CN113512125A - 一种携带stat结合基序的嵌合抗原受体分子及表达该嵌合抗原受体分子的nk细胞 - Google Patents
一种携带stat结合基序的嵌合抗原受体分子及表达该嵌合抗原受体分子的nk细胞 Download PDFInfo
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Abstract
本发明公开了一种携带STAT结合基序的嵌合抗原受体分子以及表达该嵌合抗原受体分子的NK细胞。所述嵌合抗原受体分子包括:从N‑末端到C‑末端依次为(1)识别靶抗原的抗体单链可变区;(2)跨膜结构域;(3)共刺激结构域;(4)信号转导结构域;(5)STAT结合基序。本发明实施例利用NK细胞中特有的的信号转导元件与影响NK细胞增殖的信号通路,以此优化CAR‑NK中CAR分子的共刺激分子结构域、细胞信号转导域及其组合,以提高CAR‑NK细胞在体内的增殖能力、持续时间,进而发挥最佳治疗疗效的同时降低副作用。
Description
技术领域
本发明涉及生物技术领域,具体涉及一种携带STAT结合基序的嵌合抗原受体分子及表达该嵌合抗原受体分子的NK细胞。
背景技术
NK细胞是一种天然免疫细胞,占外周血淋巴细胞的10-15%左右。NK细胞对肿瘤细胞的杀伤作用受其表面的激活性受体与抑制性受体共同调控,激活性受体包括自然细胞毒受体(NCRs),例如NKG2D、CD16(FcgRIIIa)、FasL、肿瘤坏死因子相关凋亡诱导配体(TRAIL)与共刺激受体例如LFA-1、CD244 (2B4)、and CD137(41BB)。这些激活性受体通过胞浆内的免疫受体酪氨酸激活基序(ITAMs)与其它跨膜信号桥接转导子触发细胞裂解程序、细胞因子与趋化因子的分泌。NK细胞的信号转导途径与T细胞不同,NK细胞活化需要细胞膜表面多个激活受体交联,才能引起细胞内ITAM磷酸化。NKG2D是表达在CD8 T细胞与NK细胞表面的强激活性受体,但它的膜定位与信号转导依赖于另一膜蛋白DNAX激活蛋白(DAP10),DAP10含有YxxM信号转导基序,可以激活PI3K信号转导通路。2B4是属于SLAM家族的NK细胞特异性共刺激受体,其胞内域通过与SLAM相关蛋白(SAP)相互作用传递NK细胞活化信号。
NK细胞无需抗原致敏即可广泛识别与杀伤各类肿瘤细胞,其抗肿瘤作用不受MHC限制,可进行异体回输而不会引起移植物抗宿主病(graft-versus-host disease,GVHD),因此,经过基因修饰的NK细胞既具有了对肿瘤细胞杀伤的靶向性,又保留着本身的“off-the-shelf”特性,可实现异体回输,具有通用性,便于标准化、规模化。鉴于此,NK细胞目前成为嵌合抗原受体(Chimeric Antigen receptor,CAR)治疗的新的效应细胞之一。
嵌合抗原受体(chimeric antigen receptor,CAR)是一个人工合成的融合受体,在结构上包括胞外抗原结合区、跨膜区、胞内信号转导区与共刺激信号区。胞外区为识别肿瘤相关抗原的抗体单链可变区序列(single chain variable fragment,ScFV),跨膜区连接胞外区与胞内区,常用的跨膜区分子有CD3、 CD4、CD8与CD28等。人们通过分子克隆方法将上述元件在体外进行重组,形成重组质粒,通过病毒载体、电穿孔等手段将重组质粒转导入效应细胞,继之在体外培养扩增,最后回输到病人体内,起到治疗肿瘤或感染性疾病的目的。这种经过基因修饰与改造的NK细胞即称为CAR NK细胞。CAR NK细胞通过ScFV段识别并结合抗原,通过胞内信号区激活NK细胞,这样改造的CAR NK细胞在应用时就具有了两大特点:①靶向性;②通用性。目前,已有多项 CAR NK产品进行了临床试验,例如(ClinicalTrials.gov:NCT00995137, NCT01974479,NCT02839954,NCT02892695,NCT02742727,and NCT02944162)。2020年,Liu等将CD19 CAR NK细胞治疗淋巴瘤的I、II期临床试验结果公布在新英格兰医学杂志上,11例入组病人当中,8人有应答 (73%),其中4例病人完全缓解,完全缓解率为25%,这显示CAR NK细胞治疗是一种有前景的细胞治疗。
虽然临床前研究与部分临床试验皆显示CAR NK是针对肿瘤或感染性疾病的有潜力的一种细胞疗法,但NK细胞本身的特点也使得这种疗法有其本身的局限性。临床试验中,NK细胞的来源主要有NK92细胞系、外周血来源的单个核细胞、脐带血来源的单个核细胞以及诱导多能干细胞(iPSC)。NK92 是FDA唯一批准的用于临床试验的NK细胞株,但NK92来自于NHL病人的永生化细胞株,为降低潜在的致瘤风险,在回输给病人之前必须经过辐照,保留其靶细胞杀伤活性而去其增殖活性,而后者恰恰与治疗效果密切相关,因此经过辐照的CAR NK92的治疗效果就大打折扣。而其它三种来源的NK细胞,也都存在着明显缺陷,那就是在没有细胞因子支持的条件下,回输后在体内持续时间很短,进而影响疗效。
为了解决这一问题,有的研究小组尝试将IL-2、IL-15共同构建到CAR 载体上,与CAR共表达,例如Liu等的研究小组将IL-15构建到CD19 CAR 分子上,这样IL-15就会以旁分泌的形式促进CAR-NK的增殖与存活,但这样做的一个缺点就是随着CAR NK细胞在病人体内的扩增,细胞因子也会系统性作用于病人全身,从而引起各种各样的副作用。
