CN110041433B - 一种靶向bcma的嵌合抗原受体及其应用 - Google Patents
一种靶向bcma的嵌合抗原受体及其应用 Download PDFInfo
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Abstract
本发明涉及一种靶向BCMA的嵌合抗原受体，包括胞外识别区、铰链区、跨膜区和胞内信号区，所述胞外识别区为抗‑BCMA纳米抗体序列，所述抗‑BCMA纳米抗体序列为结合BCMA的来源于羊驼的重链可变区序列。更具体地，所述抗‑BCMA纳米抗体序列为BCMA单克隆抗体B1或B65，所述B1的氨基酸序列如SEQ ID NO.1所示，所述B65的氨基酸序列如SEQ ID NO.2所示。本发明采用羊驼来源的纳米抗体，相比传统的鼠源或人源化的SCFV具有较小分子量及免疫原性，以此为基础制备的CAR‑T细胞在体内产生HAMA效应的可能性更小，其在体内存留时间可能更长，其通过靶向肿瘤细胞表面的BCMA蛋白并激活T细胞下游的信号通路，赋予T细胞杀伤带有BCMA靶点肿瘤细胞的能力，可高效特异的治疗BCMA阳性血液肿瘤。
Description
技术领域
本发明涉及细胞免疫治疗技术领域，尤其涉及一种靶向BCMA的嵌合抗原受体及其应用。
背景技术
B细胞成熟抗原(B cell maturation antigen，BCMA)是一种表达在浆细胞，浆母细胞和骨髓浆细胞的抗原，其不在B细胞或者造血干细胞上表达。BCMA的表达与许多癌症，自身免疫性疾病和感染性疾病相关。具有增加的BCMA表达的癌症包括一些血液癌症，例如多发性骨髓瘤，霍奇金淋巴瘤和非霍奇金淋巴瘤，各种白血病和胶质母细胞瘤等。这种有限的表达细胞类型，使得BCMA可能作为治疗血液瘤的靶点，以开发单抗、抗体偶联药物、双特异性抗体、CAR-T等疗法。当前还没有靶向BCMA的药物上市，但是有少数通过抗体偶联药物，CAR-T疗法等来通过靶向BCMA以治疗多发性骨髓瘤的疗法在进行临床试验，CAR-T技术在多发性骨髓瘤领域的应用取得了一定的效果，欧美临床试验的数据表明，现有的BCMAchimeric antigen receptor T(carT)技术，治疗多发性骨髓瘤客观治愈率(objectiveresponse，OBB)达50％左右，但还存在的临床不足如下：治疗有效率低于典型的CD19carT70-90％完全治愈率，有效率有待提高。
纳米抗体是目前已知的可结合目标抗原的最小单位，分子量只有15KD，是传统抗体的十分之一；临床上应用较多的鼠源抗体，免疫原性更强，更可能产生HAMA效应，即人抗鼠抗体效应，这种效应会导致鼠源性单抗对人体具有异种蛋白的免疫原性，在人体内半衰期较短，多次使用可引起人抗鼠抗体(HAMA)的产生，从而使其应用受到限制。
存在于骆驼或者羊驼等动物体内的重链抗结构简单，仅包含重链可变区，不包含轻链。进一步的，其重链可变区被称为单域抗体或者是纳米抗体。相较于普通的抗体结构，单域抗体具有分子小，结构更简单，稳定性高，易表达等特点。并且其与人源抗体VH3的序列高度同源，其同源性远超过鼠源单克隆抗体。基于以上优点，近年来对骆驼或者羊驼来源的纳米抗体的研究以及在疾病诊断和治疗中的应用越来越广泛。
因此，开发一种含有靶向BCMA的单域抗体的嵌合抗原受体对高效特异的治疗BCMA阳性血液肿瘤具有十分重要的意义。
发明内容
基于现有技术中存在的缺陷，本发明提供一种BCMA特异性嵌合抗原受体(CAR)，这种CAR分子含有的单链抗体序列仅含有重链可变区，其减小靶向BCMA抗原的CAR分子中SCFV序列的免疫原性，延长CAR-T细胞在体内的存活时间，本发明还验证其在血液瘤治疗中的潜在应用。
为实现上述目的，本发明采用如下技术方案：
本发明的第一个目的是提供一种靶向B细胞成熟抗原(BCMA)的嵌合抗原受体，包括胞外识别区、铰链区、跨膜区和胞内信号区，所述胞外识别区为抗-BCMA纳米抗体序列，所述抗-BCMA纳米抗体序列为结合BCMA的来源于羊驼的重链可变区(scFv)序列。
为了进一步优化上述嵌合抗原受体，本发明所采取的技术措施还包括：
进一步地，所述抗-BCMA纳米抗体序列为BCMA单克隆抗体B1或B65，所述B1的氨基酸序列如SEQ ID NO.1所示，所述B65的氨基酸序列如SEQ ID NO.2所示。
进一步地，所述铰链区为CD8hinge区域。
更进一步地，所述CD8hinge区域的氨基酸序列如SEQ ID NO.3所示
进一步地，所述跨膜区选自CD8跨膜区、CD28跨膜区、ICOS跨膜区中的任一个。更进一步地，所述CD8跨膜区的氨基酸序列如SEQ ID NO.4所示，所述CD28跨膜区的氨基酸序列如SEQ ID NO.5所示，所述ICOS跨膜区的氨基酸序列如SEQ ID NO.6所示。
进一步地，所述胞内信号区包含CD28、4-1BB、ICOS、CD3ζ中的至少一个。更进一步地，所述CD28的氨基酸序列如SEQ ID NO.7所示，所述4-1BB的氨基酸序列如SEQ ID NO.8所示，所述ICOS的氨基酸序列如SEQ ID NO.9所示，所述CD3ζ的氨基酸序列如SEQ ID NO.10所示。
进一步地，基于以上BCMA特异性CAR分子的结构，所述BCMA嵌合抗原受体为B1-BBZ，其胞外识别区为B1，铰链区为CD8hinge区域，跨膜区为CD8，胞内信号区为4-1BB-CD3ζ。更进一步地，所述B1-BBZ的氨基酸序列如SEQ ID NO.11所示。
进一步地，所述BCMA嵌合抗原受体为B65-BBZ，其胞外识别区为B65，铰链区为CD8hinge区域，跨膜区为CD8，胞内信号区为4-1BB-CD3ζ。更进一步地，所述B65-BBZ的氨基酸序列如SEQ ID NO.12所示。
可以理解的是，也可根据本领域适用的其他结构来组成BCMA嵌合抗原受体。进一步地，在不同的CAR分子中，其跨膜区可相同，也可不同；其胞内信号区可相同，也可不同。
本发明的第二个目的是提供一种编码任一上述的BCMA特异性嵌合抗原受体的核酸。
进一步地，所述核酸包括SEQ ID NO.13～SEQ ID NO.14所示的核苷酸序列中的至少一个。更具体地，SEQ ID NO.13所示序列的核酸编码所述B1-BBZ，SEQ ID NO.14所示序列的核酸编码所述B65-BBZ。
