CN111944047B - 抗bcma的人源化单链抗体及应用 - Google Patents
抗bcma的人源化单链抗体及应用 Download PDFInfo
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- CN111944047B CN111944047B CN201910402960.3A CN201910402960A CN111944047B CN 111944047 B CN111944047 B CN 111944047B CN 201910402960 A CN201910402960 A CN 201910402960A CN 111944047 B CN111944047 B CN 111944047B
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Abstract
本发明属于基因工程技术领域，具体涉及一种抗BCMA的人源化单链抗体及其应用，所述抗BCMA的人源化单链抗体氨基酸序列如SEQ ID NO:17‑20或34‑41任一序列所示。所述抗BCMA的人源化单链抗体由轻链可变区、Linker和重链可变区依次连接形成，人源化程度高，可以有效地降低CAR的免疫原性，增强CAR‑T在体内的持续和安全性。
Description
技术领域
本发明属于基因工程技术领域，具体涉及一种抗BCMA的人源化单链抗体及其应用。
背景技术
BCMA全称为tumor necrosis factor receptor superfamily member 17，又称为B-cell maturation antigen(BCMA)或CD269或TNFRSF13A，主要表达于成熟B淋巴细胞和浆细胞表面，在MM组织和细胞中高表达，是治疗恶性血液病多的合适的靶点，而发性骨髓瘤(MM)属于恶性血液病中的一种。
多发性骨髓瘤又称multiple myeloma，简写为MM，据统计MM的高发年龄段在65-74岁，并发症包括高钙血症，肾脏机能不全、贫血和感染。虽然初次治疗MM对多种细胞毒性药物均较为敏感，但是由于高度异质性和耐药性MM复发概率高，目前不能治愈。
抗体是免疫系统中最重要的分子之一，也是目前免疫疗法中主要治疗手段之一，但是直接使用小鼠抗体进行人体治疗时，因为鼠抗的异质性会引起人抗鼠抗体反应(Humananti-mouse antibody reaction，HAMA)，导致抗体半衰期短，在循环系统中被很快清除，失去疗效。人源化抗体可以大大减少异源抗体对人类机体造成的免疫副反应，因此，抗体的人源化修饰以提高抗体的人源化程度、减弱HAMA就显得至关重要。
此外，抗体的稳定性和可靠性仍然长久以来困扰着抗体产业，也是整个生物学研究领域需要突破的大的瓶颈。而我们针对鼠源抗体的人源化以及稳定性、特异性和亲和性改造是很有必要的。
单链抗体作为抗体的一种，除了可以发挥抗体的作用，还可以应用于病原靶点检测，也是最新的细胞治疗如CAR-T的CAR结构中重要的组成部分，其选择对CAR-T疗效起到至关重要的作用。
发明内容
有鉴于此，本发明的目的之一在于提供一种靶向BCMA的人源化单链抗体，所述抗BCMA的人源化单链抗体可以有效地降低BCMA-CAR的免疫原性，增强CAR-T在体内的持续和安全性。。
并非所有改造的抗BCMA ScFv均能够具有活性，并且形状稳定；也并非所有改造的抗BCMA ScFv的免疫原性能够降低；并非所有改造的抗BCMA ScFv能够作为CAR结构中抗原识别区应用。由于不同鼠源骨架区对抗体功能的影响不同，简单的进行人源框架的替换可能会导致改造的ScFv丧失活性或者获得的人源化ScFv虽然亲和力；另一方面，人源化改造势必降低ScFv的亲和力，不同的亲和力对CAR-T功能影响也有不同。因此需要进行大量的筛选和研究寻找更稳定有效的识别BCMA的ScFv。
为实现上述目的，本发明采用以下方案：
所述的抗BCMA的人源化单链抗体通过以下步骤改造得到：
1)通过分子对接模拟，对鼠源抗体骨架区序列进行人源化修饰改造，以此获得具有共同活性区域的人源化的单链抗体；
2)将步骤1)获得的人源化的单链抗体进行回复突变和免疫原性的优化，以此获得活性好、低免疫原性的人源化的单链抗体。
所述抗BCMA的人源化单链抗体，轻链CDR1的氨基酸序列如SEQ ID NO:3所示，轻链CDR2的氨基酸序列如SEQ ID NO:4所示，轻链CDR3的氨基酸序列如SEQ ID NO:5所示；所述重链CDR1的氨基酸序列如SEQ ID NO:6所示，重链CDR2的氨基酸序列如SEQ ID NO:7所示，重链CDR3的氨基酸序列如SEQ ID NO:8所示。
所述的抗BCMA的人源化单链抗体还包含Linker区，所述Linker的氨基酸序列如SEQ ID NO:1或2所示。
进一步，所述单链抗体的轻链CDR1、CDR2、CDR3区分别为SEQ ID NO:9的第27-36位，第54-56位以及第101-109位氨基酸。
具体的，所述单链抗体重链CDR1、CDR2、CDR3区分别为SEQ ID NO:13的第26-33位，第51-58位，以及第97-107位氨基酸。
进一步，所述轻链的氨基酸序列如SEQ ID NO:9-12任一所示；所述重链的氨基酸序列如SEQ ID NO:13-16任一所示。
进一步，所述轻链的核苷酸序列如SEQ ID NO:26-29任一序列所示；所述重链的核苷酸序列如SEQ ID NO:30-33任一所示。
进一步，所述抗BCMA的人源化单链抗体的氨基酸序列如SEQ ID NO:17-20任一序列所示。
某些实施例中，所述抗BCMA的人源化单链抗体的氨基酸序列如SEQ ID NO：34-41任一所示。
进一步，所述抗BCMA的人源化单链抗体的核苷酸序列SEQ ID NO:21-24任一序列所示。
本发明的目的之三在于提供一种所述抗BCMA的人源化单链抗体在构建靶向BCMA的嵌合抗原受体中的应用。
本发明的目的之四在于提供所述的抗BCMA的人源化单链抗体在构建包含所述抗BCMA的人源化单链抗体的表达载体中的应用。
具体的，所述的载体选自慢病毒表达载体、逆转录病毒表达载体、腺病毒表达载体、腺相关病毒表达载体、DNA载体，RNA载体或质粒。
本发明的目的之五在于提供所述的抗BCMA的人源化单链抗体在制备治疗表达BCMA抗原的恶性血液肿瘤药物中的应用。。
