CN109402168A - 微环dna表达连接her2阳性细胞与效应细胞的桥接分子及其应用 - Google Patents
微环dna表达连接her2阳性细胞与效应细胞的桥接分子及其应用 Download PDFInfo
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- CN109402168A CN109402168A CN201811277450.XA CN201811277450A CN109402168A CN 109402168 A CN109402168 A CN 109402168A CN 201811277450 A CN201811277450 A CN 201811277450A CN 109402168 A CN109402168 A CN 109402168A
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Abstract
本申请涉及微环DNA表达连接Her2阳性细胞与效应细胞的桥接分子及其应用。具体涉及一种用于在体内表达抗Her2双特异性抗体的微环DNA载体。双特异性抗体介导效应细胞(T细胞或NK细胞)杀灭Her2阳性癌细胞(靶细胞)。本申请首次披露Her2阳性细胞与效应细胞桥接分子(MC.Her2‑BTEC)的微环DNA载体设计方案，适用于Her2相关癌症的治疗。
Description
技术领域
本发明属于生物医药领域，具体涉及一种微环(Minicircle，MC)DNA载体，更具体为一种用于在体内表达连接Her2阳性细胞与效应细胞的桥接分子的微环DNA载体。
背景技术
Her2(human epidermal growth factor receptor-2，人表皮生长因子受体2)，又称Her2/neu或ErbB2，为Ⅰ型跨膜酪氨酸激酶受体家族的成员，属于跨膜蛋白的一种，其超量表达或突变时往往诱导Her2同二聚化或Her2与家族其他成员间异二聚化的产生，进而激活下游的RAS-MAPK、靶向mTOR的AKT信号通路，导致细胞的异常增殖和存活。目前已发现Her2在多种癌症细胞表面高表达，包括乳腺癌、非小细胞肺癌、唾液腺癌、胃癌、肠癌、胰腺癌、膀胱癌、子宫内膜癌、卵巢癌等，是一种广谱的癌症免疫治疗靶点。
目前已有Her2单抗药物上市，比如Trastuzumab曲妥珠单抗(Herceptin赫赛汀)或Pertuzumab帕妥珠单抗(Perjeta)，其用于治疗乳腺癌、胃癌等癌症，并取得了良好的临床治疗效果。不过，近年来理论研究表明双特异性抗体对于癌症/肿瘤的治疗疗效更佳，已有靶向Her2的双特异性抗体进入临床试验阶段，比如Her2-TDB。现有报道的Her2双特异性抗体(双抗)均通过传统的基因工程方法在哺乳动物细胞中表达，之后通过蛋白纯化方法得到。总体而言，传统的生产制备、纯化以及储存运输等过程均很复杂，成本很高，并且存在药品污染的较大风险。另外，双抗的半衰期较短，往往需要持续给药，增加用量，这无形中增加了患者的经济负担，并且存在药物耐受性的风险。
本发明通过微环DNA基因载体，在体内表达双特异性抗体，介导效应细胞(T细胞或NK细胞)杀灭Her2阳性癌细胞(靶细胞)。这种以基因投递的方式在体内产生Her2双特异性抗体的研究在现有技术中未见相关报道。本发明避免了上述现有技术中存在的问题，而且安全、高效、成本较低、患者可负担。与本发明最接近的技术是微环DNA载体表达双特异性抗体的技术MC.BsAb(CN201710245146.6)。
发明内容
本发明涉及微环(Minicircle，MC)DNA载体在体内表达连接Her2阳性细胞与效应细胞的桥接分子，用于治疗Her2相关癌症。
本发明提供了一种表达Her2阳性细胞与效应细胞桥接分子(Bridge betweenHer2-positive cells and effector cells，Her2-BTEC)的重组基因载体，所述桥接分子包含：与Her2阳性细胞作用靶点特异性结合的部分A，和与效应细胞作用靶点特异性结合的部分B。
在一个方面中，所述重组基因载体选自非病毒基因载体，如标准质粒或其它环状表达盒子。优选的，所述重组基因载体选自微环DNA载体。
在一个方面中，所述重组基因载体选自重组表达载体。优选的，所述重组基因载体选自原核表达载体或真核表达载体。更优选的，所述重组基因载体选自真核表达载体。特别优选的，所述重组基因载体选自用于哺乳动物细胞表达的重组表达载体。
在一个方面中，所述桥接分子选自蛋白或多肽。优选的，所述桥接分子选自双特异性抗体。更优选的，所述桥接分子选自人-猴交叉性双特异性抗体(Human-Monkey cross-reactive Bispecific Antibody，hm-BsAb)。
在一个方面中，所述部分A和所述部分B分别选自蛋白分子或多肽分子。优选的，所述部分A和部分B分别选自Fab、Fab’、单链抗体(scFv)、单域抗体(VHH)、单链T细胞受体(scTCR)和其它。
在一个方面中，所述Her2阳性细胞选自Her2阳性癌细胞、Her2过表达细胞或其它。所述效应细胞选自T细胞、NK细胞或其它。
在一个方面中，所述部分A特异性结合的作用靶点选自Her2的各个抗原表位。所述部分B特异性结合的作用靶点选自CD3、CD16、CD28、4-1BB、OX40、TCR、CD56、NKG2D、NCR或其它。
在一个方面中，所述部分A选自单链抗体(scFv)，其包含：重链可变区，和轻链可变区，其氨基酸序列如SEQ ID NO：1和3所示。