上述CAR分子的氨基酸序列及其编码核酸序列如下表所示：
本发明的第三个目的是提供一种含有上述核酸的重组表达载体。
进一步地，所述重组表达载体包括慢病毒、逆转录病毒、腺病毒、腺相关病毒或质粒等；更进一步地，原始重组表达载体为慢病毒。在一具体实施方式中，所使用的载体为慢病毒载体。CAR慢病毒载体质粒在辅助包装质粒pSPAX2和VSV-G包膜质粒pMD2.G存在的情况下，共转染HEK293T细胞，即可包装为带有CAR分子的慢病毒。
本发明的第四个目的是提供一种含有上述重组表达载体的宿主细胞。
进一步地，所述宿主细胞为T细胞或含有T细胞的细胞群
本发明的第五个目的是提供一种上述宿主细胞的构建方法，其包括重组表达载体的构建步骤、重组表达载体的包装步骤以及将重组表达载体转导至宿主细胞的步骤。
本发明的第六个目的是提供上述BCMA特异性嵌合抗原受体，上述核酸，上述重组表达载体以及上述宿主细胞在制备哺乳动物血液瘤治疗药物中的应用。
进一步地，哺乳动物血液瘤主要包括各类白血病、多发性骨髓瘤以及恶性淋巴瘤等。
进一步地，所述应用为一种BCMA特异性的CAR-T细胞，其通过慢病毒介导的转导使得T细胞带有BCMA特异性CAR，从而赋予了T细胞识别BCMA分子的能力，并靶向BCMA阳性的哺乳动物多发性骨髓瘤。
在一个具体实施方式中，将BCMA CAR-T细胞与表达BCMA的肿瘤细胞系U266及人工构建的表达BCMA的肿瘤细胞系A549-BCMA共孵育，结果显示BCMA CAR-T细胞能够在靶细胞的刺激下大量的产生IFN-γ及IL2；但是却不能在与BCMA阴性的细胞系A549共孵育时产生IFN-γ及IL2；同时T细胞不能够在BCMA阳性细胞刺激下产生IFN-γ及IL2。该实施例说明了BCMA CAR-T细胞的良好的特异性靶向性，能够在BCMA刺激下将T细胞杀伤功能激活，且B1-BBZ及B65-BBZ体外杀伤BCMA阳性肿瘤细胞的活性优于11D5-3-28Z(B1-BBZ、B65-BBZ、11D5-3-28Z的结构如图1所示)。
在另一个具体实施方式中，证明了在一定的效靶比(CAR-T细胞：靶细胞)下，BCMACAR-T细胞能够有效的杀伤BCMA阳性的肿瘤细胞；但是T细胞不能够有效杀伤靶细胞。该实施例说明了BCMA CAR-T能够在体外能够有效的裂解BCMA阳性的肿瘤细胞，且B1-BBZ及B65-BBZ体外杀伤BCMA阳性肿瘤细胞的效果优于11D5-3-28Z。
在另一个具体实施方式中，基于BCMA阳性肺癌细胞系A549-BCMA构建了NOD-SCID免疫缺陷鼠皮下移植肿瘤模型。使用本发明BCMA CAR-T细胞B1-BBZ、B65-BBZ及11D5-3-28Z治疗该荷瘤小鼠，结果说明，B1-BBZ、B65-BBZ及11D5-3-28Z细胞可以有效清除BCMA阳性肿瘤细胞，但是对照T细胞组中肿瘤不断长大，且B1-BBZ及B65-BBZ体内清除BCMA阳性肿瘤细胞的效果优于11D5-3-28Z。
与现有技术相比，本发明所述的技术方案具有以下有益效果：
本发明采用羊驼来源的纳米抗体，其天然缺失轻链，分子量小，相比传统的鼠源或人源化的SCFV具有较小分子量及免疫原性，以此为基础制备的CART细胞在体内产生HAMA效应的可能性更小，其在体内存留时间可能更长。采用上述纳米抗体制备的CAR-T细胞，通过靶向肿瘤细胞表面的BCMA蛋白并激活T细胞下游的信号通路，赋予T细胞杀伤带有BCMA靶点肿瘤细胞的能力，可高效特异的治疗BCMA阳性血液肿瘤。
附图说明
图1为本发明一实施例中BCMA特异性嵌合抗原受体(CAR)分子结构的说明示意图；
图2为本发明一实施例中流式细胞术检测BCMACAR转导T细胞转导效率的结果示意图；
图3为本发明一实施例中不同肿瘤细胞系中BCMA表达水平的示意图；
图4A、4B、4C及4D为本发明一实施例中BCMA CAR-T细胞IFN-γ及IL2分泌情况的示意图；
图5A和图5B为本发明一实施例中BCMA CAR-T细胞体外杀伤BCMA靶细胞的结果示意图；
图6A和图6B为本发明一实施例中BCMA CAR-T细胞小鼠体内杀伤A549-BCMA阳性移植肿瘤的结果示意图。
图7为本发明一实施例中BCMA CAR-T细胞小鼠体内杀伤U266阳性移植肿瘤的结果示意图。
具体实施方式
本发明涉及一种靶向BCMA的嵌合抗原受体，包括包括胞外识别区、铰链区、跨膜区和胞内信号区，所述胞外识别区为抗-BCMA纳米抗体序列，所述抗-BCMA纳米抗体序列为结合BCMA的来源于羊驼的重链可变区序列。更具体地，所述抗-BCMA纳米抗体序列为BCMA单克隆抗体B1或B65，所述B1的氨基酸序列如SEQ ID NO.1所示，所述B65的氨基酸序列如SEQ IDNO.2。本发明还涉及上述靶向BCMA的嵌合抗原受体的相关应用及其制备方法。
具体地，本发明提供一种BCMA特异性嵌合抗原受体(即靶向BCMA的CAR分子)，其包含胞外识别区、铰链区、跨膜区和胞内信号区，其中胞外识别区为抗-BCMA抗体序列(scFv氨基酸序列，SEQ ID NO.1或SEQ ID NO.2)，铰链区为CD8hinge区域(SEQ ID NO.3)，跨膜区为CD8跨膜区(SEQ ID NO.4)、CD28跨膜区(SEQ ID NO.5)、ICOS跨膜区(SEQ ID NO.6)中的至少一个，胞内信号区包含CD28(SEQ ID NO.7)、4-1BB(SEQ ID NO.8)、ICOS(SEQ ID NO.9)、CD3ζ(SEQ ID NO.10)中的至少一个。
具体地，本发明的嵌合抗原受体具体为B1-BBZ(SEQ ID NO.11)、B65-BBZ(SEQ IDNO.12)，其分别由SEQ ID NO.13～SEQ ID NO.14所示序列的核酸编码。
下面结合附图和实施例，对本发明的具体实施方式作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
实施例1
本实施例提供了构建上述CAR分子到慢病毒载体pHAGE中的方法。
通过本实施例构建BCMA CAR分子，根据CAR分子抗原识别区域及信号区域的不同，将其分为了B1-BBZ，B65-BBZ，11D5-3-28Z三种：其中B1-BBZ中采用的胞内信号区为4-1BB-CD3ζ，抗原识别区采用B1；B65-BBZ中采用的胞内信号区为4-1BB-CD3ζ，抗原识别区采用B65；而在11D5-3-28Z中所采用的胞内信号区为CD28-CD3ζ，抗原识别区采用11D5-3；其分子结构模式图如图1所示。通过常规分子克隆手段将如上CAR分子构建到了慢病毒载体pHAGE中。
