗(Jackson,code:109-035-098)。

实验方法：

血清收集：

1)雌性Balb/C小鼠，3只/组，分别于尾静脉或者腹腔给药，200μg待测抗体/只；

2)按照实验设计时间点尾静脉采血，收集血样，室温放置30min以上，4000rpm，15min收集血清，-20℃保存，为防止血清蒸发，最后血清收集体积尽量大于20μl；

3)最后一次收集血清至少于-20℃冻存24h。

检测方法：

1)分别PBS包被结合抗原、anti-IgG Fab单克隆抗体于96孔酶联板，0.2μg/ml，100μl/孔，4℃过夜；

2)配置所需试剂：

封闭液5％BSA+PBS

抗体稀释液5％BSA+PBS+20％空白小鼠血清

酶联板洗涤液0.1％Tween+PBS

3)包被好的酶联板PBS清洗三遍，300μl/孔；

4)加入封闭液，200μl/孔，37℃封闭1h；

5)起始血清使用封闭液稀释至合适浓度，用含有相同血清浓度的抗体稀释液稀释至合适的浓度范围，具体浓度的稀释倍数需根据预实验来调整，原则上使检测的血清最终显色值在标曲显色值范围内；

6)抗体稀释液稀释抗体标准品，标准品的稀释仍然根据预实验来调整，使标准品拟合出线性曲线(如有合适软件，也可拟合出S形曲线)。

7)倒掉封闭液，两种包被方法的酶联板分别加入稀释好的抗体标准品与待测血清，100μl/孔，于37℃孵育1h；

8)PBST洗板3遍；

9)1:5000稀释二抗，加入洗涤好的酶联板中，100μl/孔，37℃孵育40min；

10)PBST洗板3遍；

11)TMB显色，100μl/孔，避光10min；

12)加入50μl 2M HCL终止，450nm读数。

结果见表13。

表13-1本发明抗体的小鼠体内药物代谢性质

表13-2本发明抗体的小鼠体内药物代谢性质

以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。

序列表

<110> 迈威（上海）生物科技有效公司

上海普铭生物科技有限公司

<120> 抗人CD38抗体及其应用

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Gly Phe Ser Leu Thr Ser Tyr Gly Val His

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<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 3