在一个方面中，所述部分B选自单链抗体(scFv)，(1)其包含：重链可变区和轻链可变区，其氨基酸序列如选自SEQ ID NO：5和7，或9和11的组所示；所述部分B特异性结合的作用靶点选自CD3；或者(2)其包含：重链可变区和轻链可变区，其氨基酸序列如SEQ ID NO：13和15所示；所述部分B特异性结合的作用靶点选自CD16。
在一个方面中，所述部分A包含的重链可变区具有与SEQ ID NO：1所示序列至少90％、95％、98％或99％同源性的氨基酸序列，包含的轻链可变区与SEQ ID NO：3所示序列具有至少90％、95％、98％或99％同源性的氨基酸序列，且具有与之前实施方案中所述部分A具有相同功能，即特异性结合相同的作用靶点。
在一个方面中，所述部分B包含的重链可变区具有与SEQ ID NO：5或9所示序列至少90％、95％、98％或99％同源性的氨基酸序列，包含的轻链可变区具有与SEQ ID NO：7或11所示序列至少90％、95％、98％或99％同源性的氨基酸序列，且具有与之前实施方案中所述部分B具有相同功能，即特异性结合相同的作用靶点。
本发明提供了一种表达Her2阳性细胞与效应细胞桥接分子的重组基因载体，所述重组基因载体包含所述桥接分子的编码基因。
在一个方面中，所述重组基因载体包含：部分A的编码基因，和/或包含部分B的编码基因。
在一个方面中，部分A选自单链抗体(scFv)，其编码基因包含：重链可变区和轻链可变区的编码基因，其核苷酸序列如SEQ ID NO：2和4所示。
在一个方面，部分B选自单链抗体(scFv)，其编码基因(1)包含：重链可变区和轻链可变区的编码基因，其核苷酸序列如选自SEQ ID NO：6和8、或10和12的组所示；或者(2)包含：重链可变区和轻链可变区的编码基因，其核苷酸序列如SEQ ID NO：14和16所示。
在一个方面中，所述重组基因载体包含：与上述部分A和/或部分B的编码基因的核苷酸序列具有至少90％、95％、98％或99％同源性的核苷酸序列，且编码得到的桥接分子具有与之前实施方案中所述桥接分子相同的功能。本领域技术人员公知，在不改变所编码的氨基酸的情况下，所述编码基因序列中的一个或多个密码子可以进行等义替换，如一个或几个密码子，如1、2、3、4、5、6、7、8、9、10、15、20、30、40、50个密码子。
本发明提供了一种由之前实施方案中所述重组基因载体所表达的桥接分子。
在一个方面中，所述重组基因载体选自非病毒基因载体，如标准质粒或其它环状表达盒子。优选的，所述重组基因载体选自微环DNA载体。
本发明提供了一种之前实施方案中所述重组基因载体的制备方法，具体步骤包括：
(1)从现有技术中分别获取Her2抗体、CD3抗体及CD16抗体的轻链可变区(VL)序列、重链可变区(VH)序列；
(2)根据上述(1)中VH、VL序列设计成多种组合形式的桥接分子，并构建表达所述桥接分子的重组基因载体；
任选的，
(3)在体内外鉴定所述重组基因载体的表达水平，并检测表达产物介导效应细胞对Her2阳性细胞的杀伤效果。
在一个方面中，所述Her2阳性细胞选自Her2阳性癌细胞、Her2过表达细胞或其它。所述效应细胞选自T细胞、NK细胞或其它。
在一个方面中，所述重组基因载体选自非病毒基因载体，如标准质粒或其它环状表达盒子。优选的，所述重组基因载体选自微环DNA载体。
在一个方面中，所述桥接分子选自蛋白或多肽。优选的，所述桥接分子选自双特异性抗体。特别优选的，所述桥接分子选自人-猴交叉性双特异性抗体(Human-Monkey cross-reactive Bispecific Antibody，hm-BsAb)。
本发明提供了一种宿主细胞，包含之前实施方案中所述重组基因载体，或由之前实施方案中所述制备方法所得到的重组基因载体。
在一个实施方案中，所述宿主细胞包括细菌细胞、酵母菌细胞、昆虫细胞或哺乳动物细胞。
本发明提供了一种之前实施方案中所述桥接分子的制备方法，具体步骤包括：
(1)构建所述重组基因载体；
(2)将所述重组基因载体导入宿主细胞；
(3)在适合表达的条件下，培养宿主细胞，诱导表达，分离纯化，获得所述桥接分子。
本发明提供了一种药物组合物，包含之前实施方案中所述重组基因载体，或由之前实施方案中所述制备方法所得到的重组基因载体，或由之前实施方案中所述重组基因载体所表达的桥接分子，以及药学上可接受的载体。
在一个方面中，所述药物组合物可根据常规方法制成药物制剂。制剂过程中，优选将重组基因载体或双特异性抗体与药学上可接受的载体混合或用载体稀释。当载体作为稀释剂时，其可以为固体、半固体或液体。制剂选自片剂、丸剂、粉剂、胶囊、混悬剂、乳剂、溶液剂、气溶胶、注射用溶液等形式。合适的载体、赋形剂或稀释剂包括水、乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、硅酸钙、纤维素、聚乙烯吡咯烷酮、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油等。制剂还可以包括填充剂、抗凝血剂、润滑剂、保湿剂、调味剂、乳化剂、防腐剂等。
本发明提供了之前实施方案中所述重组基因载体、所述桥接分子、所述宿主细胞或所述药物组合物在制备用于治疗Her2相关癌症的药物中的用途。优选的，所述Her2相关癌症选自乳腺癌、非小细胞肺癌、唾液腺癌、胃癌、肠癌、胰腺癌、膀胱癌、子宫内膜癌、卵巢癌。特别优选的，所述Her2相关癌症选自乳腺癌、胃癌。
本发明的积极效果包括：本发明首次公开Her2特异性的Her2阳性细胞与效应细胞桥接分子的微环DNA载体(MC.Her2-BTEC)设计方案，适用于Her2相关癌症的治疗。Her2-BTEC能够大幅度提高效应细胞对Her2阳性细胞的杀伤作用。细胞毒性作用随Her2-BTEC浓度的增加而不断增大。与未治疗的荷瘤对照小鼠相比，Her2-BTEC治疗能够显著降低瘤负荷并延长荷瘤小鼠的生存期。本发明的Her2-BTEC除了结合人的抗原分子之外，还能交叉识别猴的抗原，有利于BTEC(BsAb，双特异性抗体)药物基于非人灵长类动物模型的临床前安全性与有效性评价。可见，本发明的Her2-BTEC、微环DNA载体对于预防和治疗Her2相关癌症具有很好的前景，并提供了新的临床思路。
