CN113106067B - 一种嵌合抗原受体-单核/巨噬细胞(car-m)的构建及其应用 - Google Patents
一种嵌合抗原受体-单核/巨噬细胞(car-m)的构建及其应用 Download PDFInfo
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Abstract
本发明涉及一种嵌合抗原受体‑单核/巨噬细胞(CAR‑M)的构建及其应用。运用基因编辑手段设计、优化适于导入单核/巨噬细胞细胞膜组构的基因工程受体分子作为嵌合抗原受体，包括前导肽，识别区，铰链区和跨膜/胞内信号区，具体地，所述嵌合抗原受体包括如SEQ ID NO.1‑SEQ ID NO.18所示的序列。本发明还涉及上述嵌合抗原受体‑单核/巨噬细胞(CAR‑M)的应用，本发明采用单核/巨噬细胞作为细胞免疫治疗的载体细胞，是利用其良好的组织浸润性与细胞因子趋化性，可以解决CAR‑T无法进入实体瘤内部的问题。本发明利用嵌合抗原受体赋予单核/巨噬细胞对肿瘤细胞的靶向性，并增强对肿瘤细胞的吞噬，进一步可以递呈肿瘤抗原给T细胞，增强抗肿瘤免疫。本发明所构建的嵌合抗原受体‑单核/巨噬细胞(CAR‑M)可用于肝癌、胃癌、肺癌、乳腺癌等实体瘤的细胞免疫治疗。
Description
技术领域：
本发明属于免疫治疗技术领域，具体涉及嵌合抗原受体-单核/巨噬细胞(CAR-M)的构建及其应用。
背景技术：
目前国际上用于细胞免疫治疗的细胞主要分为两大类：第一类包括淋巴因子激活杀伤细胞(LAK)、自然杀伤细胞(NK)及细胞因子诱导杀伤细胞(CIK)等；第二类是具有肿瘤抗原特异性的T淋巴细胞，包括肿瘤浸润淋巴细胞(TIL)、细胞毒性T细胞(CTL)。其中第一类技术体系较为简单，尤其是CIK细胞的治疗在我国较为流行，第二类的技术体系相对复杂，细胞培养周期较长，培养的成功率相对较低，但由于对杀伤肿瘤细胞具有高度的特异性，因此疗效更为明显。CAR-T是基于以上两类研究获得的新的治疗细胞，CAR是Chimericantigen receptor(嵌合抗原受体)的缩写，CAR-T细胞免疫治疗是将患者的T细胞通过基因工程修饰，加上一个嵌合抗原受体，然后经过体外扩增再回输至病人体内。在急性白血病、非霍奇金淋巴瘤等血液***肿瘤的治疗上，CAR-T细胞已取得显著的疗效。然而CAR-T细胞免疫治疗在实体瘤临床治疗过程中遭遇了前所未有的挑战：1)实体瘤细胞外基质阻碍了CAR-T细胞浸润；2)实体瘤免疫抑制微环境(大量浸润的免疫抑制细胞，Treg、TAMs、MDSC等；免疫抑制细胞因子，TGF-β、IL-10等；抑制蛋白的表达，PD-1/PD-L1、CTLA-4等)抑制CAR-T肿瘤杀伤活性；3)实体瘤高度异质性使得CAR-T细胞疗法缺乏有效的肿瘤抗原。
巨噬细胞具有强大的吞噬功能，每天可以清除大约2×1011个红细胞，相当于每年机体可以循环利用3kg的血红蛋白。另外，巨噬细胞在吞噬、抗原递呈、免疫平衡调节等方面发挥重要作用，对维持机体的免疫稳态发挥重要的监视功能。巨噬细胞通过表面受体能够侦查出周围环境中的组织损伤信号或微生物入侵信号，一旦发现异常，即可诱导出巨噬细胞的吞噬作用和抗原递呈作用，促进机体的特异性免疫反应。例如肺泡巨噬细胞能有效清除肺部的过敏原；肝巨噬细胞(Kupffer细胞)能帮助清除血液中循环的病原体和毒素。巨噬细胞还能吞噬免疫原性死亡的肿瘤细胞并递呈肿瘤抗原给T细胞，发挥抗肿瘤免疫作用。
然而，近年来研究发现，肿瘤组织中的肿瘤细胞或其他细胞通过释放CCL2、CXCL12、 CSF1等趋化因子招募巨噬细胞浸润，在实体瘤微环境中巨噬细胞是浸润比例最高的免疫细胞。肿瘤组织中浸润的巨噬细胞又称为肿瘤相关巨噬细胞(tumor associatedmacrophages， TAMs)，在肿瘤的发生、发展、转移中发挥重要作用。在肿瘤微环境中，肿瘤细胞可通过CD47、 MHCI分子与巨噬细胞上的受体结合，抑制巨噬细胞对肿瘤细胞的吞噬。同时，调控TAMs 中的脂质代谢，促进脂滴堆积，导致巨噬细胞的吞噬能力受损。因此，肿瘤组织中浸润的巨噬细胞虽然具备杀伤肿瘤细胞的潜能，却由于肿瘤细胞表面CD47等分子的抑制作用，导致 TAMs不仅不杀死肿瘤细胞，还可以通过促进血管增生等作用，促进肿瘤的生长。
基于此，我们将单核/巨噬细胞作为细胞免疫治疗的载体细胞，结合目前嵌合抗原受体技术蓬勃发展的优势与日渐成熟的基因优化技术，从分子水平上改造单核/巨噬细胞，制备获得嵌合抗原受体-巨噬细胞(CAR-M)，利用其高效浸润性，增强其吞噬能力及抗原递呈能力，使CAR-M有望成为细胞免疫治疗的新一代主角。
发明内容：
本发明的目的在于运用基因编辑手段设计、优化适于导入单核/巨噬细胞细胞膜组构的基因工程受体分子，获得能够特异性识别并吞噬肿瘤细胞的嵌合抗原受体单核/巨噬细胞。据此建立用于肿瘤过继治疗的高效单核/巨噬细胞免疫治疗体系。
为达到上述发明目的，本发明所采用的技术方案是
本发明提供了用于增强巨噬细胞吞噬能力的嵌合抗原受体。包括前导肽、胞外识别区、铰链区和跨膜/胞内信号区。
所述前导肽为集落刺激因子2受体α(CSF2Rα)的前导肽，所述CSF2Rα前导肽的氨基酸序列如SEQ ID NO.1所示。
所述胞外识别区为抗肿瘤特异抗原的单链抗体scFv，在具体实施方式中，选择HER2 作为肿瘤抗原，所述抗HER2的单链抗体scFv氨基酸序列如SEQ ID NO.2所示。
所述铰链区为CD28hinge区，进一步地，所述CD28hinge区域的氨基酸序列如SEQID NO.3所示。