本发明的目的之六在于提供所述的抗BCMA的人源化单链抗体在制备治疗表达BCMA抗原的恶性血液肿瘤药物中的应用。
本发明的目的还在于，提供所述的抗BCMA的人源化单链抗体在BCMA靶点相关肿瘤的诊断、预后评估或抗原纯化中的应用
为实现上述目的，本发明采用以下方案；
所述的抗BCMA的人源化单链抗体在制备治疗恶性血液肿瘤药物中的应用。
具体的，常见的血液肿瘤主要包括各类白血病、多发性骨髓瘤以及恶性淋巴瘤。
进一步，所述所述恶性血液肿瘤为MM。
进一步，所述恶性血液肿瘤的细胞或组织能够表达BCMA。
本发明的有益效果在于：
1)本发明提供的抗BCMA的人源化单链抗体人源化程度高，可以有效地降低其单独或组合使用时在体内的免疫原性，增强CAR-T在体内的持续和安全性；
2)本发明提供的抗BCMA的人源化单链抗体可应用于靶向BCMA的CAR-T治疗，不仅可以有效的清除表达BCMA抗原的肿瘤靶细胞，而对阴性抗原(不表达BCMA)的肿瘤细胞没有毒性作用；并且能够维持靶向BCMA的嵌合抗原受体在病人细胞培养过程中的阳性率，在靶抗原刺激后能够长时间的进行增殖，能够用于肿瘤的靶向治疗；
3)由本发明提供的抗BCMA的人源化单链抗体制备的嵌合抗原受体能够稳定表达于T淋巴细胞尤其是病人来源的T淋巴细胞，可以用于制备治疗恶性血液病的药物中针对恶性血液病的过继细胞治疗。
附图说明
图1为scFv的活性和纯度。
图2为靶向BCMA人源化单克隆抗体亲和力测定。
图3为靶向BCMA人源化单克隆抗体亲和力测定。
图4为人源化ScFv对不同种属BCMA抗原的特异性。
图5为流式检测靶细胞BCMA表达。
图6为RT检测不同肿瘤来源靶细胞BCMA表达。
图7为改造的ScFv构建的CAR-T细胞功能验证。
图8为可溶性BCMA对不同改造的ScFv构建的CAR-T细胞功能影响。
具体实施方式
以下将参照附图，对本发明的优选实施例进行详细描述。优选实施例中未注明具体条件的实验方法，通常按照常规条件，例如分子克隆实验指南(第三版，J.萨姆布鲁克等著)中所述的条件，或按照制造厂商所建议的条件。所举实施例是为了更好地对本发明的内容进行说明，但并不是本发明的内容仅限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
实施例1设计抗人BCMA抗原的人源化单链抗体
经过分子对接模拟，对鼠源抗体骨架序列进行人源化修饰改造，在此基础上分别对人源化ScFv进行回复突变和免疫原性优化，以获得活性好和免疫原性更低的ScFv。
其中所述抗体的轻链氨基酸序列分别如SEQ ID NO:9-12所示；所述抗体的重链氨基酸序列分别如SEQ ID NO:13-16所示。
所述人源化单链抗体氨基酸序列分别如SEQ ID NO:17-20任一所示；核苷酸序列如SEQ ID NO:21-24任一所示。
实施例2靶向BCMA人源化单克隆抗体表达纯化
将载有单克隆抗体的质粒构建慢病毒表达系统，利用病毒感染的方式感染CHO表达细胞，筛选高表达scFv的单克隆细胞株，每三天收集细胞表达上清并进行纯化。收集的细胞上清利用AKTA Prime仪器进行纯化，具体实验步骤参考AKTA Prime使用手册。纯化的蛋白通过SDS验证scFv的活性和纯度，如图1所示，其中最左和最右的m是蛋白maker(thermo26619 ladder)，m左侧标识为maker的每条条带代表的大小，1通道是ScFv1的蛋白条带，2通道是ScFv2的蛋白条带，抗体大小在25-35kDa，改造的scFv具有高纯度。
实施例3靶向BCMA人源化单克隆抗体亲和力测定
采用Fortebio Octet K2和Nicoya OpenSPR进行单克隆抗体亲和力测定，选择的传感器为ProA biosensor和Ni+NTA，检测样本浓度梯度为：100nM，50nM，25nM，12.5nM，6.25nM；以及250nM，125nM，62.5nM，31.25nM，15.625nM，具体实验步骤见仪器操作规程。结果如图2和图3所示，ScFv1和ScFv2具有较好的亲和力，亲和力常数KD＝4.65nM和16.4nM。
| Sample ID | Loading Sample ID | KD(M) | KD(nm) | kon(1/Ms) | kdis(1/s) |
| ScFv1 | hBCMA-hFc | 4.65E-09 | 4.65 | 9.42E+04 | 4.38E-04 |
| ScFv2 | hBCMA-hFc | 1.64E-08 | 16.4 | 2.66E+05 | 4.37E-03 |
实施例4靶向BCMA人源化单克隆抗体特异性测定
1)优选的纯化的标记有His标签的人源化ScFv2用PBS稀释2个梯度，商业购买的抗BCMA抗体(Biolegend，货号357504)分别孵育BCMA阳性细胞MM1S和阴性细胞K562检测抗体对BCMA识别的特异性，结果如下表所示，筛选的ScFv有较好的特异性。
2)包含人源化ScFv的CAR感染CHO细胞系，筛选表达在90％左右的CAR阳性细胞进行扩大培养后，用不同种属BCMA抗原(人BCMA、鼠BCMA和食蟹猴BCMA抗原，Acro-biosystems，货号分别为BC7-H5254、BCA-M5258、BCA-C5253)依据说明书溶解后PBS稀释6个梯度，分别孵育表达人源化ScFvCAR的CHO细胞，抗His-647二抗染色标记，流式检测浓度梯度下His-647阳性(即BCMA的阳性率)，进行流式MFI(平均荧光强度)统计，对人源化scFv于BCMA的亲和力进行分析。结果如图4所示，A和B为人源化ScFv对不同种属BCMA抗原的特异性，结果表明人源化的ScFv对仅对人BCMA有亲和力，对鼠源和食蟹猴来源BCMA不识别。
实施例5包含所述ScFv靶向人BCMA抗原的嵌合抗原受体活性验证
(1)制备靶向人BCMA抗原的嵌合抗原受体T细胞
合成依次含前导肽(又称信号肽)、抗人BCMA抗原的单链抗体ScFv，铰链区、跨膜区和胞内信号段的嵌合抗原受体序列并制备病毒感染T细胞。其中抗人BCMA抗原的人源化单链抗体核苷酸序列如SEQ ID NO:21-24任一所示，氨基酸序列如SEQ ID NO:17-20任一所示。；
2)靶向人BCMA抗原的嵌合抗原受体(CAR)表达检测