附图说明
图1：pMC.Her2-BTEC微环DNA母质粒载体图谱。
图2：MC.Her2-BTEC微环制备与BTEC表达；(左)琼脂糖凝胶电泳检测MC；(右)SDS-PAGE检测BTEC蛋白表达；Lane A：细胞上清；Lane B：流穿液；Lane C：20mM咪唑洗脱液；LaneD：50mM咪唑洗脱液；Lane E：200mM咪唑洗脱液；Lane F：500mM咪唑洗脱。
图3：Her2-BTEC介导效应细胞(T细胞)对靶细胞(人卵巢癌SKOV3细胞)的细胞毒性作用；T细胞和Her2阳性的卵巢癌SKOV3细胞共孵育12小时，效靶比10:1，LDH释放法检测Her2-BTEC介导的细胞杀伤率。
图4：人卵巢癌移植瘤小鼠治疗实验的结果。
具体实施方式
下述实验方法如无特别说明，均为常规方法，所使用的实验材料如无特别说明，均可容易地从商业公司获取。在不背离本发明精神的情况下，本领域技术人员结合公知技术，可以对本发明做出许多修改，这样的修改也落入本发明的范围。
实施例1、Her2阳性细胞与效应细胞桥接分子(Her2-BTEC)的构建
设计Her2-BTEC并构建相应的微环DNA表达载体，Her2-BTEC表达框包括多种结构，分列如下：
(1)scFv-scFv结构：
其中，SP为信号肽(Signal Peptide)；Linker为连接序列。VL代表轻链可变区，VH代表重链可变区。anti-Her2scFv、antiCD3(或antiCD16)scFv位置可互换。
其中，antiHer2.VH的氨基酸序列如SEQ ID NO：1所示，编码基因的核苷酸序列如SEQ ID NO：2所示；antiHer2.VL的氨基酸序列如SEQ ID NO：3所示，编码基因的核苷酸序列如SEQ ID NO：4所示；antiCD3.VH的氨基酸序列如SEQ ID NO：5或9所示，编码基因的核苷酸序列如SEQ ID NO：6或10所示；antiCD3.VL的氨基酸序列如SEQ ID NO：7或11所示，编码基因的核苷酸序列如SEQ ID NO：8或12所示；antiCD16.VH的氨基酸序列如SEQ ID NO：13所示，编码基因的核苷酸序列如SEQ ID NO：14所示；antiCD16.VL的氨基酸序列如SEQ ID NO：15所示，编码基因的核苷酸序列如SEQ ID NO：16所示。
(2)双特异性抗体DART(Dual-Affinity Re-Targeting antibody)结构：
DART表达框经翻译、剪切后形成两条链(Chain 1、Chain 2)；这两条链通过配对的E/K-coli形成稳定的异二聚体。Chain1、Chain2位置可互换。
其中，SP为信号肽(Signal Peptide)；Linker为连接序列，Furin为furin蛋白酶剪切位点，2A为2A自剪切位点。Furin剪切位点的氨基酸序列为R-X-[R/K]-R(比如RRKR)，X指代任一种氨基酸；E/K coli为电性相反、配对的螺旋结构，且K coli和E coli可互换位置；2A包括E2A、F2A、P2A和T2A等。
其中，antiHer2.VH、antiHer2.VL、antiCD3.VH、antiCD3.VL、antiCD16.VH、antiCD16.VL各元件的氨基酸序列及其编码基因与上述(1)中的一致。
(3)双特异性抗体DART-Fc结构：
DART-Fc表达框经翻译、剪切后形成两条链(Chain 1、Chain 2)；Chain 1和Chain2通过配对的E/K-coli以及Fc“knob-into-hole”结构形成稳定的异二聚体。“knob-into-hole”设计既可避免同二聚体的产生，还能增加半衰期。Chain1、Chain2位置可互换。
其中，SP为信号肽(Signal Peptide)；Linker为连接序列，Furin为furin蛋白酶剪切位点，2A为2A自剪切位点。Furin剪切位点的氨基酸序列为R-X-[R/K]-R(比如RRKR)，X指代任一种氨基酸；E/K coli为电性相反、配对的螺旋结构，且K coli和E coli可互换位置；Fc-knob和Fc-hole分别为IgG Fc段CH2-CH3突变体，它们也可互换位置；2A包括E2A、F2A、P2A和T2A等。
其中，antiHer2.VH、antiHer2.VL、antiCD3.VH、antiCD3.VL、antiCD16.VH、antiCD16.VL各元件的氨基酸序列及其编码基因与上述(1)中的一致。
实施例2、Her2-BTEC微环DNA载体的构建及微环(MC)的制备
一、实验方法
1、合成Her2-BTEC的编码基因，为方便BTEC蛋白纯化与检测，在C端插入6xHis标签。
2、选择合适的位点双酶切线性化微环DNA空载体pMC.BESPX。
3、使用seamless克隆或者传统克隆方法(如，酶切-连接)将Her2-BTEC的编码基因插入线性化的空载体pMC.BESPX中，构建成微环DNA载体pMC.Her2-BTEC。
4、微环DNA载体pMC.Her2-BTEC转化大肠杆菌E coli.ZYCY10P3S2T，按标准微环制备方法得到微环MC.Her2-BTEC。
其中，微环DNA空载体pMC.BESPX、工程菌E coli.ZYCY10P3S2T，以及微环制备方法见参考文献Nat Biotechnol.2010,28:1287-1289.