所述跨膜/胞内信号区选择的是CD16(FcγRIIIA)、CD32(FcγRIIA)、CD64(FcγRIA)， FCER1G或CD36分子对应的跨膜/胞内序列。CD16、CD32和CD64属于FcγR家族(Fc-gamma receptor family)，可以识别并结合Ig的Fc片段，能够有效的清除IgG-Ag复合物，在天然免疫、获得性免疫中均具有非常重要的作用。FCER1G含有一种基于酪氨酸的免疫受体激活基序(ITAM)，可从各种免疫受体传递激活信号，作为高亲和力免疫球蛋白E(IgE)受体的组成部分，介导肥大细胞的过敏性炎症信号。CD36属于清道夫受体超家族，可以识别氧化性低密度脂蛋白、胶原、长链脂肪酸等，主要表达于单核/巨噬细胞膜表面，该受体不仅可以介导吞噬的发生，还可以促进TLR4、TLR6异二聚体的形成，从而激活无菌性炎症反应。而TLR信号通路的激活可以促进巨噬细胞向抗肿瘤的M1型巨噬细胞极化。因此，本发明选择上述受体分子的细胞膜内区域作为内部信号序列，以激活巨噬细胞吞噬能力。所述CD16的跨膜/胞内区氨基酸如SEQ ID NO.4所示，所述CD32的跨膜/胞内区氨基酸序列如SEQ ID NO.5所示，所述CD64的跨膜/胞内区氨基酸如SEQ ID NO.6所示，所述FCER1G的跨膜/胞内区氨基酸序列如SEQ ID NO.7所示，所述CD36的跨膜/胞内区氨基酸序列如SEQ ID NO.8所示。
所述嵌合抗原受体具体为CAR-16，CAR-32、CAR-64、CAR-R1G和CAR-36。所述嵌合抗原受体CAR-16的氨基酸序列如SEQ ID NO.9所示。所述嵌合抗原受体CAR-32的氨基酸序列如SEQ ID NO.10所示。所述嵌合抗原受体CAR-64的氨基酸序列如SEQ ID NO.11 所示。所述嵌合抗原受体CAR-RIG的氨基酸序列如SEQ ID NO.12所示。所述嵌合抗原受体CAR-36的氨基酸序列如SEQ ID NO.13所示。
所述嵌合抗原受体CAR-16的核苷酸序列如SEQ ID NO.14所示。所述嵌合抗原受体CAR-32的核苷酸序列如SEQ ID NO.15所示。所述嵌合抗原受体CAR-64的核苷酸序列如SEQID NO.16所示。所述嵌合抗原受体CAR-RIG的核苷酸序列如SEQ ID NO.17所示。所述嵌合抗原受体CAR-36的核苷酸序列如SEQ ID NO.18所示。
本发明提供一种含有上述核酸片段的重组表达载体。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。
本发明提供一种含有上述重组表达载体的宿主细胞。
所述宿主细胞为单核细胞和巨噬细胞。
本发明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。
本发明提供上述嵌合抗原受体，上述核酸片段，上述重组表达载体以及上述宿主细胞在制备人类肿瘤治疗药物中的应用。
进一步地，所述人类肿瘤主要指的是实体瘤。
进一步地，所述应用为一种肿瘤抗原特异性的CAR-M细胞 (CAR-monocyte/macrophage)，其通过慢病毒介导的转导使得单核/巨噬细胞带有肿瘤抗原特异性CAR，从而赋予了单核/巨噬细胞识别特定肿瘤抗原的能力，并吞噬肿瘤细胞。
在具体实施方式中，选择肿瘤抗原是HER2，使用的嵌合抗原受体含有靶向HER2的单链抗体，选择的肿瘤细胞系是HER2阳性的乳腺癌细胞系MDA-MB-453和HER2阳性的胃癌细胞系MKN45。
与现有技术相比，本发明提供的技术方案具有以下有益效果：
1.本发明选择的宿主细胞是单核/巨噬细胞。目前公认在治疗血液癌症中有确切治疗效果的CAR-T，无法进入实体瘤内部，而单核/巨噬细胞具有良好的组织浸润性与细胞因子趋化性。
2.本发明根据单核/巨噬细胞的免疫细胞生物学特征，通过基因改造，赋予单核/巨噬细胞肿瘤靶向性，增强其吞噬能力，进一步递呈肿瘤抗原，改善肿瘤免疫微环境，增强抗肿瘤免疫，具有显著的技术创新特点。
附图说明：
图1嵌合抗原受体模式图。
图2流式检测巨噬细胞中嵌合抗原受体的表达。
图3流式检测CAR-36巨噬细胞对MDA-MB-453乳腺癌细胞的吞噬能力。
图4流式检测CAR-36巨噬细胞对MKN45胃癌细胞的吞噬能力。
图5(A)构建MKN45胃癌小鼠皮下模型，静脉注射对照巨噬细胞和CAR-36巨噬细胞，每隔3天测量肿瘤生长；(B)处死小鼠，取出肿瘤并称重分析；(C)流式检测肿瘤内GFP阳性细胞比例，以分析回输的巨噬细胞的浸润情况。
图6活体成像检测MKN45胃癌腹腔播散模型中的肿瘤大小。处死小鼠，解剖腹腔拍摄腹腔成瘤状况。
具体实施方式：
下面结合具体实施例对本发明进行详细说明：根据下述实施例，可以更好的理解本发明。然而，实施例所述的具体物料比、工艺条件及其结果仅使用说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实施例一
本实施例为靶向HER2的嵌合抗原受体分子的组装，其包含前导肽、胞外识别区、铰链区、跨膜区/胞内信号区，从N端到C端顺序依次为前导肽为CSF2Rα前导肽(SEQ ID NO.1)，胞外识别区为抗-HER2抗体序列(scFv氨基酸序列，SEQ ID NO.2)，铰链区为CD28hinge区域(SEQ ID NO.3)，跨膜区/胞内信号区为CD16(SEQ ID NO.4)，CD32(SEQ ID NO.5)、 CD64(SEQ ID NO.6)，FCER1G(SEQ ID NO.7)或CD36(SEQ ID NO.8)。具体核酸序列 CAR-16(SEQID NO.14)，CAR-32(SEQ ID NO.15)和CAR-64(SEQ ID NO.16)，CAR-R1G(SEQ ID NO.17)和CAR-36(SEQ ID NO.18)于生工生物进行人工合成，得到嵌合抗原受体序列。图1 为嵌合抗原受体模式图。
具体地，本发明的嵌合抗原受体具体为CAR-16，CAR-32，CAR-64，CAR-R1G和 CAR-36。将所得CAR序列碱基序列通过酶切的方法整合到慢病毒质粒载体pLenti6/v5，方法为：Spe I/Xho I双酶切载体与CAR碱基序列，T4连接酶链接，得到目的质粒，为 pLenti-CAR-16，pLenti-CAR-32，pLenti-CAR-64，pLenti-CAR-R1G和pLenti-CAR-36。