B1-BBZ载体构建：首先从编码B1的纳米抗体质粒中PCR得到相应抗体序列，使用NheI/BamHI双酶切得到B1片段。NheI/BamHI双酶切编码CD19-CAR慢病毒载体pHAGE-FMC63-BBZ，电泳后凝胶回收8KB大小左右DNA片段。将B1与载体使用T4DNA连接酶，室温连接1-2小时，随后转化stbl3感受态细胞。第二天接种单菌落至LB扩增培养，并提取质粒。酶切验证所得质粒是否正确。将正确质粒送测序，进一步验证其序列是否正确。留下正确的质粒命名为pHAGE-B1-BBZ进行下一步实验。
B65-BBZ载体构建：首先从编码B65的纳米抗体质粒中PCR得到相应抗体序列，使用NheI/BamHI双酶切得到B65片段。NheI/BamHI双酶切编码CD19-CAR慢病毒载体pHAGE-FMC63-BBZ，电泳后凝胶回收8KB大小左右DNA片段。将B1与载体使用T4DNA连接酶，室温连接1-2小时，随后转化stbl3感受态细胞。第二天接种单菌落至LB扩增培养，并提取质粒。酶切验证所得质粒是否正确。将正确质粒送测序，进一步验证其序列是否正确。留下正确的质粒命名为pHAGE-B65-BBZ进行下一步实验。
11D5-3-28Z载体序列与临床研究(Ali SA,Shi V.T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions ofmultiple myeloma.Blood.2016.29；128(13):1688-700.)中的序列相一致，在本实施例中作为杀伤靶细胞能力的对照。
实施例2
本实施例为BCMA CAR-T细胞的构建，其CAR分子包装成为慢病毒，转导T细胞，测定转染效率的方式。
CAR慢病毒的包装：首先使用QIAGEN无内毒素大提质粒试剂盒分别提取实施例1所制备的质粒。
构建的慢病毒质粒pHAGE-B1-BBZ、pHAGE-B65-BBZ、pHAGE-11D5-3-28Z以及慢病毒系统辅助包装质粒pMD2.G和pSPAX2。在转染前一天将1.8×10E7293T铺至T175培养瓶中。转染前1小时将293T细胞培养基换为30ml无血清培养基。使用磷酸钙沉淀法将质粒共转染到293T细胞中，转染后24小时将细胞培养基换为60ml完全培养基DMEM+10％FBS。转染后48小时收取细胞上清，并加入60ml新鲜完全培养基。72小时再次收取细胞上清，弃去细胞。将收取的细胞上清5000g离心3min以去除杂质，之后使用0.45um滤膜过滤，随后40000g离心4小时，沉淀病毒，使用0.1ml PBS重悬病毒，检测病毒滴度。放置-80℃冻存备用。
T细胞转导：提前一天包被retronectin、抗人CD3及CD28抗体在6孔板中，4℃过夜，用前PBS洗两次备用。采用常规方法采血并分离PBMC，使用STEMCELL T细胞分选试剂盒分选T细胞，计数，将获得T细胞按1×10E6/ml密度重悬在含有5％人AB血清和100IU/ml白细胞介素-2的X-VIVO15培养基中，置入包被的培养板培养。开始培养以后24小时，加入5ug/ml的polybrene并按MOI3加入相应慢病毒(B1-BBZ，B65-BBZ及11D5-3-28Z)，混匀，37℃感染24小时。然后离心收集细胞沉淀，更换为5％人AB血清和100IU/ml白细胞介素-2的X-VIVO15培养基培养。后续培养通过补加培养基将细胞保持在1×10E6/ml密度，72小时后利用流式细胞术检测SCFV表达以检测CAR分子转导效率。CART-B1-BBZ及CART-B65-BBZ使用抗羊驼重链抗体检测，CART-11D5-3-28Z使用抗鼠Fab抗体检测。如图2所示，观察到B1-BBZ，B65-BBZ及11D5-3-28Z在T细胞上阳性率大约在50％-70％，T细胞作为对照细胞。
实施例3
本实施例为BCMA靶细胞构建及BCMA CAR-T细胞活性的测定。
BCMA CAR-T靶细胞的鉴定和构建：使用流式检测U266及A549等细胞系上BCMA的表达，如图3所示，U266细胞系高表达BCMA抗原，而A549几乎不表达BCMA抗原。使用编码BCMA基因的慢病毒载体，利用嘌呤霉素筛选，构建得到高表达BCMA抗原的A549细胞系A549-BCMA。A549-BCMA细胞系的BCMA表达水平见图3。根据图3结果可知，A549-BCMA，U266细胞系为BCMA阳性表达，而A549细胞系为BCMA阴性。
IFN-γ及IL2分泌实验：在96孔板中将B1-BBZ、B65-BBZ及11D5-3-28Z三种CART细胞及对照T细胞四种效应细胞与靶细胞U266以5：1效靶比混合。在37℃培养4小时，之后使用标准ELISA方法检测上清中IFN-γ及IL2的表达。结果如图4A及4B所示，当效应细胞与U266靶细胞共培养时，CAR-T细胞会大量分泌IFN-γ及IL2，并且B1-BBZ及B65-BBZ相当于或优于11D5-3-28Z的分泌量，说明B1-BBZ及B65-BBZ的活性优于11D5-3-28Z，对照T细胞则只有本底因子释放。在96孔板中将B1-BBZ、B65-BBZ及11D5-3-28Z三种CART效应细胞与靶细胞A549-BCMA及对照靶细胞A549以5：1效靶比混合。在37℃培养24小时，之后使用标准ELISA方法检测上清中IFN-γ及IL2的表达。结果如图4C及4D所示，当效应细胞与A549-BCMA靶细胞共培养时，CAR-T细胞会大量分泌IFN-γ及IL2，并且B1-BBZ及B65-BBZ相当于或优于11D5-3-28Z的分泌量，说明B1-BBZ及B65-BBZ的活性优于11D5-3-28Z；当效应细胞与A549对照靶细胞共培养时，CAR-T细胞只分泌少量IFN-γ及IL2，说明本发明所构建CAR-T细胞具有良好的靶向特异性。
实施例4
本实施例验证BCMA CAR-T细胞体外杀伤BCMA靶细胞的能力。