在培养过程中对培养至第6天和9天的已感染病毒的T细胞进行CAR阳性率检测。检测方法为流式检测，结果如下表所示不同ScFv来源的病毒载体感染T细胞后CAR阳性率，其中BCMA011-014包含了SEQ ID NO:21-24核苷酸序列所示的ScFv，BCMA023、BCMA024、BCMA034以及BCMA035分别包含ScFv1和ScFv2，核苷酸序列为SEQ ID NO:24或SEQ ID NO:22所示，氨基酸序列为SEQ ID NO:20或SEQ ID NO:18。可见核苷酸序列为SEQ ID NO:24或SEQID NO:22，氨基酸序列为SEQ ID NO:20或SEQ ID NO:18的单链抗体可以制备靶向BCMA的嵌合抗原受体(CAR)，并且在不同CAR结构中均能正常表达。
| 病毒 | CAR+ | 病毒 | CAR+ | 病毒 | CAR+ |
| BCMA011 | 65.60％ | BCMA022 | / | BCMA033 | / |
| BCMA012 | 59.90％ | BCMA023 | 59.70％ | BCMA034 | 22.80％ |
| BCMA013 | 70.60％ | BCMA024 | 60.68％ | BCMA035 | 31.48％ |
| BCMA014 | 74.20％ | BCMA025 | BCMA036 | / | |
| BCMA021 | 40.20％ | / | / | / |
3)不同改造的ScFv来源的嵌合抗原受体T细胞抗肿瘤效果验证。
以稳定表达萤火虫荧光素酶的BCMA阳性H929细胞(简称为H929-luc)、阴性细胞K562-Luc以及利用K562体外构建的BCMA高表达细胞K562-BCMA-Luc作为靶细胞，靶细胞BCMA表达检测如图5和图6所示，分别利用流式细胞术和RT方法检测H929为BCMA高表达阳性细胞，K562为BCMA阴性细胞。
由于CAR结构过多，因此有效性验证分为2组进行；CAR-T细胞均采用8:1/4:1/2:1效靶比铺效应细胞。使用
Luciferase Assay System(Promega Cat.#E2520)试剂盒提供的标准方法检测杀伤效果，杀伤率用下列公式计算：
杀伤结果如图7所示，由于不同供者细胞感染CAR阳性率有所差别，因此A、B和C这3批次最高杀伤率有所差异，但是并不影响不同CAR-T细胞杀伤趋势，在每批次杀伤组组内对比杀伤效果，结果表明BCMA012、BCMA013、BCMA014、BCMA023、BCMA024、BCMA034、和BCMA021均具有较好的体外杀伤效果，因此核苷酸序列为SEQ ID NO:24或SEQ ID NO:22，氨基酸序列为SEQ ID NO:20或SEQ ID NO:18的单链抗体可以制备靶向BCMA的嵌合抗原受体(CAR)，并且在不同CAR结构中均能发挥活性。
实施例6可溶性BCMA对CAR-T有效性影响
在多发性骨髓瘤患者血液中具有高浓度的可溶性BCMA(sBCMA)，需要验证是否sBCMA的存在会影响CAR-T的有效性。
利用K562体外构建的BCMA高表达细胞K562-BCMA-Luc作为靶细胞，采用实施例5的方法制备CAR-T细胞，分为加入sBCMA组和未加sBCMA组两组，杀伤效靶比16:1，使用
Luciferase Assay System(Promega Cat.#E2520)试剂盒提供的标准方法检测杀伤效果，杀伤率用下列公式计算：
杀伤结果如图8所示，结果表明BCMA013、BCMA014、BCMA023和BCMA024体外活性均不受高浓度sBCMA的影响，因此核苷酸序列为SEQ ID NO:24或SEQ ID NO:22，氨基酸序列为SEQ ID NO:20或SEQ ID NO:18的单链抗体活性不受机体内sBCMA的影响。
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利要求范围当中。
序列表
<110> 重庆精准生物技术有限公司
<120> 抗BCMA的人源化单链抗体及应用
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gatatcgtgc tgacacagag ccctgcctcc ctggccgtga gcccaggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagaagc caggacaggc acccgtgctg gtcatctacg cagcctctaa cctggagagc 180
ggagtgccag cacggttctc cggctctggc agcggcaccg actttacact gaagatctct 240
agagtggagg ccgaggatgt gggcgtgtac tattgccagc agtccatcga ggacccacgg 300
accttcggcg gaggaacaaa gctggagatc aagggctcca cctctggaag cggcaagcca 360
ggatccggag agggatctac aaagggacag gtgcagctgg tgcagtccgg agcagaggtg 420
aagaagccag gagccagcgt gaaggtgtcc tgtaaggcct ctggctacac cttcacagat 480
tactatatga actgggtgag gcagatgcca ggcaagggac tggagtggat gggcgtgatc 540
aacccttaca atggcggcac cgattataat cagaagttta agggccgcgt gaccatcaca 600
gccgacaagt ccacctctac agcctacatg gagctgagct ccctgaggag cgaggacaca 660
gccgtgtact attgtgcccg ctccgtgtac gactatcctt ttgattattg gggccagggc 720
accctggtga cagtgtctag c 741
<210> 22
<211> 741
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 22