实施例二
本实施例为带有嵌合抗原受体慢病毒的制备，选择的嵌合抗原受体为CAR-36。
实验材料：OPTI-MEM、Lipofectamine 2000(lipo2000)购买于Invitrogen公司；HEK293T。
实验步骤：
1)第一天，293T传代，用含10％FBS的DMEM在10cm*10cm皿中培养过夜，使其密度达到80％。
2)第二天，细胞转染，吸掉旧培养基，迅速加入5mL预热的OPTI-MEM，然后放回培养箱中。
3)准备DNA/lipo2000复合物：
a)在EP管中加入1.5mL OPTI-MEM，然后加入如下质粒并混匀。
pLenti-CAR-36 15μg
psPAX2 7.5μg
pMD2.G 2.5μg
b)在EP管中加入1.5mL OPTI-MEM，然后加入75μL lipo2000，混匀并室温放置5min。
c)将a)、b)混合，室温放置20min。
4)将上述DNA/lipo2000复合物逐滴加入到细胞培养皿中，轻轻摇匀，放回培养箱继续培养。
5)6h后换液，去除DNA/lipo2000复合物，加入8mL预热的含有5％FBS的DMEM，继续培养。
6)第三天，补加5mL培养基，使总体积为10-20mL。
7)第四天，收集培养基上清(特别注意：不能让培养基变黄，因为病毒在pH值在6到8之间时，半衰期只有10min)。
8)1500×rpm离心5min，去除细胞碎片，用0.4μm滤膜过滤。
9)将病毒浓缩液与过滤后的病毒上清以1∶4加入，混匀后4℃孵育过夜(12小时以上)。
10)将病毒混合液离心(2000g，30min)，离心管底部会出现白色沉淀，弃去上清，再离心(2000g，5min)，吸去所有残留液体，同时不要破坏已经沉淀的病毒颗粒。
11)用1/10的体积DMEM培养基重悬病毒沉淀，立即使用或分装保存于-80℃。
实施例三
本实施例为嵌合抗原受体单核/巨噬细胞的构建
实验材料：
Polybrene购买于Sigma；流式细胞分选仪为BD FACS Aria。
实验步骤：
1)将对数生长期的THP-1细胞铺于6孔板中(1mL)，1×106cell/well。
2)缓慢加入1mL病毒上清以及ploybrene(8μg/mL)，并轻轻摇匀。
3)1900rpm离心60min(32℃)。
4)置于细胞培养箱中培养1h。
5)重复3)一次。
6)24h后换液，再用实施例二中制备的慢病毒感染一次，操作同上。
7)48h后用荧光显微镜观察细胞内GFP的表达情况。
8)将上述细胞进行流式分选得到GFP阳性细胞。
9)所得细胞进行扩大培养，即得到表达嵌合抗原受体CAR-36的THP-1细胞系(CAR-36-THP-1)。
实施例四
本实施例为对嵌合抗原受体巨噬细胞的鉴定
1)将实施例三构建的CAR-36-THP-1单核细胞用50nM PMA诱导24h成为THP-1巨噬细胞。
2)运用体外共培养模型，将HER2+肿瘤细胞(乳腺癌细胞MDA-MB-453，胃癌细胞MKN45)与CAR-36-THP-1巨噬细胞以1∶1比例直接接触共培养，通过荧光共聚焦显微镜和流式直接观察CAR-36对HER2阳性细胞的吞噬效应。CAR表达载体上带有EGFP，绿色荧光表示嵌合抗原受体巨噬细胞；肿瘤细胞用活细胞标记染料DiR进行染色标记，显示为红色。如图3和图4所示，已构建的嵌合抗原受体巨噬细胞具有显著的肿瘤细胞吞噬的活力。
实施例五
本实施例验证CAR-36巨噬细胞在小鼠皮下瘤模型中抑制HER2阳性胃癌的能力。
选取体重为18-22g的Balb/c雄性裸鼠，在后腿种植MKN45胃癌细胞，细胞量5×106/ 只，观察记录肿瘤生长状况，在接种后第7天和第14天，通过静脉注射1×106个对照THP-1 巨噬细胞或1×106个CAR阳性的CAR-36-THP-1巨噬细胞。从接种第7天开始，每隔三天，使用测径器测量肿瘤大小。结果如图图5A显示，注射CAR-CD36-THP-1巨噬细胞组的肿瘤生长明显受到抑制。接种第30天，对小鼠进行安乐死，取出肿瘤并称重(图5B)，制备单细胞悬液，流式分析回输巨噬细胞的浸润情况。结果图5C显示，CAR-36能够促进THP-1巨噬细胞在肿瘤中的浸润。
实施例六
本实施例验证CAR-36巨噬细胞在小鼠腹腔播散模型中抑制HER2阳性胃癌的能力。
选取带有荧光素酶的胃癌细胞系MKN45，胰酶消化后收集细胞，用生理盐水重悬至107个/ml；选取体重为18-22g的BABL/C雄性裸鼠(SPF级)，用1ml无菌注射器对裸鼠进行腹腔肿瘤种植，细胞种植量约为106个/只；在接种后第14和21天后，腹腔注射1×106个对照THP-1巨噬细胞或1×106个CAR阳性的CAR-36-THP-1巨噬细胞。接种后第40天，活体成像检测小鼠腹腔肿瘤大小。结果如图6显示，注射CAR-36-THP-1巨噬细胞组的小鼠肿瘤完全消退。
以上实施例进一步说明本发明的内容，但不应理解为对本发明的限制。对于本领域的技术人员来说，在不背离本发明精神和实质的情况下对本发明方法、步骤或条件所做的修改和替换，均属于本发明的范围。
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115 120 125
Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Val Val Lys Thr Gly
165 170 175
Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly
180 185 190
Tyr Phe Ile Asn Trp Val Lys Lys Asn Ser Gly Lys Ser Pro Glu Trp
195 200 205
Ile Gly His Ile Ser Ser Ser Tyr Ala Thr Ser Thr Tyr Asn Gln Lys
210 215 220