用5-羧基荧光素琥珀酰亚胺基(CFSE)将效应细胞染色，分别取实施例2中的CAR-T细胞及T细胞与BCMA阳性的U266以1：1，5：1，15：1的效靶比混合共培养，经过4小时共培养后，将细胞用Annexin V及PI试剂盒染色，同时设置U266对照组，对照组中只加入靶细胞但同时未加入效应CAR-T细胞。使用流式细胞术对细胞杀伤进行检测。结果见图5A。BCMA CAR-T细胞能够有效杀伤U266细胞，但是对照的T细胞不能够有效杀伤U266细胞，并且B1-BBZ及B65-BBZ的杀伤活性优于11D5-3-28Z。
在96孔板中将B1-BBZ、B65-BBZ及11D5-3-28Z三种CART效应细胞与靶细胞A549-BCMA及对照靶细胞A549以1：1，5：1，15：1效靶比混合，同时设置培养基空白对照组及靶细胞对照组。在37℃培养24小时，之后使用CCK8方法OD450吸光值。结果见图5B。BCMA CAR-T细胞能够有效杀伤A549-BCMA细胞，不能有效杀伤A549细胞，并且B1-BBZ及B65-BBZ的杀伤活性优于11D5-3-28Z。
本实施例说明B1-BBZ、B65-BBZ及11D5-3-28Z三种CAR分子构建的CAR-T细胞能够有效杀伤BCMA阳性的癌细胞并且具有良好的BCMA靶向性，另外B1-BBZ及B65-BBZ的体外杀伤活性优于11D5-3-28Z。
实施例5
本实施例验证CAR-T细胞在小鼠皮下瘤模型中抑制BCMA阳性肿瘤生长的能力。
使用6周龄NOD-SCID免疫缺陷鼠，皮下注射3×10E6个A549-BCMA细胞系，允许肿瘤生长7-15天，用测径器测量肿瘤大小，以肿瘤最长长度乘最长长度垂直方向的长度除以2得到一mm3为单位的肿瘤大小。当肿瘤大小达到20-50mm3时，通过静脉注射5×10E6个对照T细胞或5×10E6个CAR阳性的BCMA CAR-T细胞B1-BBZ、B65-BBZ及11D5-3-28Z，之后采集尾静脉血检测CART细胞在小鼠血液中比例并测量肿瘤大小。
采集小鼠尾静脉血20ul至20ul肝素钠抗凝剂中，每个样本加入1ul抗人CD45抗体，室温孵育10分钟，加入500ul红细胞裂解液裂红5分钟左右，离心收集细胞沉淀，PBS洗一次，流式细胞仪检测。本实施例结果如图6A，CART细胞在小鼠血液中的比例随时间变化可以在小鼠体内增殖，并维持在较高比例，在基本清除肿瘤细胞后，CART细胞又将至较低水平。从图6B可以看出，注射CAR-T细胞8天之后肿瘤开始变小，到19天已经基本完全清除肿瘤，对照T细胞不能够使肿瘤细胞减小。
本实施例说明，本发明的靶向BCMA的CAR-T细胞能够有效清除小鼠BCMA阳性皮下移植瘤模型中的肿瘤细胞，且B1-BBZ、B65-BBZ体内清除BCMA阳性癌细胞的能力强于11D5-3-28Z。
实施例6
本实施例验证CAR-T细胞在小鼠血液瘤模型中抑制BCMA阳性肿瘤生长的能力。
使用6周龄NOD-SCID免疫缺陷鼠，尾静脉注射5×10E6个U266细胞系，允许肿瘤生长15天，通过静脉注射5×10E6个对照T细胞或5×10E6个CAR阳性的BCMA CAR-T细胞B1-BBZ、B65-BBZ及11D5-3-28Z，观察小鼠存活情况并记录。结果如图7，BCMA CAR-T细胞组B1-BBZ、B65-BBZ及11D5-3-28Z相对于T细胞组，可明显延长小鼠生存期，在60天时T组全部死亡，B1-BBZ存活率80％，B65-BBZ组存活率60％，优于11D5-3-28Z组的40％存活率。
以上对本发明的具体实施例进行了详细描述，但其只作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何根据本发明原理进行修改和替代也可以达到同样效果。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。
序列表
<110> 上海科棋药业科技有限公司
<120> 一种靶向BCMA的嵌合抗原受体及其应用
<130> IPI191245
<160> 15
<170> SIPOSequenceListing 1.0
<210> 1
<211> 122
<212> PRT
<213> B1(Artificial Sequence)
<400> 1
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 Thr Ala Ser Gly Ser Ile Leu Ser Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Ile Asn Ile Ser Ser Asn Thr Phe Tyr Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Ala Pro Trp Gly Asp Tyr Asp Val Lys Thr Asp Phe Gly Gly Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 2
<211> 122
<212> PRT
<213> B65(Artificial Sequence)
<400> 2
Gln Leu 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 Ser Ile Ser Gly Ile Tyr
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Arg Leu Val
35 40 45
Ala Ala Ile Thr Ser Gly Gly Asp Thr Phe His Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Val Ala Pro Trp Gly Asp Tyr Asp Val Arg Ala Asp Phe Gly Ser Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 3
<211> 45
<212> PRT
<213> CD8hinge区域(Artificial Sequence)
<400> 3
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 4
<211> 24
<212> PRT
<213> CD8跨膜区(Artificial Sequence)
<400> 4