二、实验结果
图2(左)显示了MC.Her2-BTEC微环制备的琼脂糖凝胶电泳检测结果。由图中可知，通过Her2-BTEC微环DNA载体的构建方法，能够制备得到微环MC.Her2-BTEC。
实施例3、Her2-BTEC的表达、纯化
一、Her2-BTEC在293T细胞中的表达
采用superfect质粒转染试剂盒(Invitrogen公司)将上述微环DNA转染293T细胞，在无血清培养基中培养三天后分别收集293T细胞培养上清。
二、Her2-BTEC的纯化
1、收集细胞培养上清液进行低温超速离心，取上清。
2、Her2-BTEC采用His-Tag亲和树脂(cOmplete His-Tag Purification Resin，Roche)纯化。
3、纯化后的蛋白使用PAGE或Western Blot定性检测，并使用Bradford法定量检测蛋白浓度。
4、纯化产物置于-20℃或-80℃长期保存。
三、实验结果
图2(右)显示了Her2-BTEC表达的SDS-PAGE检测结果。由图中可知，通过细胞转染、蛋白表达、纯化的方法，能够制备得到Her2-BTEC。
实施例4、Her2-BTEC的结合实验
利用流式细胞术检测Her2-BTEC与靶细胞(Target，T)、效应细胞(Effector，E)的结合活性，包括如下步骤：
1、细胞培养：靶细胞(Her2阳性细胞，比如SKOV3细胞)；效应细胞(T细胞或NK细胞)。
2、收集细胞：贴壁细胞使用胰酶消化，加含血清培养基中和后离心弃上清得细胞；悬浮细胞直接离心收集。
3、两种细胞均用预冷PBS洗涤2次，200g离心4min，收集细胞，分别计数。
4、每个实验组分别分配1×105个靶细胞和效应细胞，分组如下：
空白组(不加Her2-BTEC)和Her2-BTEC组
5、加入Her2-BTEC溶液100μL/组，冰上孵育30min。
6、加入1mL预冷PBS洗涤，200g离心4min，收集细胞，加事先预冷并混好anti-flag抗体的PBS 100μL，冰上孵育30min。
7、加入1mL预冷PBS洗涤，200g离心4min，收集细胞，加入100μl PBS重悬，上流式观察结合情况。
实施例5、Her2-BTEC介导效应细胞杀伤靶细胞
一、实验分组
利用LDH(乳酸脱氢酶)释放法测定Her2-BTEC介导效应细胞(Effector，E)对靶细胞(Target，T)的杀伤作用。
实验材料：效应细胞(T细胞或NK细胞)，靶细胞(Her2阳性细胞，比如人卵巢癌SKOV3细胞)，Her2-BTEC(Her2阳性细胞与效应细胞桥接分子)。
表1Her2-BTEC介导效应细胞杀伤靶细胞的不同分组
二、实验方法
1、提前1天将靶细胞接种于96孔板上，细胞接种量为2×104/孔；同时设置分组(如表1所示；每组3个复孔)。
2、第二天更换新鲜opti-MEM培养基，100μL/孔。
3、效应细胞(E)计数并重悬于opti-MEM培养基中，按照T∶E＝1∶10的比例，根据(a)中分组加入相应数量的效应细胞(2.0×105/孔，100μL/孔)。
4、根据分组，在相应的孔中每孔加入相应浓度的Her2-BTEC，混匀；在靶细胞最大组对应孔中还需加入细胞裂解液破碎细胞，以便充分释放LDH。
5、37℃细胞培养箱孵育12小时。
6、根据LDH试剂盒(Promega，美国)说明书，检测LDH释放量并计算细胞杀伤率，公式如下：
细胞杀伤率＝(实验-效应细胞自发-靶细胞自发)/(靶细胞最大-靶细胞自发)x100％
二、实验结果
图3显示了Her2-BTEC介导效应细胞(T细胞)对靶细胞(人卵巢癌SKOV3细胞)的细胞毒性作用。由图中可知，细胞毒性作用随Her2-BTEC浓度的增加而不断增大。
实施例6、Her2阳性移植瘤小鼠治疗实验
一、实验方法
1、免疫缺陷的NOD/SCID小鼠接种带萤火虫荧光酶(firefly luciferase，luc)标记的Her2阳性肿瘤细胞(例如SKOV3-luc)。
2、接种肿瘤细胞7天后，用小动物活体成像系统(In Vivo Imaging System，IVIS)记录luciferase荧光强度、监测小鼠成瘤情况；同时设置分组，包括对照组(Control)、T细胞组和实验组三组，每组5只小鼠。
3、对照组不施加任何治疗、T细胞组在规定时间点注射人T细胞、实验组在规定时间点注射MC.Her2-BTEC微环DNA并注射人T细胞。
4、按分组实施不同治疗处理后，定期监测生存情况并用IVIS系统跟踪肿瘤生长情况(记录荷瘤小鼠luciferase荧光强度)。
二、实验结果
图4显示了人卵巢癌移植瘤小鼠治疗实验的结果。由图中可知，与未治疗的荷瘤对照小鼠相比，Her2-BTEC治疗能够显著降低瘤负荷并延长荷瘤小鼠的生存期。
序列表
SEQ ID NO：1 anti-Her2.VH氨基酸序列
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS
SEQ ID NO：2 anti-Her2.VH核苷酸序列
gaagtgcagctggtggagtcaggaggaggactggtgcagccaggaggatctctgagactgtcttgcgccgccagcggcttcaacatcaaggacacctacatccattgggtccggcaggctccaggaaaaggactcgagtgggtggccagaatctaccccaccaacggctacacccgctacgccgatagcgtgaaaggccggttcaccatcagcgccgataccagcaagaacaccgcctacctgcagatgaacagcctgagagccgaggacaccgccgtgtactattgtagccggtggggaggagacggcttctacgccatggactattggggccagggaacactggtgacagtgtcttcc
SEQ ID NO：3 anti-Her2.VL氨基酸序列
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKLEIK
SEQ ID NO：4 anti-Her2.VL核苷酸序列
gacatccagatgacccagagccctagctctctgagcgccagcgtgggcgatagagtgaccatcacctgcagagcctctcaggacgtgaacaccgcagtggcttggtaccagcagaagccagggaaggcccctaagctgctgatctacagcgcctctttcctgtacagcggcgtgcctagcaggttcagcggaagcagaagcggcaccgatttcaccctgaccatcagctctctgcagccagaggacttcgccacctactactgccagcagcactacacaacccctcctacctttggccagggcacaaagctggagatcaaa
SEQ ID NO：5 anti-CD3.VH-1氨基酸序列
EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYATYYADSVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWFAYWGQGTLVTVSS
SEQ ID NO：6 anti-CD3.VH-1核苷酸序列
gaagtgcagctggtggaaagcggaggaggactggtgcagccaggaggatctctgagactgtcttgcgccgccagcggctttacattcagcacctacgccatgaattgggtccggcaggctccaggaaaaggactcgagtgggtcggaaggatccggagcaagtacaacaactacgccacctactacgccgacagcgtgaagggcaggttcaccatcagccgggacgacagcaagaacagcctgtacctgcagatgaacagcctgaagaccgaggacacagccgtgtactattgcgtgcgccacggcaacttcggcaacagctacgtcagctggttcgcctattgggggcagggaacactggtgacagtgtctagc
SEQ ID NO：7 anti-CD3.VL-1氨基酸序列
QAVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPWTPARFSGSLLGGKAALTITGAQAEDEADYYCALWYSNLWVFGGGTKLTVLG
SEQ ID NO：8 anti-CD3.VL-1核苷酸序列