发明内容
为此,本发明提供一种携带STAT结合基序的嵌合抗原受体分子及表达该嵌合抗原受体分子的NK细胞。
为了实现上述目的,本发明提供如下技术方案:
本发明实施例提供一种携带STAT结合基序的嵌合抗原受体分子,述嵌合抗原受体分子包括:从N-末端到C-末端依次为
(1)识别靶抗原的抗体单链可变区;
(2)跨膜结构域;
(3)共刺激结构域;
(4)信号转导结构域;
(5)STAT结合基序。
本发明的一个实施例中,所述STAT结合基序为至少一个或多个至少重复一次的Stat3结合基序和/或Stat5结合基序。
本发明的一个实施例中,相邻所述结合基序之间通过(G4S)3连接。
本发明的一个实施例中,所述抗原选自如下:CD19、CD20、CD22、 CD33、CD123、CEA、GPC3和GD2。
本发明的一个实施例中,所述共刺激结构域选自CD28、4-1BB、CD137 和OX40。
本发明的一个实施例中,所述信号转导结构域为CD3ζ。
本发明的一个实施例中,所述嵌合抗原受体分子为 CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5,其嵌合抗原受体分子的氨基酸序列如SEQ ID NO:12所示。
本发明的一个实施例中,所述嵌合抗原受体分子为 CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5,与所述嵌合抗原受体分子的每个肽片段中具有95%同源性的蛋白质。
本发明还提供编码上述所述的携带STAT结合基序的嵌合抗原受体分子的核酸分子。
表达上述所述的嵌合抗原受体分子的NK细胞,也属于本发明的保护范围。
本发明中,JAK/STAT是影响T细胞与NK细胞增殖活化的重要信号通路, NK细胞从骨髓造血干细胞(HSCs)经淋巴祖细胞(CLPs)向NK系限制祖细胞(NKPs)分化的过程中需要多种细胞因子,包括IL2、IL7、IL12、IL15、 IL21、IL27与IFNs,通过JAK/STAT信号通路协同作用完成NK细胞的增殖与分化发育。JAK/STAT通路在哺乳动物中高度保守,JAK家族成员包括JAK1-3与TYK2,STAT家族成员包括STAT1-4、STAT5A、STAT5B与STAT6。在T细胞淋巴瘤与NK细胞淋巴瘤中也往往存在Stat3信号通路的异常激活。 Stat5是NK细胞功能的重要调控因子,IL15刺激可以在NK细胞内引起Stat3、 Stat5激活。IL21可以以Stat3依赖非方式调控NK细胞表面激活受体NKG2D 的表达。在慢性淋巴性增殖失控的病人、侵袭性NK细胞白血病与结外NK/T 细胞淋巴瘤病人当中皆能检测到Stat3突变,突变导致Stat3磷酸化蛋白水平升高使突变细胞优势化生长。Stat5对NK细胞的存活也非常关键,在NK细胞当中,Stat5B的转录水平远高于Stat5A,说明在NK细胞当中以Stat5B为主。 Stat5a/b基因敲除的小鼠外周血NK细胞缺失,骨髓NK细胞的发育停滞在NKP 阶段,因为NK细胞的存活依赖于Stat5下游基因Mcl1与Bcl2的表达。鉴于 Stat3与Stat5在NK细胞增殖中的作用与NK细胞来源的恶性肿瘤当中的过度激活,Stat3与Stat5都成为治疗此类肿瘤的关注点。
因此,从影响NK细胞存活的关键信号通路出发,将与NK细胞增殖关系密切的Stat3与Stat5的结合基序构建到嵌合抗原受体分子上,这样嵌合抗原受体分子在转导NK细胞在其中表达以后,就会通过此结合基序募集Stat3与 Stat5分子,进而促进NK细胞增殖与存活。
本发明具有以下优点:
本发明实施例利用NK细胞中特有的信号转导元件与影响NK细胞增殖的信号通路,以此优化CAR-NK中CAR分子的共刺激分子结构域、细胞信号转导域及其组合,以提高CAR-NK细胞在体内的增殖能力、持续时间,进而发挥最佳治疗疗效的同时降低副作用。
本发明实施例从影响NK细胞存活的关键信号通路着手,与CAR分子设计联系起来,在CAR分子上加上Stat3与Stat5的结合基序(binding motif),以此招募更多的Stat3与Stat5分子,使CAR NK细胞在回输以后在病人体内获得更好的增殖能力与持续时间,进而发挥更强的杀伤肿瘤或感染性疾病效果。
附图说明
为了更清楚地说明本发明的实施方式或现有技术中的技术方案,下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍。显而易见地,下面描述中的附图仅仅是示例性的,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据提供的附图引伸获得其它的实施附图。
图1为本发明实施例提供的携带STAT结合基序的嵌合抗原受体分子的骨架示意图;
图2为本发明实施例提供的为含编码 CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5嵌合抗原受体分子基因的 PCDH-EF1α-MCS-PURO载体的电泳图。
图3为纯化的CAR分子假病毒感染293FT细胞验证图,其中,UTD未未感染细胞,分别取0.125μL、0.25μL、0.5μL、1μL、2μL病毒感染293FT细胞,感染72小时后,流式免疫荧光染色检测CAR分子阳性比率;