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 5
<211> 28
<212> PRT
<213> CD28跨膜区(Artificial Sequence)
<400> 5
Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu
1 5 10 15
Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg
20 25
<210> 6
<211> 21
<212> PRT
<213> ICOS跨膜区(Artificial Sequence)
<400> 6
Phe Trp Leu Pro Ile Gly Cys Ala Ala Phe Val Val Val Cys Ile Leu
1 5 10 15
Gly Cys Ile Leu Ile
20
<210> 7
<211> 40
<212> PRT
<213> CD28(Artificial Sequence)
<400> 7
Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro
1 5 10 15
Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro
20 25 30
Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 8
<211> 42
<212> PRT
<213> 4-1BB (Artificial Sequence)
<400> 8
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 9
<211> 38
<212> PRT
<213> ICOS(Artificial Sequence)
<400> 9
Cys Trp Leu Thr Lys Lys Lys Tyr Ser Ser Ser Val His Asp Pro Asn
1 5 10 15
Gly Glu Tyr Met Phe Met Arg Ala Val Asn Thr Ala Lys Lys Ser Arg
20 25 30
Leu Thr Asp Val Thr Leu
35
<210> 10
<211> 112
<212> PRT
<213> CD3ζ(Artificial Sequence)
<400> 10
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 11
<211> 370
<212> PRT
<213> B1-BBZ(Artificial Sequence)
<400> 11
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Ala Ser Gln Val Gln Leu Val Glu Ser Gly Gly
20 25 30
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr Ala Ser
35 40 45
Gly Ser Ile Leu Ser Ile Tyr Ala Met Gly Trp Tyr Arg Gln Ala Pro
50 55 60
Gly Lys Gln Arg Glu Leu Val Ala Ala Ile Asn Ile Ser Ser Asn Thr
65 70 75 80
Phe Tyr Arg Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Glu Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Asn Val Ala Pro Trp Gly Asp Tyr Asp Val
115 120 125
Lys Thr Asp Phe Gly Gly Trp Gly Gln Gly Thr Gln Val Thr Val Ser
130 135 140
Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
145 150 155 160
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
165 170 175
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
180 185 190
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
195 200 205
Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu
210 215 220
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
225 230 235 240
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
245 250 255
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
260 265 270
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
275 280 285
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
290 295 300
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
305 310 315 320
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
325 330 335
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
340 345 350
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
355 360 365