caggcagtggtgacccaggaaccttctctgaccgtgtctccaggcggaacagtgacactgacctgcagaagcagcacaggcgccgtgacaaccagcaactacgccaattgggtgcagcagaagccaggacaggcccctagaggcctgattggaggcacaaacaagagagccccttggaccccagccagattctccggatctctgctgggaggcaaagccgccctgacaatcacaggagctcaggccgaagacgaggccgactactattgcgccctctggtacagcaacctctgggtgttcggcggaggaacaaagctgacagtgctggga
SEQ ID NO：9 anti-CD3.VH-2氨基酸序列
EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKDLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS
SEQ ID NO：10 anti-CD3.VH-2核苷酸序列
gaggtgcagctggtggagtccggaggaggactggtgcagccaggaggcagcctgagactgtcctgtgccgcctccggctattcttttaccggctacacaatgaattgggtgaggcaggcaccaggcaaggatctggagtgggtggccctgatcaacccttataagggcgtgtccacctacaatcagaagttcaaggatcggtttaccatctctgtggacaagagcaagaacacagcctatctgcagatgaatagcctgcgcgctgaagacaccgccgtgtactactgtgcccggtccggctactatggcgattctgactggtacttcgacgtgtggggccagggcaccctggtcacagtgtctagc
SEQ ID NO：11 anti-CD3.VL-2氨基酸序列
DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTS RLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKLELK
SEQ ID NO：12 anti-CD3.VL-2核苷酸序列
gacatccagatgacccagtccccatcctctctgtctgccagcgtgggcgatcgggtgaccatcacatgtagagcctctcaggacatcaggaactatctgaattggtaccagcagaagccaggcaaggcccccaagctgctgatctactatacctccaggctggagtctggagtgcctagccggttttccggctccggaagcggaaccgattacaccctgacaatcagctccctgcagccagaggacttcgccacatactattgccagcagggcaataccctgccctggacatttggccagggcaccaagctggagctgaag
SEQ ID NO：13 anti-CD16.VH氨基酸序列
QVQLVQSGAEVKKPGESLKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGSAYYYDFADYWGQGTLVTVSS
SEQ ID NO：14 anti-CD16.VH核苷酸序列
caagtccagcttgtgcagtcaggtgctgaggttaaaaaaccaggagaaagtctgaaggtatcatgtaaggcctcaggttatacgtttacttcatattacatgcactgggtgcgacaggctcctggtcaggggttggagtggatgggaatcatcaatccatccggtggtagcaccagctacgcacaaaagtttcagggtcgcgtgacaatgacaagagacacgtccacgtccacggtctacatggaattgtcatccctgagatcagaggacaccgccgtatattattgtgcacgcggcagtgcttactactacgatttcgcagattattgggggcaggggactttggttacagtctcctcc
SEQ ID NO：15 anti-CD16.VL氨基酸序列
SYVLTQPSSVSVAPGQTATISCGGHNIGSKNVHWYQQRPGQSPVLVIYQDNKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQVWDNYSVLFGGGTKLTVL
SEQ ID NO：16 anti-CD16.VL核苷酸序列
tcctacgttctcactcagcccagtagtgtctcagttgctccagggcaaacggccacgattagttgcggaggtcacaacataggcagtaagaatgtacattggtaccaacagcgaccaggccagagccccgttttggtcatctatcaggataataagcggccaagtggaataccggagcggttcagcggtagtaacagtgggaacaccgccactctgactatatccggtacgcaagctatggacgaagcagactactattgccaggtgtgggataactacagcgtactgttcggaggcgggacgaaacttacagtcttg
SEQ ID NO：17 Fc-knob氨基酸序列
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO：18 Fc-knob核苷酸序列
gctccagaagcagcaggaggacctagcgtgttcctgttccctcccaagcctaaggacaccctgatgatcagccggaccccagaagtgacttgcgtggtggtggacgtgtcccacgaagaccccgaggtcaagttcaattggtacgtggacggagtggaggtgcacaacgctaagaccaagcccagggaggagcagtacaacagcacctacagggtggtgtccgtgctgacagtgctgcaccaggattggctgaacggcaaggagtacaagtgcaaggtgtccaacaaggccctgccagcccctatcgagaagaccatcagcaaggccaagggccagcctagagaacctcaggtgtacaccctgccccctagcagagaggagatgaccaagaaccaggtctccctctggtgcctggtgaagggcttctaccctagcgacatcgccgtggagtgggaatctaacggtcagccagagaacaactacaagaccacccccccagtgctggacagcgacggcagcttcttcctgtacagcaagctgaccgtggacaaaagccgctggcagcagggcaacgtgttctcttgcagcgtgatgcacgaggccctgcacaaccactacacccagaagagcctgagcctgagcccaggaaag
SEQ ID NO：19 Fc-hole氨基酸序列
APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNRYTQKSLSLSPGK
SEQ ID NO：20 Fc-hole核苷酸序列
gctccagaagcagcaggaggacctagcgtgttcctgttccctcccaagcctaaggacaccctgatgatcagccggaccccagaagtgacttgcgtggtggtggacgtgtcccacgaagaccccgaggtcaagttcaattggtacgtggacggagtggaggtgcacaacgctaagaccaagcccagggaggagcagtacaacagcacctacagggtggtgtccgtgctgacagtgctgcaccaggattggctgaacggcaaggagtacaagtgcaaggtgtccaacaaggccctgccagcccctatcgagaagaccatcagcaaggccaagggccagcctagagaacctcaggtgtacaccctgccccctagcagagaggagatgaccaagaaccaggtgtccctgtcttgcgccgtgaagggcttctaccctagcgacatcgccgtggagtgggaatctaacggtcagccagagaacaactacaagaccaccccccccgtgctggatagcgacggcagcttcttcctggtgtccaagctgaccgtggacaaaagccgctggcagcagggcaacgtgttctcttgcagcgtgatgcacgaggccctgcataacagatacacccagaagagcctgagcctgagcccaggaaag