图4本发明实施例的CAR NK细胞的转导效率检测图,其中,A:未转导CAR的NK细胞,B:转导的CAR的NK细胞;
图5为本发明实施例提供的不同效靶比条件下,表达 CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5嵌合抗原受体分子的 CAR NK细胞对NALM6的杀伤效率分析图;
图6为本发明实施例提供的以NALM6尾静脉注射建立B淋巴细胞白血病(B-ALL)小鼠模型,以表达CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3- Stat5嵌合抗原受体分子的CARNK细胞治疗B-ALL小鼠的生存期分析图;
具体实施方式
以下由特定的具体实施例说明本发明的实施方式,熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1、具STAT结合基序的嵌合抗原受体蛋白的设计
本实施例提供的携带STAT结合基序的嵌合抗原受体分子的设计过程如下:其携带STAT结合基序的嵌合抗原受体分子中,从N-末端到C-末端依次为(1)可识别靶抗原的抗体单链可变区;(2)跨膜结构域;(3)共刺激结构域;(4)信号转导结构域;(5)STAT结合基序。
其中,ScFV特异性识别肿瘤细胞或感染细胞的靶抗原,肿瘤抗原靶点包括,但不局限于CD19、CD20、CD22、CD33、CD123、CEA、GPC3、GD2 等。嵌合抗原受体CAR分子的跨膜结构域NKG2D,共刺激结构域包括 CD28、4-1BB、CD137、OX40等对于CAR T或CAR NK细胞的充分激活及回输后在体内的持续时间至关重要。信号转导结构域CD3ζ是通过与ZAP70 相互作用,传递TCR信号,本发明实施例中,将共刺激结构域CD137、2B4、 DAP10、CD28等作为共刺激信号,将识别靶点的ScFV序列、跨膜结构域 NKG2D与共刺激结构域CD137、2B4、DAP10、CD28与信号转导结构域 CD3ζ顺序串联,在信号转导结构域CD3ζ尾部加上Stat3和/或与Stat5结合基序(motif),两个相邻基序之间以(G4S)3相连,依此来招募Stat3与Stat5 分子,设计的相关STAT结合基序的嵌合抗原受体分子如图1所示,其通式可以表示为:信号肽-跨膜结构域-共刺激结构域-信号转导结构域-STAT结合基序(sp-TM-cosDM-CD3ζ-STAT motif),其中,STAT结合基序为至少一个或多个至少重复一次的Stat3结合基序和/或Stat5结合基序。
其中,信号肽的氨基酸序列如SEQ ID NO:1所示,核苷酸序列如SEQ ID NO:13所示;anti-CD19的单链可变区(ScFv)序列氨基酸序列如SEQ ID NO: 2所示,核苷酸序列如SEQ ID NO:14所示;NKG2D的氨基酸序列如SEQ ID NO:3所示,核苷酸序列如SEQ ID NO:15所示;DAP10的氨基酸序列如 SEQ ID NO:4所示,核苷酸序列如SEQ ID NO:16所示;2B4氨基酸序列如 SEQ ID NO:5所示,核苷酸序列如SEQ ID NO:17所示;CD28氨基酸序列如SEQ IDNO:6所示,核苷酸序列如SEQ ID NO:18所示;CD137氨基酸序列如SEQ ID NO:7所示,核苷酸序列如SEQ ID NO:19所示;CD3ζ氨基酸序列如SEQ ID NO:8所示,核苷酸序列如SEQ ID NO:20所示。Stat3结合基序氨基酸序列如SEQ ID NO:10所示,核苷酸序列如SEQ ID NO:22所示,Stat5结合基序氨基酸序列如SEQ ID NO:11所示,核苷酸序列如SEQ ID NO:23所示,两个结构域之间必要时,以(G4S)3linker相连,其氨基酸序列如9所示,核苷酸序列如SEQ IDNO:21所示。
实施例2、编码CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5嵌合抗原受体分子基因序列合成
构建CAR分子:信号肽-跨膜结构域-共刺激结构域-信号转导结构域-结合基序,本实施例的设计好CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5 的CAR分子在苏州金唯智生物科技有限公司进行全基因合成,克隆入病毒载体(PCDH-EF1α-MCS-puro),载体可为慢病毒载体,也可为逆转录病毒载体(MSCV)。
本实施例利用全基因合成的方式合成CD19ScFV-NKG2D-CD137-CD3ζ -Stat3(G4S)3-Stat5基因序列,即信号肽-CD19ScFV-NKG2D-CD137-CD3ζ -YRHQ(G4S)3-LMDNAYFCEAD,该嵌合抗原受体分子的氨基酸序列如SEQ ID NO:12所示,编码嵌合抗原受体分子核苷酸序列如SEQ ID NO:24所示,利用酶切位点Nhe I与Sal 1克隆到优选的慢病毒载体,所述慢病毒载体为 PCDH-EF1α-MCS-PURO或其它任何一种慢病毒过表达载体。
将表达载体转化STBL3大肠杆菌菌株,氨苄青霉素筛选,酶切鉴定获得阳性克隆,经测序验证正确后即为CD19嵌合抗原受体病毒载体,如图2所示为含编码CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5嵌合抗原受体分子基因的PCDH-EF1α-MCS-PURO载体的电泳图。