Pro Arg
370
<210> 12
<211> 370
<212> PRT
<213> B65-BBZ(Artificial Sequence)
<400> 12
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Ala Ser Gln Leu Gln Leu Val Glu Ser Gly Gly
20 25 30
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
35 40 45
Gly Ser Ile Ser Gly Ile Tyr Ala Met Gly Trp Tyr Arg Gln Ala Pro
50 55 60
Gly Lys Gln Arg Arg Leu Val Ala Ala Ile Thr Ser Gly Gly Asp Thr
65 70 75 80
Phe His Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Asn Thr Met Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Asn Val Ala Pro Trp Gly Asp Tyr Asp Val
115 120 125
Arg Ala Asp Phe Gly Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser
130 135 140
Ser Gly Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro
145 150 155 160
Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro
165 170 175
Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
180 185 190
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
195 200 205
Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu
210 215 220
Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu
225 230 235 240
Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys
245 250 255
Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys
260 265 270
Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu
275 280 285
Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly
290 295 300
Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu
305 310 315 320
Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly
325 330 335
Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser
340 345 350
Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro
355 360 365
Pro Arg
370
<210> 13
<211> 1113
<212> DNA
<213> 编码B1-BBZ的核酸(Artificial Sequence)
<400> 13
atggccctgc ccgtgaccgc tctgctgctg cctctggccc tgctgctgca cgccgctaga 60
cccgctagcc aggtgcagct cgtggagtct gggggaggct tggtgcagcc cggggggtca 120
ctgagactct cctgtacagc ctctggaagc atcctcagta tctatgccat gggctggtac 180
cgccaggctc cggggaagca gcgcgagttg gtcgctgcta ttaatatcag tagtaacaca 240
ttctaccgag actccgtgaa gggccgattc accatctcca gagacaacgc cgagaacacg 300
gtgtatctgc aaatgaacag cctgaaacct gaggacacgg ccgtctatta ctgtaatgtg 360
gcgccttggg gcgactatga cgtgaaaact gactttggtg gctggggcca ggggacccag 420
gtcaccgtct cctcgggatc caccacgacg ccagcgccgc gaccaccaac accggcgccc 480
accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 540
gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 600
gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 660
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 720
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 780
aagttcagca ggagcgcaga cgcccccgcg tacaagcagg gccagaacca gctctataac 840
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 900