Phe Lys Asn Lys Ala Ala Phe Thr Val Asp Thr Ser Ser Ser Thr Ala
225 230 235 240
Phe Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr
245 250 255
Cys Val Arg Ser Gly Asn Tyr Glu Glu Tyr Ala Met Asp Tyr Trp Gly
260 265 270
Gln Gly Thr Ser Val Thr Val Ser Ser Ile Glu Val Met Tyr Pro Pro
275 280 285
Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys
290 295 300
Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro
305 310 315 320
Phe Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu Val Asn Thr
325 330 335
Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys Arg Lys Lys Lys Trp
340 345 350
Asp Leu Glu Ile Ser Leu Asp Ser Gly His Glu Lys Lys Val Ile Ser
355 360 365
Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu Leu Lys Cys Gln Glu
370 375 380
Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His Arg Lys Glu Pro Gln
385 390 395 400
Gly Ala
<210> 12
<211> 384
<212> PRT
<213> 人工序列
<400> 12
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Ala Ala Gln Pro Ala Asp Ile Val Leu Thr
20 25 30
Gln Thr Pro Ser Ser Leu Pro Val Ser Val Gly Glu Lys Val Thr Met
35 40 45
Thr Cys Lys Ser Ser Gln Thr Leu Leu Tyr Ser Asn Asn Gln Lys Asn
50 55 60
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu
65 70 75 80
Ile Ser Trp Ala Phe Thr Arg Lys Ser Gly Val Pro Asp Arg Phe Thr
85 90 95
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Gly Ser Val Lys
100 105 110
Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Tyr Pro
115 120 125
Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Val Val Lys Thr Gly
165 170 175
Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly
180 185 190
Tyr Phe Ile Asn Trp Val Lys Lys Asn Ser Gly Lys Ser Pro Glu Trp
195 200 205
Ile Gly His Ile Ser Ser Ser Tyr Ala Thr Ser Thr Tyr Asn Gln Lys
210 215 220
Phe Lys Asn Lys Ala Ala Phe Thr Val Asp Thr Ser Ser Ser Thr Ala
225 230 235 240
Phe Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr
245 250 255
Cys Val Arg Ser Gly Asn Tyr Glu Glu Tyr Ala Met Asp Tyr Trp Gly
260 265 270
Gln Gly Thr Ser Val Thr Val Ser Ser Ile Glu Val Met Tyr Pro Pro
275 280 285
Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys
290 295 300
Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro
305 310 315 320
Phe Leu Cys Tyr Ile Leu Asp Ala Ile Leu Phe Leu Tyr Gly Ile Val
325 330 335
Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile Gln Val Arg Lys Ala Ala
340 345 350
Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val Tyr Thr Gly Leu Ser Thr
355 360 365
Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys His Glu Lys Pro Pro Gln
370 375 380