实施例3、含编码CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5 嵌合抗原受体蛋白的核酸分子的CAR NK慢病毒载体的假慢病毒颗粒的制备
1、第0天铺板:0.25%胰酶消化293FT细胞,铺在含有10ml DMEM(含有10%FBS)的10cm培养皿中,37℃,5%CO2恒温培养箱培养,保证24后细胞汇合度达到90-95%。
2、293FT细胞转染:转染前2小时,293FT细胞换液。将实施例2中靶向CD19嵌合抗原受体慢病毒载体以及辅助载体(pspax2与pMD2.G)与PEI 混合,吹打均匀,室温静置15min,得到DNA/PEI混合物。将制备好的 DNA/PEI混合物逐滴加到293FT细胞中,继续培养4-6小时,换液。
3、假病毒浓缩纯化:分别收集上述293FT细胞转染24小时与48小时的细胞上清,0.45μM滤器过滤后,可用两种方法浓缩慢病毒,一是可用仕必纯中空纤维柱浓缩20~100倍,将病毒分装,-80℃冻存病毒沉淀,待用。还可以用超速离心法浓缩慢病毒,即将含慢病毒的细胞上清用0.45μM滤器过滤后,25,000rpm,超速离心,120min,最后利用PBS将沉淀溶解,分装后,-80℃冻存,得到CD19嵌合抗原受体病毒假慢病毒颗粒。我们将不同体积(0.125μl、0.5μl、1μl、2μl)的病毒悬液感染293FT细胞进行验证,72 小时后,收取细胞,进行CAR分子的流式免疫荧光染色,测定CAR分子阳性比率,结果如图3所示。
实施例4、表达CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5嵌合抗原受体分子的CAR NK细胞制备
NK细胞的扩增,Ficoll淋巴细胞分离液分离外周血PBMC,利用磁珠去掉CD3阳性细胞,并富集CD56阳性细胞,利用辐照过的K562(4-1BBL+IL21) 作为饲养细胞,在X-VIVO15(5%自体血清),IL2 500U/ml的条件下扩增获得的NK细胞。
利用美天旎NK细胞分选试剂盒中,从人外周血PBMC分选NK细胞,流式免疫荧光染色(anti-CD3-APC与anti-CD56-PE)验证NK细胞纯度,使 CD3-CD56+细胞比率达到95%以上。然后利用辐照过(100Gy)的稳定表达 4-1BBL与IL21的K562作为饲养细胞,饲养细胞与分选的NK细胞的比例是 2:1,培养基可选择含有的X-VIVO15(5%血清替代物、IL2 100U/ml)。
将实施例3中制备的CD19嵌合抗原受体病毒假慢病毒以Moi 5~10的比例感染NK细胞,感染体系中加入鱼精蛋白8μg/ml或polybrene 6μg/ml作为转导增强剂,以提高感染效率。感染72小时后,利用上海近岸的CAR19流式检测试剂盒进行流式免疫荧光染色,分析CAR NK的感染效率,确定CD19 嵌和抗原受体在NK细胞上的表达。确定表达后,如图4所示,感染效率在 20~50%之间,继续在含有IL-2的无血清培养基中培养10~14天,即得到表达CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5嵌合抗原受体分子的 CAR NK细胞。本实施例中,无血清培养基也可选用X-VIVO15(Lonza)、 AIM-V(Invitrogen)、GT-T551(Takara)中的一种,无血清培养基中可加入浓度为1~10%的自体血清,即来源于与CAR NK细胞同一供体的血清;或含有 5%的人AB血清。本实施例中,CAR NK细胞培养扩增过程中,每隔2~3天补充新鲜无血清培养基、自体血清(或AB血清、IL-2)等,以保证细胞营养成分足够,扩增良好。
实施例5、表达CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5嵌合抗原受体分子的CAR NK细胞毒性功能验证
利用eFluor670对CD19阳性靶细胞NALM6进行活细胞标记,将实施例 4制备的CARNK细胞与靶细胞NALM6以0.5:1、3:1、6:1的效靶比共培养, 4小时后,收集细胞,7-AAD染色,流式分析eFluor670阳性细胞群中7-AAD 阳性细胞的比例,判断CAR-T对靶细胞的杀伤效率。
结果如图5所示,在所设定的三个效靶比条件下,本发明实施例的CAR NK细胞较传统NK细胞,其杀伤效率有明显提高。
实施例6、本实施例的CAR NK细胞细胞对小鼠急性B细胞白血病的治疗作用
将6~8周的雌性NOD/SCID小鼠随机分组,本发明实施例的CAR NK治疗组与对照组,尾静脉注射带有荧光素酶的CD19阳性B细胞白血病细胞株 NALM6-LUC,建立白血病小鼠模型,注射NALM6-LUC后第6天,通过小动物成像观察建模情况,确定建模成功后,给予CD19CAR NK细胞治疗,尾静脉注射,1×107/只。分别在治疗后不同时间点(第4天、第11天、21天)进行小动物成像,观察白血病消退情况,记录各组小鼠生存期,绘制小鼠生存曲线,综合分析本发明携带STAT结合基序的CAR NK细胞对小鼠白血病的治疗作用是否优于不携带者,结果如图6所示,与不携带者及生理盐水对照组相比,本发明实施例制备的CAR NK细胞治疗的小鼠生存期明显延长。