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 960
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1020
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1080
gcccttcaca tgcaggccct gccccctcgc taa 1113
<210> 14
<211> 1113
<212> DNA
<213> 编码B65-BBZ的核酸(Artificial Sequence)
<400> 14
atggccctgc ccgtgaccgc tctgctgctg cctctggccc tgctgctgca cgccgctaga 60
cccgctagcc agttgcagct cgtggagtct gggggaggct tggtgcagcc tggggggtct 120
ctgagacttt cctgtgcagc ctctggaagc atcagcggta tctatgccat gggctggtac 180
cgccaggctc cagggaagca gcgccggttg gtcgcagcta ttactagtgg tggtgacacg 240
ttccatgcag actccgtgaa gggccgattc accatctcca gagacaacgc caagaacaca 300
atgtatctgc aaatgaacag cctgaaacct gaggacacgg ccgtctatta ctgtaatgtg 360
gcgccttggg gcgactatga cgtgagggct gactttggtt cctggggcca ggggacccag 420
gtcaccgtct cctcgggatc caccacgacg ccagcgccgc gaccaccaac accggcgccc 480
accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 540
gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 600
gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 660
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 720
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 780
aagttcagca ggagcgcaga cgcccccgcg tacaagcagg gccagaacca gctctataac 840
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 900
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 960
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1020
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1080
gcccttcaca tgcaggccct gccccctcgc taa 1113
<210> 15
<211> 1524
<212> DNA
<213> 编码11D5-3-28Z的核酸(Artificial Sequence)
<400> 15
atggccctgc ccgtgaccgc tctgctgctg cctctggccc tgctgctgca cgccgctaga 60
cccgctagcg acatcgtgct gacacagtcc cccccttccc tggccatgtc cctgggcaag 120
agggccacaa tcagctgtag agccagcgag tccgtgacaa tcctgggctc ccacctgatc 180
cactggtacc agcagaagcc tggccagccc cctaccctgc tgatccagct ggccagcaat 240
gtgcagacag gcgtgcctgc cagattctcc ggctccggct ccaggaccga tttcaccctg 300
accatcgatc ctgtggagga ggacgatgtg gccgtgtact actgcctgca gagcagaacc 360
atccctagga cctttggcgg cggcaccaag ctggagatca agggctccac aagcggctcc 420
ggcaagcctg gctccggcga aggaagcaca aagggccaga tccagctggt gcagtccggc 480
cctgagctga agaagcctgg cgagaccgtg aagatcagct gcaaggcctc cggctacacc 540
tttaccgact acagcatcaa ctgggtgaag agagcccccg gcaagggcct gaagtggatg 600
ggctggatca acaccgagac aagagagcct gcctacgcct acgacttcag aggcagattt 660
gccttcagcc tggagacaag cgccagcaca gcctacctgc agatcaacaa tctgaagtac 720
gaggatacag ccacctactt ctgtgccctg gactactcct acgccatgga ctactggggc 780
cagggcacca gcgtgaccgt gtccagcgga tccttcgtgc ctgtgttcct gcccgccaag 840
cccacaacca cccctgcccc aagacccccc acacccgctc ctacaatcgc cagccagccc 900
ctgagcctga gacccgaggc ctgcagaccc gccgctggag gagctgtgca cacaagaggc 960