Gly Met Ile Thr Thr Gly Tyr Ala Met Asp Tyr

1 5 10

<210> 4

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 4

Lys Ala Ser Glu Asp Ile Tyr Asn Arg Leu Ala

1 5 10

<210> 5

<211> 7

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR2

<400> 5

Gly Ala Thr Ser Leu Glu Thr

1 5

<210> 6

<211> 8

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 6

Gln Gln Tyr Trp Ser Thr Pro Thr

1 5

<210> 7

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 7

Gly Phe Ser Leu Thr Ser Phe Gly Ile His

1 5 10

<210> 8

<211> 16

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 8

Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Leu Ser

1 5 10 15

<210> 9

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 9

Ser Met Ile Thr Thr Gly Tyr Ala Met Asp Tyr

1 5 10

<210> 10

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 10

Gln Gln Tyr Trp Ser Thr Pro Trp Thr

1 5

<210> 11

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 11

Gly Phe Ser Leu Thr Asn Tyr Gly Val His

1 5 10

<210> 12

<211> 16

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 12

Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met Ser

1 5 10 15

<210> 13

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 13

Thr Thr Leu Thr Arg Val Trp Tyr Cys Asp Val

1 5 10

<210> 14

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 14

Lys Ser Ser Glu Asp Ile Tyr Asn Arg Leu Ala

1 5 10

<210> 15

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 15

Gln Gln Tyr Trp Asn Thr Pro Leu Thr

1 5

<210> 16

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 16

Gly Phe Ser Leu Leu Ser Tyr Gly Val His

1 5 10

<210> 17

<211> 16

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 17

Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met Ser

1 5 10 15

<210> 18

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 18

Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr

1 5 10

<210> 19

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 19

Gln Gln Phe Trp Asn Thr Pro Trp Thr

1 5

<210> 20

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 20

Gly Tyr Thr Phe Thr Asn Phe Gly Met Asn

1 5 10

<210> 21

<211> 17

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 21

Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Asn Ala Asp Asp Phe Lys

1 5 10 15

Gly

<210> 22

<211> 5

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 22

Lys Gly Phe Ala Tyr

1 5

<210> 23

<211> 15

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 23

Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met His

1 5 10 15

<210> 24

<211> 7

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR2

<400> 24

Arg Ala Ser Asn Leu Glu Ser

1 5

<210> 25

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 25

Gln Gln Ile Asn Glu Asp Pro Phe Thr

1 5

<210> 26

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 26

Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn

1 5 10

<210> 27

<211> 17

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 27

Trp Ile Asn Thr Tyr Thr Ala Glu Pro Thr Tyr Ala Asp Asp Phe Lys

1 5 10 15

Gly

<210> 28

<211> 5

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 28

Lys Tyr Gly Gly Tyr

1 5

<210> 29

<211> 15

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 29

Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Ile His

1 5 10 15

<210> 30

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 30

Gln Gln Val Asn Glu Asp Pro Leu Thr

1 5

<210> 31

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 31

Gly Tyr Thr Phe Thr Asn Tyr Trp Met Asn

1 5 10

<210> 32

<211> 17

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 32

Tyr Ile Ile Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 33

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 33

Tyr Pro Tyr Arg Gly Tyr Ala Met Asp Tyr

1 5 10

<210> 34

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 34

Ser Ala Ser Ser Ser Val Ser Tyr Met Tyr

1 5 10

<210> 35

<211> 7

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR2

<400> 35

Leu Thr Ser Asn Leu Ala Ser

1 5

<210> 36

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 36

Gln Gln Trp Ser Thr Asn Pro Trp Thr

1 5

<210> 37

<211> 17

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 37

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

1 5 10 15

Gly

<210> 38

<211> 7

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 38

Asn Pro Gly Trp Phe Ala Tyr

1 5

<210> 39

<211> 15

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 39

Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Ser Phe Met His

1 5 10 15

<210> 40

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 40

Gln Gln Ser His Glu Ala Pro Trp Thr

1 5

<210> 41

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 41

Gly Tyr Asn Leu Thr Asn Tyr Gly Met Asn

1 5 10

<210> 42

<211> 17

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR2

<400> 42

Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys

1 5 10 15

Gly

<210> 43

<211> 7

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 43

Tyr Pro Gly Trp Phe Ala Tyr

1 5

<210> 44

<211> 15

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 44

Arg Thr Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met His

1 5 10 15

<210> 45

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 45

Gln Gln Ser Asn Glu Asp Pro Trp Thr

1 5

<210> 46

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 46

Thr Thr Leu Thr Arg Val Trp Tyr Phe Asp Val

1 5 10

<210> 47

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 47

Thr Thr Leu Thr Arg Val Trp Tyr Val Asp Val

1 5 10

<210> 48

<211> 11

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 48

Thr Thr Leu Thr Arg Val Trp Tyr Tyr Asp Val

1 5 10

<210> 49

<211> 15

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 49

Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His

1 5 10 15

<210> 50

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 50

Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met

50 55 60

Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Lys Gly Met Ile Thr Thr Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 51

<211> 106

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 51

Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 52

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 52

Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Phe

20 25 30

Gly Ile His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Leu

50 55 60

Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Ile Asn Ser Leu Arg Ala Asp Asp Thr Ala Ile Tyr Phe Cys Ala

85 90 95

Lys Ser Met Ile Thr Thr Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 53

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 53

Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Ile Leu Ser Ile Thr Ser Leu Gln Thr

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 54

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 54

Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Leu Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met

50 55 60

Ser Arg Leu Asn Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Lys Thr Thr Leu Thr Arg Val Trp Tyr Cys Asp Val Trp Gly Ala Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 55

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 55

Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr

65 70 75 80

Glu Asp Val Val Thr Tyr Tyr Cys Gln Gln Tyr Trp Asn Thr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 56

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 56

Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 57

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 57

Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly His Ala Pro Arg Leu Leu Ile

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 58

<211> 114

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 58

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Asn Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys

85 90 95

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

100 105 110

Ser Ala

<210> 59

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 59

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

1 5 10 15

Gln Arg Thr Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr

20 25 30

Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ile Asn

85 90 95

Glu Asp Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 60

<211> 114

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 60

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Ala Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys

85 90 95

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

100 105 110

Ser Ser

<210> 61

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 61

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

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ser Tyr

20 25 30

Gly Asn Ser Phe Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Val Asn

85 90 95

Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 62

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 62

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Trp Met Asn Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Ile Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Gly 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

Ser Arg Tyr Pro Tyr Arg Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 63

<211> 106

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 63

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

1 5 10 15

Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr

35 40 45

Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Thr Asn Pro Trp Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 64

<211> 116

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 64

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Val Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asn Pro Gly Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

<210> 65

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 65

Asp Ile Val Leu Thr Gln Ser Pro Val Phe Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr

20 25 30

Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser His

85 90 95

Glu Ala Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys

100 105 110

<210> 66

<211> 116

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 66

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Asn Leu Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

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

100 105 110

Thr Val Ser Ala

115

<210> 67

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 67

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

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Thr Ser Glu Ser Val Asp Ser Tyr

20 25 30

Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 68

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 68

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Arg Thr Thr Leu Thr Arg Val Trp Tyr Cys Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 69

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 69

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Thr Thr Leu Thr Arg Val Trp Tyr Cys Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 70

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 70

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 71

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 71

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Thr Thr Leu Thr Arg Val Trp Tyr Val Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 72

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 72

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Thr Asn Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Thr Thr Leu Thr Arg Val Trp Tyr Tyr Asp Val Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 73

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 73

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Arg Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 74

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 74

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 75

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 75

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 76

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 76

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 77

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 77

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 78

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 78

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 79

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 79

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 80

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 80

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 81

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 81

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 82

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 82

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Ser Leu Leu Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Arg Gly Gly Ser Ala Asp Tyr Asn Ala Ala Phe Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Ser Met Ile Thr Thr Gly Phe Thr Leu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 83

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 83

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

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Ile Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe

50 55 60

Lys Asp 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 Tyr Pro Tyr Arg Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 84

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 84

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

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Tyr Ile Ile Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Arg Val Thr Met Thr Lys Asp Asn Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ser Arg Tyr Pro Tyr Arg Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 85

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 85

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

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Tyr Ile Ile Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Tyr Pro Tyr Arg Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 86

<211> 119

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 86

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

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Tyr Ile Ile Pro Ser Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Ala Gly 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

Ser Arg Tyr Pro Tyr Arg Gly Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 87

<211> 116

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 87

Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu 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

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Val Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Gly Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 88

<211> 116

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 88

Gln Ile Gln Leu Val Gln Ser Gly Ser Glu Leu 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

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Val Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asn Pro Gly Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 89

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 89

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 Lys Ser Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Asn Thr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 90

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 90

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Asn Thr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 91

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 91

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser 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 Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 92

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 92

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 93

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 93

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser 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 Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 94

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 94

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 95

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 95

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys 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 Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 96

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 96

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 97

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 97

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser 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 Val Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 98

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 98

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 99

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 99

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 100

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 100

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 Lys Ala Ser Glu Asp Ile Tyr Asn Arg

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Phe Trp Asn Thr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 101

<211> 106

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 101

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 Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr

35 40 45

Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu

65 70 75 80

Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Thr Asn Pro Trp Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 102

<211> 106

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 102

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 Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile Tyr

35 40 45

Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu

65 70 75 80

Asp Ala Ala Val Tyr Tyr Cys Gln Gln Trp Ser Thr Asn Pro Trp Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 103

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 103

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

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr

20 25 30

Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser His

85 90 95

Glu Ala Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 104

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 104

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

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr

20 25 30

Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser His

85 90 95

Glu Ala Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 105

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 105

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

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr

20 25 30

Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Gly Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser His

85 90 95

Glu Ala Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 106

<211> 330

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链恒定区

<400> 106

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 Leu 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

Arg 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 Leu 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 Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Leu 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> 107