<210> 13
<211> 354
<212> PRT
<213> 人工序列
<400> 13
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Ala Ala Gln Pro Ala Asp Ile Val Leu Thr
20 25 30
Gln Thr Pro Ser Ser Leu Pro Val Ser Val Gly Glu Lys Val Thr Met
35 40 45
Thr Cys Lys Ser Ser Gln Thr Leu Leu Tyr Ser Asn Asn Gln Lys Asn
50 55 60
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu
65 70 75 80
Ile Ser Trp Ala Phe Thr Arg Lys Ser Gly Val Pro Asp Arg Phe Thr
85 90 95
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Gly Ser Val Lys
100 105 110
Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asn Tyr Pro
115 120 125
Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Val Val Lys Thr Gly
165 170 175
Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly
180 185 190
Tyr Phe Ile Asn Trp Val Lys Lys Asn Ser Gly Lys Ser Pro Glu Trp
195 200 205
Ile Gly His Ile Ser Ser Ser Tyr Ala Thr Ser Thr Tyr Asn Gln Lys
210 215 220
Phe Lys Asn Lys Ala Ala Phe Thr Val Asp Thr Ser Ser Ser Thr Ala
225 230 235 240
Phe Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr
245 250 255
Cys Val Arg Ser Gly Asn Tyr Glu Glu Tyr Ala Met Asp Tyr Trp Gly
260 265 270
Gln Gly Thr Ser Val Thr Val Ser Ser Ile Glu Val Met Tyr Pro Pro
275 280 285
Pro Tyr Leu Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys
290 295 300
Gly Lys His Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro
305 310 315 320
Phe Leu Leu Gly Leu Ile Glu Met Ile Leu Leu Ser Val Gly Val Val
325 330 335
Met Phe Val Ala Phe Met Ile Ser Tyr Cys Ala Cys Arg Ser Lys Thr
340 345 350
Ile Lys
<210> 14
<211> 1104
<212> DNA
<213> 人工序列
<400> 14
atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60
atcccagccg cccagccagc cgacatcgta ctaacacaga caccatcatc cctccctgta 120
tcagtaggcg agaaagtaac aatgacatgc aaatcatcac agacactctt atactcaaac 180
aaccaaaaga attaccttgc atggtatcag cagaagcctg gtcaatcgcc aaagctgtta 240
atctcttggg cattcactag aaagtcaggt gtgcctgata gattcactgg tagcggctca 300
ggtacggatt tcacgttgac gattggctcg gtgaaggctg aagatttggc ggtttactat 360
tgtcagcaat atagcaatta tccgtggact ttcggtgggg gaactagatt agagattaag 420
cgtggtggtg gaggatcagg tggaggcgga tcaggaggag gaggatcagg aggaggtgga 480
tcagaagtac aacttcagca gtctggacca gaagtagtaa agactggagc atccgttaag 540
atttcatgca aggcatcagg atattcgttc acaggatact tcatcaactg ggtaaagaag 600
aactcaggaa agtcaccaga gtggatcgga cacatttcat catcatacgc cacatcaacg 660
tataaccaga agttcaagaa caaggccgca ttcactgtag acacttcatc atcaacggct 720
ttcatgcagc taaactcact cacctcagaa gactctgccg tctactactg cgttaggtca 780
ggtaattacg aagagtacgc gatggactac tggggtcaag gtacttcagt aaccgtgtca 840