gatatcgtgc tgacacagag ccctgcctcc ctggccgtga gcctgggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagaagc ctggacagcc acccgtgctg gtcatctacg cagcctctaa cctggagagc 180
ggagtgccag caaggttctc cggatctgga agcggaaccg actttacact gaagatccac 240
ccagtggagg cagaggatgt gggcgtgtac tattgccagc agtctatcga ggaccctcgc 300
accttcggcg gaggaacaaa gctggagatc aagggctcca cctctggaag cggcaagcca 360
ggatccggag agggatctac aaagggacag gtgcagctgg tgcagtccgg accagaggtg 420
aagaagccag gagccagcgt gaaggtgtcc tgtaaggcct ctggctacac cttcacagat 480
tactatatga actgggtgcg gcagatgcac ggcaagggac tggagtggat gggcgtgatc 540
aacccataca atggcggcac cgattataat cagaagttta agggcagagt gaccatcaca 600
gccgacaagt ccacctctac agcctacatg gagctgagct ccctgaggag cgaggacaca 660
gccgtgtact attgtgcccg ctccgtgtac gactatccct ttgattattg gggccagggc 720
accctggtga cagtgtctag c 741
<210> 23
<211> 741
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 23
gacatcgtgc tgacacagag ccctgcctcc ctggccgtga gcctgggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagaagc ctggccagcc ccctaagctg gtcatctacg cagcctctaa cctggagagc 180
ggagtgccag accggttctc cggatctggc agcgagaccg acttcaccct gaacatccac 240
ccagtggagg aggaggacgt gggcgtgtac tattgccagc agtctatcga ggatcctaga 300
accttcggcg gcggcacaaa gctggagatc aagggctcca cctctggaag cggcaagcca 360
ggatccggag agggatctac aaagggacag gtgcagctgg tgcagtccgg accagtggtg 420
aagaagccag gagccagcgt gaaggtgtcc tgtgaggcct ctggctacac cttcacagac 480
tactatatga actgggtgag gcagatgcac ggcaagggcc tggagtggat gggcgtgatc 540
aacccataca atggcggcac cgactataat cagaagttta agggccgcgt gaccatcaca 600
gccgataagt ccacctctac agcctacatg gagctgagct ccctgaccag cgaggataca 660
gccgtgtact attgtgccag atccgtgtac gactatccct ttgattattg gggccagggc 720
accctggtga cagtgtctag c 741
<210> 24
<211> 741
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 24
gacatcgtga tgacccagag ccctgattcc ctggccgtga gcctgggaga gagggcaaca 60
atcaactgcc gcgcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagctgc ctggcacacc ccctaagctg ctgatctatg ccgcctctaa tctggagagc 180
ggcgtgccag acaggttctc cggatctgga agcggaaccg acttcaccct gaagatctct 240
ccagtggagg cagaggacgt gggcgtgtac tattgccagc agtccatcga ggatcctcgc 300
accttcggcg gaggaacaaa gctggagatc aagggctcca cctctggaag cggcaagcca 360
ggatccggag agggatctac aaagggacag gtgcagctgg tgcagtccgg accagccctg 420
gtgaagccag gagccagcgt gaaggtgtcc tgtaaggcct ctggctacac cttcacagac 480
tactatatga actgggtgcg gcaggcacac ggacagggac tggagtggat gggcgtgatc 540
aacccataca atggcggcac cgactataat cagaagttta agggccgggt gaccatgaca 600
agagatacct ccatctctac agcctacatg gagctgagct ccctgcggag cgaggataca 660
gccgtgtact attgtgccag atccgtgtac gactatccct ttgattattg gggccagggc 720
accctggtga cagtgtctag c 741
<210> 25
<211> 18