SEQ ID NO：21 E4coli氨基酸序列
EVAACEKEVAALEKEVAALEKEVAALEK
SEQ ID NO：22 E4coli核苷酸序列
gaagtggcagcttgcgagaaggaagtggccgctctggagaaggaagtggccgctctggaaaaggaagtggcagccctggagaag
SEQ ID NO：23 K4coli氨基酸序列
KVAACKEKVAALKEKVAALKEKVAALKE
SEQ ID NO：24 K4coli核苷酸序列
aaggtggcagcttgcaaggagaaggtggccgctctgaaggagaaagtggccgctctgaaggagaaagtggccgccctgaaggag
SEQUENCE LISTING
<110> 深圳新诺微环生物科技有限公司
<120> 微环DNA表达连接HER2阳性细胞与效应细胞的桥接分子及其应用
<160> 24
<170> PatentIn version 3.3
<210> 1
<211> 120
<212> PRT
<213> anti-Her2.VH氨基酸序列
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
<211> 360
<212> DNA
<213> anti-Her2.VH核苷酸序列
<400> 2
gaagtgcagc tggtggagtc aggaggagga ctggtgcagc caggaggatc tctgagactg 60
tcttgcgccg ccagcggctt caacatcaag gacacctaca tccattgggt ccggcaggct 120
ccaggaaaag gactcgagtg ggtggccaga atctacccca ccaacggcta cacccgctac 180
gccgatagcg tgaaaggccg gttcaccatc agcgccgata ccagcaagaa caccgcctac 240
ctgcagatga acagcctgag agccgaggac accgccgtgt actattgtag ccggtgggga 300
ggagacggct tctacgccat ggactattgg ggccagggaa cactggtgac agtgtcttcc 360
<210> 3
<211> 107
<212> PRT
<213> anti-Her2.VL氨基酸序列
<400> 3
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 Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 4
<211> 321
<212> DNA
<213> anti-Her2.VL核苷酸序列
<400> 4
gacatccaga tgacccagag ccctagctct ctgagcgcca gcgtgggcga tagagtgacc 60
atcacctgca gagcctctca ggacgtgaac accgcagtgg cttggtacca gcagaagcca 120
gggaaggccc ctaagctgct gatctacagc gcctctttcc tgtacagcgg cgtgcctagc 180
aggttcagcg gaagcagaag cggcaccgat ttcaccctga ccatcagctc tctgcagcca 240
gaggacttcg ccacctacta ctgccagcag cactacacaa cccctcctac ctttggccag 300
ggcacaaagc tggagatcaa a 321
<210> 5
<211> 125
<212> PRT
<213> anti-CD3.VH-1氨基酸序列
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 6
<211> 375
<212> DNA
<213> anti-CD3.VH-1核苷酸序列
<400> 6
gaagtgcagc tggtggaaag cggaggagga ctggtgcagc caggaggatc tctgagactg 60
tcttgcgccg ccagcggctt tacattcagc acctacgcca tgaattgggt ccggcaggct 120
ccaggaaaag gactcgagtg ggtcggaagg atccggagca agtacaacaa ctacgccacc 180
tactacgccg acagcgtgaa gggcaggttc accatcagcc gggacgacag caagaacagc 240
ctgtacctgc agatgaacag cctgaagacc gaggacacag ccgtgtacta ttgcgtgcgc 300
cacggcaact tcggcaacag ctacgtcagc tggttcgcct attgggggca gggaacactg 360
gtgacagtgt ctagc 375
<210> 7
<211> 110
<212> PRT
<213> anti-CD3.VL-1氨基酸序列
<400> 7
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Thr Gly Ala
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 8
<211> 330
<212> DNA
<213> anti-CD3.VL-1核苷酸序列
<400> 8
caggcagtgg tgacccagga accttctctg accgtgtctc caggcggaac agtgacactg 60
acctgcagaa gcagcacagg cgccgtgaca accagcaact acgccaattg ggtgcagcag 120
aagccaggac aggcccctag aggcctgatt ggaggcacaa acaagagagc cccttggacc 180
ccagccagat tctccggatc tctgctggga ggcaaagccg ccctgacaat cacaggagct 240
caggccgaag acgaggccga ctactattgc gccctctggt acagcaacct ctgggtgttc 300
ggcggaggaa caaagctgac agtgctggga 330
<210> 9
<211> 122
<212> PRT
<213> anti-CD3.VH-2氨基酸序列
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Asp Leu Glu Trp Val
35 40 45
Ala Leu Ile Asn Pro Tyr Lys Gly Val Ser Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Ala 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 Ser Gly Tyr Tyr Gly Asp Ser Asp Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 10
<211> 366
<212> DNA
<213> anti-CD3.VH-2核苷酸序列
<400> 10
gaggtgcagc tggtggagtc cggaggagga ctggtgcagc caggaggcag cctgagactg 60
tcctgtgccg cctccggcta ttcttttacc ggctacacaa tgaattgggt gaggcaggca 120
ccaggcaagg atctggagtg ggtggccctg atcaaccctt ataagggcgt gtccacctac 180