tcaattgaag ttatgtatcc tcctccttac ctagacaatg agaagagcaa tggaaccatt 900
atccatgtga aagggaaaca cctttgtcca agtcccctat ttcccggacc ttctaagccc 960
tttgtctctt tctgcttggt gatggtactc ctttttgcag tggacacagg actatatttc 1020
tctgtgaaga caaacattcg aagctcaaca agagactgga aggaccataa atttaaatgg 1080
agaaaggacc ctcaagacaa ataa 1104
<210> 15
<211> 1266
<212> DNA
<213> 人工序列
<400> 15
atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60
atcccagccg cccagccagc cgacatcgta ctaacacaga caccatcatc cctccctgta 120
tcagtaggcg agaaagtaac aatgacatgc aaatcatcac agacactctt atactcaaac 180
aaccaaaaga attaccttgc atggtatcag cagaagcctg gtcaatcgcc aaagctgtta 240
atctcttggg cattcactag aaagtcaggt gtgcctgata gattcactgg tagcggctca 300
ggtacggatt tcacgttgac gattggctcg gtgaaggctg aagatttggc ggtttactat 360
tgtcagcaat atagcaatta tccgtggact ttcggtgggg gaactagatt agagattaag 420
cgtggtggtg gaggatcagg tggaggcgga tcaggaggag gaggatcagg aggaggtgga 480
tcagaagtac aacttcagca gtctggacca gaagtagtaa agactggagc atccgttaag 540
atttcatgca aggcatcagg atattcgttc acaggatact tcatcaactg ggtaaagaag 600
aactcaggaa agtcaccaga gtggatcgga cacatttcat catcatacgc cacatcaacg 660
tataaccaga agttcaagaa caaggccgca ttcactgtag acacttcatc atcaacggct 720
ttcatgcagc taaactcact cacctcagaa gactctgccg tctactactg cgttaggtca 780
ggtaattacg aagagtacgc gatggactac tggggtcaag gtacttcagt aaccgtgtca 840
tcaattgaag ttatgtatcc tcctccttac ctagacaatg agaagagcaa tggaaccatt 900
atccatgtga aagggaaaca cctttgtcca agtcccctat ttcccggacc ttctaagccc 960
tttatcattg tggctgtggt cactgggatt gctgtagcgg ccattgttgc tgctgtagtg 1020
gccttgatct actgcaggaa aaagcggatt tcagccaatt ccactgatcc tgtgaaggct 1080
gcccaatttg agccacctgg acgtcaaatg attgccatca gaaagagaca acctgaagaa 1140
accaacaatg actatgaaac agctgacggc ggctacatga ctctgaaccc cagggcacct 1200
actgacgatg ataaaaacat ctacctgact cttcctccca acgaccatgt caacagtaat 1260
aactaa 1266
<210> 16
<211> 1212
<212> DNA
<213>人工序列
<400> 16
atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60
atcccagccg cccagccagc cgacatcgta ctaacacaga caccatcatc cctccctgta 120
tcagtaggcg agaaagtaac aatgacatgc aaatcatcac agacactctt atactcaaac 180
aaccaaaaga attaccttgc atggtatcag cagaagcctg gtcaatcgcc aaagctgtta 240
atctcttggg cattcactag aaagtcaggt gtgcctgata gattcactgg tagcggctca 300
ggtacggatt tcacgttgac gattggctcg gtgaaggctg aagatttggc ggtttactat 360
tgtcagcaat atagcaatta tccgtggact ttcggtgggg gaactagatt agagattaag 420
cgtggtggtg gaggatcagg tggaggcgga tcaggaggag gaggatcagg aggaggtgga 480
tcagaagtac aacttcagca gtctggacca gaagtagtaa agactggagc atccgttaag 540
atttcatgca aggcatcagg atattcgttc acaggatact tcatcaactg ggtaaagaag 600