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 25
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 26
<211> 333
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 26
gatatcgtgc tgacacagag ccctgcctcc ctggccgtga gcccaggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagaagc caggacaggc acccgtgctg gtcatctacg cagcctctaa cctggagagc 180
ggagtgccag cacggttctc cggctctggc agcggcaccg actttacact gaagatctct 240
agagtggagg ccgaggatgt gggcgtgtac tattgccagc agtccatcga ggacccacgg 300
accttcggcg gaggaacaaa gctggagatc aag 333
<210> 27
<211> 333
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 27
gatatcgtgc tgacacagag ccctgcctcc ctggccgtga gcctgggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagaagc ctggacagcc acccgtgctg gtcatctacg cagcctctaa cctggagagc 180
ggagtgccag caaggttctc cggatctgga agcggaaccg actttacact gaagatccac 240
ccagtggagg cagaggatgt gggcgtgtac tattgccagc agtctatcga ggaccctcgc 300
accttcggcg gaggaacaaa gctggagatc aag 333
<210> 28
<211> 333
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 28
gacatcgtgc tgacacagag ccctgcctcc ctggccgtga gcctgggaca gcgggccacc 60
atcacatgca gagcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagaagc ctggccagcc ccctaagctg gtcatctacg cagcctctaa cctggagagc 180
ggagtgccag accggttctc cggatctggc agcgagaccg acttcaccct gaacatccac 240
ccagtggagg aggaggacgt gggcgtgtac tattgccagc agtctatcga ggatcctaga 300
accttcggcg gcggcacaaa gctggagatc aag 333
<210> 29
<211> 333
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 29
gacatcgtga tgacccagag ccctgattcc ctggccgtga gcctgggaga gagggcaaca 60
atcaactgcc gcgcctccga gtctgtgagc atccacggca cccacctgat gcactggtac 120
cagcagctgc ctggcacacc ccctaagctg ctgatctatg ccgcctctaa tctggagagc 180
ggcgtgccag acaggttctc cggatctgga agcggaaccg acttcaccct gaagatctct 240
ccagtggagg cagaggacgt gggcgtgtac tattgccagc agtccatcga ggatcctcgc 300
accttcggcg gaggaacaaa gctggagatc aag 333
<210> 30
<211> 354
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 30
caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagccag cgtgaaggtg 60
tcctgtaagg cctctggcta caccttcaca gattactata tgaactgggt gaggcagatg 120
ccaggcaagg gactggagtg gatgggcgtg atcaaccctt acaatggcgg caccgattat 180
aatcagaagt ttaagggccg cgtgaccatc acagccgaca agtccacctc tacagcctac 240
atggagctga gctccctgag gagcgaggac acagccgtgt actattgtgc ccgctccgtg 300
tacgactatc cttttgatta ttggggccag ggcaccctgg tgacagtgtc tagc 354
<210> 31
<211> 354
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 31
caggtgcagc tggtgcagtc cggaccagag gtgaagaagc caggagccag cgtgaaggtg 60
tcctgtaagg cctctggcta caccttcaca gattactata tgaactgggt gcggcagatg 120
cacggcaagg gactggagtg gatgggcgtg atcaacccat acaatggcgg caccgattat 180
aatcagaagt ttaagggcag agtgaccatc acagccgaca agtccacctc tacagcctac 240