虽然,上文中已经用一般性说明及具体实施例对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
参考文献
1.Eguizabal,C.,et al.,Natural killer cells for cancer immunotherapy:pluripotent stem cells-derived NK cells as an immunotherapeuticperspective.Front Immunol,2014.5:p.439.
2.Li,Y.,et al.,Human iPSC-Derived Natural Killer Cells Engineeredwith Chimeric Antigen Receptors Enhance Anti-tumor Activity.Cell Stem Cell,2018.23(2):p.181-192e5.
3.Geller,M.A.and J.S.Miller,Use of allogeneic NK cells for cancerimmunotherapy.Immunotherapy,2011. 3(12):p.1445-59.
4.Siegler,E.L.,et al.,Off-the-Shelf CAR-NK Cells for CancerImmunotherapy.Cell Stem Cell,2018.23(2):p. 160-161.
5.Zou,F.,et al.,Engineered triple inhibitory receptor resistanceimproves anti-tumor CAR-T cell performance via CD56.Nat Commun,2019.10(1):p.4109.
6.Daher,M.and K.Rezvani,Next generation natural killer cells forcancer immunotherapy:the promise of genetic engineering.Curr Opin Immunol,2018.51:p.146-153.
7.Liu,E.,et al.,Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.N Engl J Med,2020.382(6):p.545-553.
8.Gotthardt,D.,et al.,JAK/STAT Cytokine Signaling at the Crossroad ofNK Cell Development and Maturation.Front Immunol,2019.10:p.2590.
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序列表
<110> 北京双赢科创生物科技有限公司
<120> 一种携带STAT结合基序的嵌合抗原受体分子及表达该嵌合抗原受体分子的NK细胞
<130> GG20879542A
<160> 24
<170> SIPOSequenceListing 1.0
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<211> 21
<212> PRT
<213> Artificial Sequence
<400> 1
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
20
<210> 2
<211> 242
<212> PRT
<213> Artificial Sequence
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Asp Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Asn Tyr Ala Gln Gln Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu 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 Glu Ala Val Ala Ala Asp Trp Leu Asp Pro Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
130 135 140
Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser
145 150 155 160
Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly
180 185 190
Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
195 200 205
Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
210 215 220
Gln Tyr Gly Ser Ser Arg Phe Thr Phe Gly Pro Gly Thr Lys Val Asp