aactcaggaa agtcaccaga gtggatcgga cacatttcat catcatacgc cacatcaacg 660
tataaccaga agttcaagaa caaggccgca ttcactgtag acacttcatc atcaacggct 720
ttcatgcagc taaactcact cacctcagaa gactctgccg tctactactg cgttaggtca 780
ggtaattacg aagagtacgc gatggactac tggggtcaag gtacttcagt aaccgtgtca 840
tcaattgaag ttatgtatcc tcctccttac ctagacaatg agaagagcaa tggaaccatt 900
atccatgtga aagggaaaca cctttgtcca agtcccctat ttcccggacc ttctaagccc 960
tttgtccttt tctatctggc agtgggaata atgtttttag tgaacactgt tctctgggtg 1020
acaatacgta aagaactgaa aagaaagaaa aagtgggatt tagaaatctc tttggattct 1080
ggtcatgaga agaaggtaat ttccagcctt caagaagaca gacatttaga agaagagctg 1140
aaatgtcagg aacaaaaaga agaacagctg caggaagggg tgcaccggaa ggagccccag 1200
ggggccacgt aa 1212
<210> 17
<211> 1155
<212> DNA
<213> 人工序列
<400> 17
atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60
atcccagccg cccagccagc cgacatcgta ctaacacaga caccatcatc cctccctgta 120
tcagtaggcg agaaagtaac aatgacatgc aaatcatcac agacactctt atactcaaac 180
aaccaaaaga attaccttgc atggtatcag cagaagcctg gtcaatcgcc aaagctgtta 240
atctcttggg cattcactag aaagtcaggt gtgcctgata gattcactgg tagcggctca 300
ggtacggatt tcacgttgac gattggctcg gtgaaggctg aagatttggc ggtttactat 360
tgtcagcaat atagcaatta tccgtggact ttcggtgggg gaactagatt agagattaag 420
cgtggtggtg gaggatcagg tggaggcgga tcaggaggag gaggatcagg aggaggtgga 480
tcagaagtac aacttcagca gtctggacca gaagtagtaa agactggagc atccgttaag 540
atttcatgca aggcatcagg atattcgttc acaggatact tcatcaactg ggtaaagaag 600
aactcaggaa agtcaccaga gtggatcgga cacatttcat catcatacgc cacatcaacg 660
tataaccaga agttcaagaa caaggccgca ttcactgtag acacttcatc atcaacggct 720
ttcatgcagc taaactcact cacctcagaa gactctgccg tctactactg cgttaggtca 780
ggtaattacg aagagtacgc gatggactac tggggtcaag gtacttcagt aaccgtgtca 840
tcaattgaag ttatgtatcc tcctccttac ctagacaatg agaagagcaa tggaaccatt 900
atccatgtga aagggaaaca cctttgtcca agtcccctat ttcccggacc ttctaagccc 960
tttctctgct atatcctgga tgccatcctg tttctgtatg gaattgtcct caccctcctc 1020
tactgtcgac tgaagatcca agtgcgaaag gcagctataa ccagctatga gaaatcagat 1080
ggtgtttaca cgggcctgag caccaggaac caggagactt acgagactct gaagcatgag 1140
aaaccaccac agtag 1155
<210> 18
<211> 1065
<212> DNA
<213> 人工序列
<400> 18
atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60
atcccagccg cccagccagc cgacatcgta ctaacacaga caccatcatc cctccctgta 120
tcagtaggcg agaaagtaac aatgacatgc aaatcatcac agacactctt atactcaaac 180
aaccaaaaga attaccttgc atggtatcag cagaagcctg gtcaatcgcc aaagctgtta 240
atctcttggg cattcactag aaagtcaggt gtgcctgata gattcactgg tagcggctca 300