atggagctga gctccctgag gagcgaggac acagccgtgt actattgtgc ccgctccgtg 300
tacgactatc cctttgatta ttggggccag ggcaccctgg tgacagtgtc tagc 354
<210> 32
<211> 354
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 32
caggtgcagc tggtgcagtc cggaccagtg gtgaagaagc caggagccag cgtgaaggtg 60
tcctgtgagg cctctggcta caccttcaca gactactata tgaactgggt gaggcagatg 120
cacggcaagg gcctggagtg gatgggcgtg atcaacccat acaatggcgg caccgactat 180
aatcagaagt ttaagggccg cgtgaccatc acagccgata agtccacctc tacagcctac 240
atggagctga gctccctgac cagcgaggat acagccgtgt actattgtgc cagatccgtg 300
tacgactatc cctttgatta ttggggccag ggcaccctgg tgacagtgtc tagc 354
<210> 33
<211> 354
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 33
caggtgcagc tggtgcagtc cggaccagcc ctggtgaagc caggagccag cgtgaaggtg 60
tcctgtaagg cctctggcta caccttcaca gactactata tgaactgggt gcggcaggca 120
cacggacagg gactggagtg gatgggcgtg atcaacccat acaatggcgg caccgactat 180
aatcagaagt ttaagggccg ggtgaccatg acaagagata cctccatctc tacagcctac 240
atggagctga gctccctgcg gagcgaggat acagccgtgt actattgtgc cagatccgtg 300
tacgactatc cctttgatta ttggggccag ggcaccctgg tgacagtgtc tagc 354
<210> 34
<211> 247
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 34
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 Ala Ser Glu Ser Val Ser Ile His
20 25 30
Gly Thr His Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Phe Cys Gln Gln Ser Ile
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
115 120 125
Gly Glu Val Gln Leu Gln Gln Ser Gly Pro Val Leu Val Lys Pro Gly
130 135 140
Ala Ser Val Lys Met Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp
145 150 155 160
Tyr Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Thr Leu Glu Trp
165 170 175
Ile Gly Val Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys
180 185 190
Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala
195 200 205
Tyr Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr
210 215 220
Cys Ala Arg Ser Val Tyr Asp Tyr Pro Phe Asp Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser
245
<210> 35
<211> 244
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 35
Glu Val Gln Leu Gln Gln Ser Gly Pro Val Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Thr Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Tyr Asp Tyr Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Ser Ile His Gly Thr His Leu Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu
180 185 190
Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe
195 200 205
Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Phe
210 215 220
Cys Gln Gln Ser Ile Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 36
<211> 246
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 36