225 230 235 240
Ile Lys
<210> 3
<211> 216
<212> PRT
<213> Artificial Sequence
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Met Gly Trp Ile Arg Gly Arg Arg Ser Arg His Ser Trp Glu Met Ser
1 5 10 15
Glu Phe His Asn Tyr Asn Leu Asp Leu Lys Lys Ser Asp Phe Ser Thr
20 25 30
Arg Trp Gln Lys Gln Arg Cys Pro Val Val Lys Ser Lys Cys Arg Glu
35 40 45
Asn Ala Ser Pro Phe Phe Phe Cys Cys Phe Ile Ala Val Ala Met Gly
50 55 60
Ile Arg Phe Ile Ile Met Val Ala Ile Trp Ser Ala Val Phe Leu Asn
65 70 75 80
Ser Leu Phe Asn Gln Glu Val Gln Ile Pro Leu Thr Glu Ser Tyr Cys
85 90 95
Gly Pro Cys Pro Lys Asn Trp Ile Cys Tyr Lys Asn Asn Cys Tyr Gln
100 105 110
Phe Phe Asp Glu Ser Lys Asn Trp Tyr Glu Ser Gln Ala Ser Cys Met
115 120 125
Ser Gln Asn Ala Ser Leu Leu Lys Val Tyr Ser Lys Glu Asp Gln Asp
130 135 140
Leu Leu Lys Leu Val Lys Ser Tyr His Trp Met Gly Leu Val His Ile
145 150 155 160
Pro Thr Asn Gly Ser Trp Gln Trp Glu Asp Gly Ser Ile Leu Ser Pro
165 170 175
Asn Leu Leu Thr Ile Ile Glu Met Gln Lys Gly Asp Cys Ala Leu Tyr
180 185 190
Ala Ser Ser Phe Lys Gly Tyr Ile Glu Asn Cys Ser Thr Pro Asn Thr
195 200 205
Tyr Ile Cys Met Gln Arg Thr Val
210 215
<210> 4
<211> 92
<212> PRT
<213> Artificial Sequence
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Met Ile His Leu Gly His Ile Leu Phe Leu Leu Leu Leu Pro Val Ala
1 5 10 15
Ala Ala Gln Thr Thr Pro Gly Glu Arg Ser Ser Leu Pro Ala Phe Tyr
20 25 30
Pro Gly Thr Ser Gly Ser Cys Ser Gly Cys Gly Ser Leu Ser Leu Pro
35 40 45
Leu Leu Ala Gly Leu Val Ala Ala Asp Ala Val Ala Ser Leu Leu Ile
50 55 60
Val Gly Ala Val Phe Leu Cys Ala Arg Pro Arg Arg Ser Pro Ala Gln
65 70 75 80
Asp Gly Lys Val Tyr Ile Asn Met Pro Gly Arg Gly
85 90
<210> 5
<211> 141
<212> PRT
<213> Artificial Sequence
<400> 5
Phe Leu Val Ile Ile Val Ile Leu Ser Ala Leu Phe Leu Gly Thr Leu
1 5 10 15
Ala Cys Phe Cys Val Trp Arg Arg Lys Arg Lys Glu Lys Gln Ser Glu
20 25 30
Thr Ser Pro Lys Glu Phe Leu Thr Ile Tyr Glu Asp Val Lys Asp Leu
35 40 45
Lys Thr Arg Arg Asn His Glu Gln Glu Gln Thr Phe Pro Gly Gly Gly
50 55 60
Ser Thr Ile Tyr Ser Met Ile Gln Ser Gln Ser Ser Ala Pro Thr Ser
65 70 75 80
Gln Glu Pro Ala Tyr Thr Leu Tyr Ser Leu Ile Gln Pro Ser Arg Lys
85 90 95
Ser Gly Ser Arg Lys Arg Asn His Ser Pro Ser Phe Asn Ser Thr Ile
100 105 110