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链恒定区

<400> 107

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> 108

<211> 357

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 108

caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccata 60

acctgcacag tctctggttt ctcattaact agctatggtg tacactgggt tcgccagtct 120

ccaggaaagg gtctggagtg gctgggagtg atatggagag gtggaagcac agactacaat 180

gcagctttca tgtccagact gagcatcacc aaggacaact ccaagagcca agttttcttt 240

aaaatgaaca gtctgcaagc tgatgacact gccatatact actgtgccaa aggtatgatt 300

acgacgggct atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 357

<210> 109

<211> 318

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 109

gacatccaga tgacacaatc ttcatcctcc ttttctgtat ctctaggaga cagagtcacc 60

attacttgca aggcaagtga ggacatatat aatcggttag cctggtatca gcagaaacca 120

ggaaatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180

agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240

gaagatgttg ctacttatta ctgtcaacag tattggagta ctcccacgtt cggagggggg 300

accaagctgg aaataaaa 318

<210> 110

<211> 357

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 110

caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccata 60

acctgcacag tctctggttt ctcattaact agctttggta tacactgggt tcgccagtct 120

ccaggaaagg gtctggagtg gctgggagtg atatggagag gtggaagcac agactacaat 180

gcagctttcc tgtccagact gagcatcacc aaggacaact ccaagagcca agttttcttt 240

aaaataaaca gtcttcgagc tgatgacact gccatatact tctgtgccaa atctatgatt 300

acgaccggct atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 357

<210> 111

<211> 321

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 111

gacatccaga tgacacaatc ttcatcctcc ttttctgtat ctctaggaga cagagtcacc 60

attacttgca aggcaagtga ggacatatat aatcggttag cctggtatca gcagaaacca 120

ggaaatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180

agattcagtg gcagtggatc tggaaaggat tacattctca gcattaccag tcttcagact 240

gaagatgttg ctacttatta ctgtcaacag tattggagta ctccgtggac gttcggtgga 300

ggcaccaagc tggagatcaa a 321

<210> 112

<211> 357

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 112

caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccata 60

acctgcacag tctctggttt ctcattaact aactatggtg tacactggct tcgccagtct 120

ccaggaaagg gtctggagtg gctgggagtg atatggagag gtggaagcac agactacagt 180

gcagctttca tgtccagact gaacatcacc aaggacaact ccaagagtca agtttttttt 240

aaaatgaaca gtctgcaagc tgatgacact gccatatact actgtgccaa aactacgctt 300

acgagggtct ggtattgcga tgtctggggc gcagggacca cggtcaccgt ctcctca 357

<210> 113

<211> 321

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 113

gacatccaga tgacacaatc ttcatcctcc ttttctgtat ctctaggaga cagagtcacc 60

attacttgca agtcaagtga ggacatatat aatcggttag cctggtatca gcagaaacca 120

ggaaatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180

agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240

gaagatgttg ttacttatta ctgtcaacag tattggaata ctccgctcac gttcggtgct 300

gggaccaagc tggagctgaa a 321

<210> 114

<211> 357

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 114

caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccata 60

acctgcacag tctctgggtt ctcattactt agttatggtg tacactgggt tcgccagtct 120

ccaggaaagg gtctggagtg gctgggagtg atatggagag gtggaagcgc agactacaat 180

gcagctttca tgtccagact gagcatcacc aaagacaact ccaagagcca agttttcttt 240

aaaatgaaca gtctgcaagc tgatgacact gccatatact actgtgccaa aagtatgatt 300

acgacggggt ttactctgga ctactggggt caaggaacct cagtcaccgt ctcctca 357

<210> 115

<211> 321

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 115

gacatccaga tgacacaatc ttcatcctcc ttttctgtat ctctaggaga cagagtcacc 60

attacttgca aggcaagtga ggacatatat aatcggttag cctggtatca gcagaaacca 120

ggacatgctc ctaggctctt aatatctggt gcaaccagtt tggaaactgg ggttccttca 180

agattcagtg gcagtggatc tggaaaggat tacactctca gcattaccag tcttcagact 240

gaagatgttg ctacttatta ctgtcaacag ttttggaata ctccgtggac gttcggtgga 300

ggcaccaagc tggaaatcaa a 321

<210> 116

<211> 342

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 116

cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60

tcctgcaagg cttctggata taccttcaca aactttggaa tgaactgggt gaagcaggct 120

ccaggaaagg gtttaaagtg gatgggctgg ataaacacct acactggaga gccaacaaat 180

gctgatgact tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240

ttgcagatca acaacctcaa aaatgaggac atggctacat atttctgtgc aagaaaaggg 300

tttgcttact ggggccaagg gactctggtc actgtctctg ca 342

<210> 117

<211> 333

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 117

gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gaggaccacc 60

atatcctgca gagccagtga aagtgttgat agttatggca atagttttat gcactggtac 120

cagcagaaac caggacagcc acccaaactc ctcatctatc gtgcatccaa cctagaatct 180

gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240

cctgtggagg ctgatgatgt tgcaacctat tactgtcagc aaattaatga ggatccattc 300

acgttcggct cggggacaaa gttggaaata aaa 333

<210> 118

<211> 342

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 118

cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60

tcctgcaagg cttctggata taccttcaca aactatggaa tgaactgggt gaagcaggct 120

ccaggaaagg gtttaaagtg gatgggctgg ataaacacct acactgcaga gccaacatat 180

gctgatgact tcaagggacg gtttgccttc tctttggaag cctctgccag cactgcctat 240

ttgcagatca acaacctcaa aaatgaggac atggctacat atttctgtgc aagaaagtat 300

ggtggctact ggggccaagg caccactctc acagtctcct ca 342

<210> 119

<211> 333

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 119

gacattgtgc tgacccaatc tccaccttct ttggctgtgt ctctagggca gagggccacc 60

atatcctgca gagccagtga aagtgttgat agttatggca atagttttat acactggtac 120

cagcagaaac caggacagtc acccaaactc ctcatctatc gtgcatccaa cctagaatct 180

gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240

cctgtggagg ctgatgatgt tgcaacctat tactgtcagc aagttaatga ggatccgctc 300

acgttcggtg ctgggaccaa gctggagctg aaa 333

<210> 120

<211> 357

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 120

caggtccagc ttcagcagtc tggggctgaa ctggcaaaac ctggggcctc agtgaagatg 60

tcctgcaagg cttctggcta cacctttact aactactgga tgaattggat aaaacagagg 120

cctggacagg gtctggaatg gattggatac attattccaa gcactgatta tactgagtac 180

aatcagaagt tcaaggacaa ggccacattg actgcagaca aatcctccgg cacagcctac 240

atgcaactga gcagcctgac atctgaggac tctgcagtct attactgttc aaggtaccct 300

tataggggct atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 357

<210> 121

<211> 318

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 121

caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60

atgacctgca gtgccagctc aagtgtaagt tacatgtact ggtaccaaca gaagccaaga 120

tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctgctcgc 180

ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagcat ggaggctgaa 240

gatgctgcca cttattactg ccagcagtgg agtactaacc cgtggacgtt cggtggaggc 300

accaagctgg aactcaaa 318

<210> 122

<211> 348

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 122

cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60

tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120

ccaggaaagg gtttaaagtg gatgggctgg ataaacacct acactggaga gccaacagtt 180

gctgatgact tcaagggacg gtttgccttc tctttggaca cctctgccag cactgcctat 240

ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagaaatccc 300

ggctggtttg cttactgggg ccaagggact ctggtcactg tctctgca 348

<210> 123

<211> 333

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 123

gacattgtgt tgacccaatc tccagttttt ttggctgtgt ctctagggca gagggccacc 60

atatcctgca gagccagtga aagtgttgat aattatggca atagttttat gcactggtac 120

cagcagaaac caggacagcc acccaaactc ctcatctatc gtgcatccaa cctagaatct 180

gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240

cctgtggagg ctgatgatgt tgcaacctat tactgtcagc aaagtcatga ggctccgtgg 300

acgttcggtg gaggcaccag gctggaaatc aaa 333

<210> 124

<211> 348

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链可变区

<400> 124

cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60

tcctgcaagg cttctgggta taacctcaca aactatggaa tgaactgggt gaagcaggct 120

ccaggaaagg gtttaaagtg gatgggctgg ataaacacct acactggaga gccaacatat 180

gctgatgact tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240

ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagataccca 300

ggctggtttg cttactgggg ccaagggact ctggtcactg tctctgca 348

<210> 125

<211> 333

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链可变区

<400> 125

gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 60

atatcctgca gaaccagtga aagtgttgat agttatggca atagttttat gcactggtac 120

cagcagaaac caggacagcc acccaaactc ctcatctatc gtgcatccaa cctagaatct 180

gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240

cctgtggagg ctgatgatgt tgcaacctat tactgtcagc aaagtaatga ggatccgtgg 300

acgttcggtg gaggcaccaa gctggaaatc aaa 333

<210> 126

<211> 990

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 重链恒定区

<400> 126

gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720

atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc tccgggtaaa 990

<210> 127

<211> 321

<212> DNA

<213> 人工(artificial)