ctggactttg cctgcgatat ctacatctgg gcccctctgg ccggcacatg cggcgttctg 1020
ctgctgagcc tggtcattac cctgtactgc aaccacagga acaggagcaa gagaagcaga 1080
ctgctgcaca gcgactacat gaatatgaca cctaggagac ccggccccac caggaagcac 1140
taccagcctt acgcccctcc tagggatttt gccgcctaca ggtccagggt gaagttttcc 1200
agatccgccg acgcccctgc ctaccagcag ggacagaacc agctgtacaa tgagctgaac 1260
ctgggcagaa gagaggagta cgatgtgctg gacaagagga gaggcaggga ccccgagatg 1320
ggcggcaagc ctagaagaaa gaacccccag gagggcctgt acaatgaact gcagaaggat 1380
aagatggccg aggcctacag cgagatcggc atgaagggcg agaggagaag gggcaagggc 1440
cacgacggcc tgtaccaggg cctgtccacc gccacaaagg atacatacga cgccctgcac 1500
atgcaggccc tgccccctag ataa 1524
Claims (7)
1.一种靶向BCMA的嵌合抗原受体，包括胞外识别区、铰链区、跨膜区和胞内信号区，其特征在于，所述BCMA嵌合抗原受体为B1-BBZ，其胞外识别区为B1，铰链区为CD8hinge区域，跨膜区为CD8的跨膜区，胞内信号区为4-1BB-CD3ζ，所述B1-BBZ的氨基酸序列如SEQ ID NO.11所示；或
所述BCMA嵌合抗原受体为B65-BBZ，其胞外识别区为B65，铰链区为CD8hinge区域，跨膜区为CD8的跨膜区，胞内信号区为4-1BB-CD3ζ，所述B65-BBZ的氨基酸序列如SEQ ID NO. 12所示。
2.一种编码如权利要求1所述的BCMA特异性嵌合抗原受体的核酸。
3.根据权利要求2所述的核酸，其特征在于，所述核酸的核苷酸序列如SEQ ID NO. 13或SEQ ID NO. 14所示。
4.一种含有如权利要求2~3中任一项所述的核酸的重组表达载体。
5.一种含有如权利要求4所述的重组表达载体的宿主细胞。
6.一种如权利要求5所述的宿主细胞的构建方法，其特征在于，包括重组表达载体的构建步骤、重组表达载体的包装步骤以及将重组表达载体转导至宿主细胞的步骤。
7.权利要求1所述的BCMA特异性嵌合抗原受体，权利要求2-3中任一项所述的核酸，权利要求4所述的重组表达载体或权利要求5所述的宿主细胞在制备哺乳动物血液瘤治疗药物中的应用。
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| WO2021043169A1 (zh) * | 2019-09-02 | 2021-03-11 | 成都盛世君联生物技术有限公司 | 特异性结合b细胞成熟抗原的抗体及其用途 |
| WO2021057866A1 (zh) * | 2019-09-26 | 2021-04-01 | 苏州克睿基因生物科技有限公司 | 一种单域抗体及包含抗体结构的嵌合抗原受体 |
| CN111333732B (zh) * | 2019-12-17 | 2023-02-28 | 中国药科大学 | 一种靶向人bcma且激活nk细胞的双特异性抗体的制备及其应用 |
| CN111333729B (zh) * | 2020-03-17 | 2022-12-06 | 深圳市南科生物工程有限公司 | 抗b细胞成熟抗原的纳米抗体及应用 |
| CN112851814B (zh) * | 2020-03-17 | 2023-07-07 | 西安宇繁生物科技有限责任公司 | 一种靶向bcma的全人源单链抗体及其制备方法与应用 |
| CN113956357B (zh) * | 2020-07-21 | 2024-02-20 | 苏州智核生物医药科技有限公司 | Cd8结合多肽及其用途 |
| CN111909271B (zh) * | 2020-08-12 | 2021-03-23 | 深圳市茵冠生物科技有限公司 | 一种基于单域抗体的bcma嵌合抗原受体及其应用 |
| CN114075287B (zh) * | 2020-08-18 | 2023-07-21 | 湖南远泰生物技术有限公司 | 人源化bcma抗体和bcma-car-t细胞 |
| CN111925451B (zh) * | 2020-10-12 | 2021-01-29 | 佑仁细胞工程(浙江)有限公司 | 一种靶向bcma的嵌合抗原受体(car)及其应用 |
| CN114763383A (zh) * | 2021-01-13 | 2022-07-19 | 博生吉医药科技(苏州)有限公司 | 靶向人bcma的单克隆抗体及其应用 |
| CN114790462B (zh) * | 2021-01-25 | 2023-10-31 | 中国医学科学院血液病医院(中国医学科学院血液学研究所) | 靶向bcma的嵌合抗原受体及其应用 |
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| CN117924496A (zh) * | 2021-03-22 | 2024-04-26 | 浙江纳米抗体技术中心有限公司 | 一种靶向bcma的纳米抗体及其应用 |
| CN114031687B (zh) * | 2021-11-12 | 2022-06-07 | 深圳市人民医院 | 靶向rage的纳米抗体及其应用 |
| CN115466331B (zh) * | 2021-11-18 | 2023-05-30 | 合源生物科技(天津)有限公司 | 靶向bcma的嵌合抗原受体及其应用 |
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