Tyr Glu Val Ile Gly Lys Ser Gln Pro Lys Ala Gln Asn Pro Ala Arg
115 120 125
Leu Ser Arg Lys Glu Leu Glu Asn Phe Asp Val Tyr Ser
130 135 140
<210> 6
<211> 41
<212> PRT
<213> Artificial Sequence
<400> 6
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 7
<211> 42
<212> PRT
<213> Artificial Sequence
<400> 7
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> 8
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 8
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys 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> 9
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 9
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 10
<211> 4
<212> PRT
<213> Artificial Sequence
<400> 10
Tyr Arg His Gln
1
<210> 11
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 11
Leu Met Asp Asn Ala Tyr Phe Cys Glu Ala Asp
1 5 10
<210> 12
<211> 663
<212> PRT
<213> 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 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Asp Ser Gly Gly
35 40 45
Thr Phe Ser Ser Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Gly Leu Glu Trp Met Gly Gly Ile Ile Pro Ile Phe Gly Thr Thr Asn
65 70 75 80
Tyr Ala Gln Gln Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser
85 90 95
Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Glu Ala Val Ala Ala Asp Trp Leu Asp
115 120 125
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr
145 150 155 160
Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
165 170 175
Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr
180 185 190
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser
195 200 205
Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
210 215 220
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
225 230 235 240
Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Arg Phe Thr Phe Gly Pro
245 250 255
Gly Thr Lys Val Asp Ile Lys Met Gly Trp Ile Arg Gly Arg Arg Ser
260 265 270
Arg His Ser Trp Glu Met Ser Glu Phe His Asn Tyr Asn Leu Asp Leu
275 280 285
Lys Lys Ser Asp Phe Ser Thr Arg Trp Gln Lys Gln Arg Cys Pro Val
290 295 300
Val Lys Ser Lys Cys Arg Glu Asn Ala Ser Pro Phe Phe Phe Cys Cys
305 310 315 320
Phe Ile Ala Val Ala Met Gly Ile Arg Phe Ile Ile Met Val Ala Ile
325 330 335
Trp Ser Ala Val Phe Leu Asn Ser Leu Phe Asn Gln Glu Val Gln Ile
340 345 350