aatcagaagt tcaaggatcg gtttaccatc tctgtggaca agagcaagaa cacagcctat 240
ctgcagatga atagcctgcg cgctgaagac accgccgtgt actactgtgc ccggtccggc 300
tactatggcg attctgactg gtacttcgac gtgtggggcc agggcaccct ggtcacagtg 360
tctagc 366
<210> 11
<211> 107
<212> PRT
<213> anti-CD3.VL-2氨基酸序列
<400> 11
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 Arg Ala Ser Gln Asp Ile Arg Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 12
<211> 321
<212> DNA
<213> anti-CD3.VL-2核苷酸序列
<400> 12
gacatccaga tgacccagtc cccatcctct ctgtctgcca gcgtgggcga tcgggtgacc 60
atcacatgta gagcctctca ggacatcagg aactatctga attggtacca gcagaagcca 120
ggcaaggccc ccaagctgct gatctactat acctccaggc tggagtctgg agtgcctagc 180
cggttttccg gctccggaag cggaaccgat tacaccctga caatcagctc cctgcagcca 240
gaggacttcg ccacatacta ttgccagcag ggcaataccc tgccctggac atttggccag 300
ggcaccaagc tggagctgaa g 321
<210> 13
<211> 120
<212> PRT
<213> anti-CD16.VH氨基酸序列
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly 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 Gly Ser Ala Tyr Tyr Tyr Asp Phe Ala Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 14
<211> 360
<212> DNA
<213> anti-CD16.VH核苷酸序列
<400> 14
caagtccagc ttgtgcagtc aggtgctgag gttaaaaaac caggagaaag tctgaaggta 60
tcatgtaagg cctcaggtta tacgtttact tcatattaca tgcactgggt gcgacaggct 120
cctggtcagg ggttggagtg gatgggaatc atcaatccat ccggtggtag caccagctac 180
gcacaaaagt ttcagggtcg cgtgacaatg acaagagaca cgtccacgtc cacggtctac 240
atggaattgt catccctgag atcagaggac accgccgtat attattgtgc acgcggcagt 300
gcttactact acgatttcgc agattattgg gggcagggga ctttggttac agtctcctcc 360
<210> 15
<211> 106
<212> PRT
<213> anti-CD16.VL氨基酸序列
<400> 15
Ser Tyr Val Leu Thr Gln Pro Ser Ser Val Ser Val Ala Pro Gly Gln
1 5 10 15
Thr Ala Thr Ile Ser Cys Gly Gly His Asn Ile Gly Ser Lys Asn Val
20 25 30
His Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Asn 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 Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Asn Tyr Ser Val Leu
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 16
<211> 318
<212> DNA
<213> anti-CD16.VL核苷酸序列
<400> 16
tcctacgttc tcactcagcc cagtagtgtc tcagttgctc cagggcaaac ggccacgatt 60
agttgcggag gtcacaacat aggcagtaag aatgtacatt ggtaccaaca gcgaccaggc 120
cagagccccg ttttggtcat ctatcaggat aataagcggc caagtggaat accggagcgg 180
ttcagcggta gtaacagtgg gaacaccgcc actctgacta tatccggtac gcaagctatg 240
gacgaagcag actactattg ccaggtgtgg gataactaca gcgtactgtt cggaggcggg 300
acgaaactta cagtcttg 318
<210> 17
<211> 217
<212> PRT
<213> Fc-knob氨基酸序列
<400> 17
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
115 120 125
Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215
<210> 18
<211> 651
<212> DNA
<213> Fc-knob核苷酸序列
<400> 18
gctccagaag cagcaggagg acctagcgtg ttcctgttcc ctcccaagcc taaggacacc 60
ctgatgatca gccggacccc agaagtgact tgcgtggtgg tggacgtgtc ccacgaagac 120
cccgaggtca agttcaattg gtacgtggac ggagtggagg tgcacaacgc taagaccaag 180
cccagggagg agcagtacaa cagcacctac agggtggtgt ccgtgctgac agtgctgcac 240
caggattggc tgaacggcaa ggagtacaag tgcaaggtgt ccaacaaggc cctgccagcc 300
cctatcgaga agaccatcag caaggccaag ggccagccta gagaacctca ggtgtacacc 360
ctgcccccta gcagagagga gatgaccaag aaccaggtct ccctctggtg cctggtgaag 420
ggcttctacc ctagcgacat cgccgtggag tgggaatcta acggtcagcc agagaacaac 480
tacaagacca cccccccagt gctggacagc gacggcagct tcttcctgta cagcaagctg 540
accgtggaca aaagccgctg gcagcagggc aacgtgttct cttgcagcgt gatgcacgag 600
gccctgcaca accactacac ccagaagagc ctgagcctga gcccaggaaa g 651
<210> 19
<211> 217
<212> PRT
<213> Fc-hole氨基酸序列
<400> 19
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
115 120 125
Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215
<210> 20
<211> 651
<212> DNA
<213> Fc-hole核苷酸序列
<400> 20