ggtacggatt tcacgttgac gattggctcg gtgaaggctg aagatttggc ggtttactat 360
tgtcagcaat atagcaatta tccgtggact ttcggtgggg gaactagatt agagattaag 420
cgtggtggtg gaggatcagg tggaggcgga tcaggaggag gaggatcagg aggaggtgga 480
tcagaagtac aacttcagca gtctggacca gaagtagtaa agactggagc atccgttaag 540
atttcatgca aggcatcagg atattcgttc acaggatact tcatcaactg ggtaaagaag 600
aactcaggaa agtcaccaga gtggatcgga cacatttcat catcatacgc cacatcaacg 660
tataaccaga agttcaagaa caaggccgca ttcactgtag acacttcatc atcaacggct 720
ttcatgcagc taaactcact cacctcagaa gactctgccg tctactactg cgttaggtca 780
ggtaattacg aagagtacgc gatggactac tggggtcaag gtacttcagt aaccgtgtca 840
tcaattgaag ttatgtatcc tcctccttac ctagacaatg agaagagcaa tggaaccatt 900
atccatgtga aagggaaaca cctttgtcca agtcccctat ttcccggacc ttctaagccc 960
tttctccttg gcctgataga aatgatctta ctcagtgttg gtgtggtgat gtttgttgct 1020
tttatgattt catattgtgc atgcagatcg aaaacaataa aataa 1065
Claims (8)
1.一种嵌合抗原受体-单核/巨噬细胞(CAR-M)，其特征在于，运用基因编辑手段设计、优化适于导入单核/巨噬细胞细胞膜组构，增强单核/巨噬细胞吞噬能力的嵌合抗原受体，所述嵌合抗原受体包括前导肽，识别区，铰链区和跨膜区/胞内信号区，其中，所述前导肽为集落刺激因子2受体α(CSF2Rα)的前导肽，所述CSF2Rα前导肽的氨基酸序列如SEQ ID NO.1所示；所述识别区为结合HER2的单链抗体scFv，所述结合HER2的单链抗体scFv的氨基酸序列如SEQ ID NO .2所示；所述铰链区为CD28 hinge区域，所述CD28 hinge区域的氨基酸序列如SEQ ID NO.3所示；所述的跨膜区/胞内信号区为能够激活巨噬细胞吞噬信号的CD36分子跨膜区/胞内功能区，所述CD36分子的氨基酸序列如SEQ ID NO.8所示。
2.根据权利要求1所述的嵌合抗原受体，其特征在于，所述嵌合抗原受体包括SEQ IDNO.13所示的氨基酸序列。
3.一种编码权利要求1或2所述的嵌合抗原受体的核酸。
4.根据权利要求3所述的核酸，其特征在于，所述核酸的核苷酸序列包括SEQ ID NO.18所示的核苷酸序列。
5.一种含有权利要求3或4所述的核酸的重组表达载体。
6.一种含有权利要求5所述的重组表达载体的单核/巨噬细胞。
7.一种权利要求6所述的单核/巨噬细胞的构建方法，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单核/巨噬细胞的步骤。
8.权利要求1或2所述的嵌合抗原受体，权利要求3或4所述的核酸，权利要求5所述的重组表达载体以及权利要求6所述的单核/巨噬细胞在用于制备治疗人类实体瘤的药物中的应用，所述人类实体瘤选自胃癌或乳腺癌。
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| CN114657143B (zh) * | 2022-03-11 | 2022-10-25 | 西安电子科技大学 | 一种肿瘤微环境调控型car-单核/巨噬细胞及其制备方法和应用 |
| CN114854692B (zh) * | 2022-04-02 | 2023-11-10 | 北京默赛尔生物科技有限责任公司 | Car-巨噬细胞及其制备方法 |
| CN115212299A (zh) * | 2022-06-21 | 2022-10-21 | 深圳先进技术研究院 | Car-t和car-m联用在制备抗肿瘤药物中的应用 |
| CN115011561A (zh) * | 2022-06-22 | 2022-09-06 | 深圳先进技术研究院 | 一种嵌合抗原受体巨噬细胞及其制备方法和应用 |
| CN115957335B (zh) * | 2023-01-03 | 2024-05-28 | 华中科技大学同济医学院附属协和医院 | 基于嵌合抗原受体修饰的单核细胞外囊泡类似物、制备方法及应用 |
| CN116240173A (zh) * | 2023-02-02 | 2023-06-09 | 西安电子科技大学 | 一种冷热肿瘤调控型car-单核/巨噬细胞及其制备方法和应用 |
| CN117343908B (zh) * | 2023-12-05 | 2024-02-09 | 南京大学 | 一种通过真菌精准激活的car-t细胞、制备方法、应用及药物组合物 |
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| CN108025024A (zh) * | 2015-07-28 | 2018-05-11 | 宾夕法尼亚大学董事会 | 表达嵌合抗原受体的修饰单核细胞/巨噬细胞及其用途 |
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