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Met Ser Leu Gly
1 5 10 15
Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Ser Val Ile
20 25 30
Gly Ala His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Thr Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp
65 70 75 80
Pro Val Glu Glu Asp Asp Val Ala Ile Tyr Ser Cys Leu Gln Ser Arg
85 90 95
Ile Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly
100 105 110
Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys
115 120 125
Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly
130 135 140
Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp
145 150 155 160
Tyr Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp
165 170 175
Met Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp
180 185 190
Phe Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala
195 200 205
Tyr Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe
210 215 220
Cys Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Ser Val Thr Val Ser Ser
245
<210> 37
<211> 243
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 37
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 Asp Tyr
20 25 30
Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe
50 55 60
Arg 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 Tyr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
130 135 140
Met Ser Leu Gly Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
145 150 155 160
Val Ser Val Ile Gly Ala His Leu Ile His Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Thr
180 185 190
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Asp Pro Val Glu Glu Asp Asp Val Ala Ile Tyr Ser Cys
210 215 220
Leu Gln Ser Arg Ile Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 38
<211> 244
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 38
Gln Val Gln Leu Val Gln Ser Gly Pro Val Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Met His Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Val Tyr Asp Tyr Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Ser Ile His Gly Thr His Leu Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Lys Leu Val Ile Tyr Ala Ala Ser Asn Leu Glu
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe
195 200 205
Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Gln Gln Ser Ile Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 39
<211> 244
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Pro Ala Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala His Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile 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 Ser Val Tyr Asp Tyr Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Ser Ile His Gly Thr His Leu Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Ala Ala Ser Asn Leu Glu