gctccagaag cagcaggagg acctagcgtg ttcctgttcc ctcccaagcc taaggacacc 60
ctgatgatca gccggacccc agaagtgact tgcgtggtgg tggacgtgtc ccacgaagac 120
cccgaggtca agttcaattg gtacgtggac ggagtggagg tgcacaacgc taagaccaag 180
cccagggagg agcagtacaa cagcacctac agggtggtgt ccgtgctgac agtgctgcac 240
caggattggc tgaacggcaa ggagtacaag tgcaaggtgt ccaacaaggc cctgccagcc 300
cctatcgaga agaccatcag caaggccaag ggccagccta gagaacctca ggtgtacacc 360
ctgcccccta gcagagagga gatgaccaag aaccaggtgt ccctgtcttg cgccgtgaag 420
ggcttctacc ctagcgacat cgccgtggag tgggaatcta acggtcagcc agagaacaac 480
tacaagacca ccccccccgt gctggatagc gacggcagct tcttcctggt gtccaagctg 540
accgtggaca aaagccgctg gcagcagggc aacgtgttct cttgcagcgt gatgcacgag 600
gccctgcata acagatacac ccagaagagc ctgagcctga gcccaggaaa g 651
<210> 21
<211> 28
<212> PRT
<213> E4 coli氨基酸序列
<400> 21
Glu Val Ala Ala Cys Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val
1 5 10 15
Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
20 25
<210> 22
<211> 84
<212> DNA
<213> E4 coli核苷酸序列
<400> 22
gaagtggcag cttgcgagaa ggaagtggcc gctctggaga aggaagtggc cgctctggaa 60
aaggaagtgg cagccctgga gaag 84
<210> 23
<211> 28
<212> PRT
<213> K4 coli氨基酸序列
<400> 23
Lys Val Ala Ala Cys Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val
1 5 10 15
Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
20 25
<210> 24
<211> 84
<212> DNA
<213> K4 coli核苷酸序列
<400> 24
aaggtggcag cttgcaagga gaaggtggcc gctctgaagg agaaagtggc cgctctgaag 60
gagaaagtgg ccgccctgaa ggag 84
Claims (10)
1.一种表达Her2阳性细胞与效应细胞桥接分子(Bridge between Her2-positivecells and effector cells，Her2-BTEC)的重组基因载体，其特征在于，所述桥接分子包含：与Her2阳性细胞作用靶点特异性结合的部分A，和与效应细胞作用靶点特异性结合的部分B；
优选的，所述重组基因载体选自非病毒基因载体，如标准质粒或其它环状表达盒子；更优选的，所述重组基因载体选自微环DNA载体；
再优选的，所述桥接分子选自蛋白或多肽；更优选的，所述桥接分子选自双特异性抗体；特别优选的，所述桥接分子选自人-猴交叉性双特异性抗体(Human-Monkey cross-reactive Bispecific Antibody，hm-BsAb)；
更优选的，所述部分A和所述部分B分别选自蛋白分子或多肽分子；特别优选的，所述部分A和部分B分别选自Fab、Fab’、单链抗体(scFv)、单域抗体(VHH)、单链T细胞受体(scTCR)和其它。
2.如权利要求1所述重组基因载体，所述Her2阳性细胞选自Her2阳性癌细胞、Her2过表达细胞或其它；所述效应细胞选自T细胞、NK细胞或其它；
优选的，所述部分A特异性结合的作用靶点选自Her2的各个抗原表位；优选的，所述部分B特异性结合的作用靶点选自CD3、CD16、CD28、4-1BB、OX40、TCR、CD56、NKG2D、NCR或其它。
3.如权利要求1或2所述重组基因载体，所述部分A选自单链抗体(scFv)，其包含重链可变区和轻链可变区，其氨基酸序列如SEQ ID NO：1和3所示；
和/或，所述部分B选自单链抗体(scFv)，(1)其包含：重链可变区和轻链可变区，其氨基酸序列如选自SEQ ID NO：5和7，或9和11的组所示；所述部分B特异性结合的作用靶点选自CD3；或者(2)其包含：重链可变区和轻链可变区，其氨基酸序列如SEQ ID NO：13和15所示；所述部分B特异性结合的作用靶点选自CD16。
4.如权利要求1-3中任一项所述重组基因载体，所述重组基因载体包含所述桥接分子的编码基因；
优选的，所述重组基因载体包含：部分A的编码基因，和/或包含部分B的编码基因；
更优选的，部分A选自单链抗体(scFv)，其编码基因包含：重链可变区和轻链可变区的编码基因，其核苷酸序列如SEQ ID NO：2和4所示；
更优选的，部分B选自单链抗体(scFv)，其编码基因(1)包含：重链可变区和轻链可变区的编码基因，其核苷酸序列如选自SEQ ID NO：6和8、或10和12的组所示；或者(2)包含：重链可变区和轻链可变区的编码基因，其核苷酸序列如SEQ ID NO：14和16所示。
5.如权利要求1-4中任一项所述重组基因载体所表达的桥接分子。
6.如权利要求1-4中任一项所述重组基因载体的制备方法，具体步骤包括：
(1)从现有技术中分别获取Her2抗体、CD3抗体及CD16抗体的轻链可变区(VL)序列、重链可变区(VH)序列；
(2)根据上述(1)中VH、VL序列设计成多种组合形式的桥接分子，并构建表达所述桥接分子的重组基因载体；
任选的，
(3)在体内外鉴定所述重组基因载体的表达水平，并检测表达产物介导效应细胞对Her2阳性细胞的杀伤效果。
7.如权利要求6所述制备方法，所述Her2阳性细胞选自Her2阳性癌细胞、Her2过表达细胞或其它。所述效应细胞选自T细胞、NK细胞或其它；
优选的，所述重组基因载体选自非病毒基因载体，更优选的，所述重组基因载体选自微环DNA载体；
再优选的，所述桥接分子选自蛋白或多肽；更优选的，所述桥接分子选自双特异性抗体；特别优选的，所述桥接分子选自人-猴交叉性双特异性抗体(Human-Monkey cross-reactive Bispecific Antibody，hm-BsAb)。
8.一种宿主细胞，其包含权利要求1-4中任一项所述重组基因载体，或由权利要求6或7所述制备方法所得到的重组基因载体；
优选的，所述宿主细胞包括细菌细胞、酵母菌细胞、昆虫细胞或哺乳动物细胞。
9.一种药物组合物，其包含如权利要求1-4中任一项所述重组基因载体，或如权利要求5所述桥接分子，或由权利要求6或7所述制备方法所得到的重组基因载体，以及药学上可接受的载体。
10.如权利要求1-4中任一项所述重组基因载体，由权利要求6或7所述制备方法所得到的重组基因载体，如权利要求5所述桥接分子，如权利要求8所述宿主细胞，或如权利要求9所述药物组合物在制备用于治疗Her2相关癌症的药物中的用途；
优选的，所述Her2相关癌症选自乳腺癌、非小细胞肺癌、唾液腺癌、胃癌、肠癌、胰腺癌、膀胱癌、子宫内膜癌、卵巢癌；特别优选的，所述Her2相关癌症选自乳腺癌、胃癌。
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| WO2020088365A1 (zh) * | 2018-10-30 | 2020-05-07 | 深圳新诺微环生物科技有限公司 | 微环dna表达连接her2阳性细胞与效应细胞的桥接分子及其应用 |
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