<220>

<221> gene

<222> ()..()

<223> 轻链恒定区

<400> 127

cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60

ggaactgcct ctgttgtgtg cctgctgaat aacttctatc cccgcgaggc caaagtacag 120

tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180

agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240

aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300

agcttcaacc gcggagagtg t 321

<210> 128

<211> 122

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> Daratumumab，重链可变区

<400> 128

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> 129

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> Daratumumab，轻链可变区

<400> 129

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> 130

<211> 120

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> Isatuximab，重链可变区

<400> 130

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

1 5 10 15

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

20 25 30

Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Gly Tyr Ala Gln Lys Phe

50 55 60

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

65 70 75 80

Met His Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Asp Tyr Tyr Gly Ser Asn Ser Leu Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 131

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> Isatuximab，轻链可变区

<400> 131

Asp Ile Val Met Thr Gln Ser His Leu Ser Met Ser Thr Ser Leu Gly

1 5 10 15

Asp Pro Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Val

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Arg Leu Ile

35 40 45

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

50 55 60

Ser Gly Ala Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Pro Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 132

<211> 120

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> Mor202，重链可变区

<400> 132

Gln 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 Ser Ser Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 133

<211> 107

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> Mor202，轻链可变区

<400> 133

Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Leu Arg His Tyr Tyr Val

20 25 30

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

35 40 45

Gly Asp Ser Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu

65 70 75 80

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

85 90 95

Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 134

<211> 106

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 134

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

1 5 10 15

Glu Arg Ala Thr Leu Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Trp Ile Tyr

35 40 45

Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu

65 70 75 80

Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Thr Asn Pro Trp Thr

85 90 95

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 135

<211> 106

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 135

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

1 5 10 15

Glu Arg Ala Thr Leu Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Arg Pro Trp Ile Tyr

35 40 45

Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu

65 70 75 80

Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Thr Asn Pro Trp Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 136

<211> 12

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 136

Ser Ala Ser Ser Ser Val Ser Tyr Met Tyr Trp Tyr

1 5 10

<210> 137

<211> 9

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR3

<400> 137

Ser Met Ile Thr Thr Gly Phe Thr Leu

1 5

<210> 138

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 138

Gln Gln Phe Trp Asn Thr Pro Trp Thr Phe

1 5 10

<210> 139

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR3

<400> 139

Gln Gln Trp Ser Thr Asn Pro Trp Thr Phe

1 5 10

<210> 140

<211> 116

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 140

Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala

1 5 10 15

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

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Thr Val Ser Ser

115

<210> 141

<211> 116

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 141

Gln Ile Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala

1 5 10 15

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

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Thr Val Ser Ser

115

<210> 142

<211> 116

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链可变区

<400> 142

Gln Ile Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala

1 5 10 15

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

20 25 30

Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Thr Val Ser Ser

115

<210> 143

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 143

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

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Thr Ser Glu Ser Val Asp Ser Tyr

20 25 30

Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Glu Asp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 144

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 144

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

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Thr Ser Glu Ser Val Asp Ser Tyr

20 25 30

Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Glu Asp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 145

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 145

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

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Thr Ser Glu Ser Val Asp Ser Tyr

20 25 30

Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Glu Asp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 146

<211> 111

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链可变区

<400> 146

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

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Thr Ser Glu Ser Val Asp Ser Tyr

20 25 30

Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

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

65 70 75 80

Pro Val Glu Ala Gln Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Glu Asp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 147

<211> 10

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 重链，CDR1

<400> 147

Gly Tyr Ala Leu Thr Asn Tyr Gly Met Asn

1 5 10

<210> 148

<211> 15

<212> PRT

<213> 人工(artificial)

<220>

<221> PEPTIDE

<222> ()..()

<223> 轻链，CDR1

<400> 148

Arg Thr Ser Glu Ser Val Asp Ser Tyr Gly Asn Thr Phe Met His

1 5 10 15