180 185 190
Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Gln Gln Ser Ile Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 40
<211> 244
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 40
Gln Val Gln Leu Val Gln Ser Gly Pro 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 Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Met His Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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
Ala Arg Ser Val Tyr Asp Tyr Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
130 135 140
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Ser Ile His Gly Thr His Leu Met His Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Gln Pro Pro Val Leu Val Ile Tyr Ala Ala Ser Asn Leu Glu
180 185 190
Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile His Pro Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Gln Gln Ser Ile Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 41
<211> 244
<212> PRT
<213> 人工序列(Artificial sequence)
<400> 41
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 Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys 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
Ala Arg Ser Val Tyr Asp Tyr Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
130 135 140
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu
145 150 155 160
Ser Val Ser Ile His Gly Thr His Leu Met His Trp Tyr Gln Gln Leu
165 170 175
Pro Gly Thr Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Lys Ile Ser Pro Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
210 215 220
Cys Gln Gln Ser Ile Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
Claims (9)
1.抗BCMA的人源化单链抗体，其特征在于，所述人源化单链抗体包括氨基酸序列如SEQID NO:10所示的轻链和氨基酸序列如SEQ ID NO:14所示的重链；或所述人源化单链抗体包括氨基酸序列如SEQ ID NO:12所示的轻链和氨基酸序列如SEQ ID NO:16所示的重链；所述轻链的CDR1的氨基酸序列如SEQ ID NO:3所示，所述轻链的CDR2的氨基酸序列如SEQ IDNO:4所示，所述轻链的CDR3的氨基酸序列如SEQ ID NO:5所示；所述重链的CDR1的氨基酸序列如SEQ ID NO:6所示，所述重链的CDR2的氨基酸序列如SEQ ID NO:7所示，所述重链的CDR3的氨基酸序列如SEQ ID NO:8所示。
2.权利要求1所述的抗BCMA的人源化单链抗体，其特征在于，所述抗BCMA的人源化单链抗体还包含Linker区，所述Linker的氨基酸序列如SEQ ID NO:1或2所示。
3.根据权利要求1所述的抗BCMA的人源化单链抗体，其特征在于，所述轻链的核苷酸序列如SEQ ID NO: 27或SEQ ID NO: 29所示；所述重链的核苷酸序列如SEQ ID NO: 31或SEQ ID NO:33所示。
4.根据权利要求1所述的抗BCMA的人源化单链抗体，其特征在于，所述抗BCMA的人源化单链抗体的氨基酸序列如SEQ ID NO:18或SEQ ID NO:20所示。
5.根据权利要求4所述的抗BCMA的人源化单链抗体，其特征在于，所述抗BCMA的人源化单链抗体的核苷酸序列如SEQ ID NO:22或SEQ ID NO:24所示。
6.权利要求1-5任一项所述的抗BCMA的人源化单链抗体在构建靶向BCMA的嵌合抗原受体中的应用。
7.权利要求1-5任一项所述的抗BCMA的人源化单链抗体在构建包含所述抗BCMA的人源化单链抗体的表达载体中的应用。
8.权利要求1-5任一项所述的抗BCMA的人源化单链抗体在制备治疗恶性血液肿瘤药物中的应用。
9.权利要求1-5任一项所述的抗BCMA的人源化单链抗体在制备BCMA靶点相关肿瘤的诊断、预后评估试剂或设备中的应用；所述相关肿瘤为白血病、多发性骨髓瘤或恶性淋巴瘤。
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