Pro Leu Thr Glu Ser Tyr Cys Gly Pro Cys Pro Lys Asn Trp Ile Cys
355 360 365
Tyr Lys Asn Asn Cys Tyr Gln Phe Phe Asp Glu Ser Lys Asn Trp Tyr
370 375 380
Glu Ser Gln Ala Ser Cys Met Ser Gln Asn Ala Ser Leu Leu Lys Val
385 390 395 400
Tyr Ser Lys Glu Asp Gln Asp Leu Leu Lys Leu Val Lys Ser Tyr His
405 410 415
Trp Met Gly Leu Val His Ile Pro Thr Asn Gly Ser Trp Gln Trp Glu
420 425 430
Asp Gly Ser Ile Leu Ser Pro Asn Leu Leu Thr Ile Ile Glu Met Gln
435 440 445
Lys Gly Asp Cys Ala Leu Tyr Ala Ser Ser Phe Lys Gly Tyr Ile Glu
450 455 460
Asn Cys Ser Thr Pro Asn Thr Tyr Ile Cys Met Gln Arg Thr Val Lys
465 470 475 480
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
485 490 495
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
500 505 510
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
515 520 525
Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu
530 535 540
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
545 550 555 560
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
565 570 575
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
580 585 590
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
595 600 605
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
610 615 620
Leu His Met Gln Ala Leu Pro Pro Arg Tyr Arg His Gln Gly Gly Gly
625 630 635 640
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Met Asp Asn
645 650 655
Ala Tyr Phe Cys Glu Ala Asp
660
<210> 13
<211> 60
<212> DNA
<213> Artificial Sequence
<400> 13
gccttaccag tgaccgcctt gctcctgccg ctggccttgc tgctccacgc cgccaggccg 60
<210> 14
<211> 726
<212> DNA
<213> Artificial Sequence
<400> 14
caagtgcagc tggtgcagag cggcgccgag gtgaagaagc ccggcagcag cgtgaaggtg 60
agctgcaagg acagcggcgg caccttcagc agctacgcca tcagctgggt gagacaagcc 120
cccggccaag gcctggagtg gatgggcggc atcatcccca tcttcggcac caccaactac 180
gctcagcagt tccaaggcag agtgaccatc accgccgacg agagcacaag caccgcctac 240
atggagctga gcagcctgag aagcgaggac accgctgttt actactgcgc ccgggaggcg 300
gttgcggccg attggctcga tccctggggg caaggcaccc tggttaccgt tagcagcggt 360
ggaggcggca gcggcggtgg aggctcgggt ggtgggggat ctgagatcgt gctgacacag 420
tcgcccggca ccctaagcct gtcgcccggc gaaagagcca ccctgagctg cagagcttct 480
cagagcgtga gcagcagcta cctggcctgg tatcagcaga agcccggcca agcccctaga 540
ctgctgatct acggcgctag cagcagagcc accggcatcc ccgacagatt cagcggcagc 600
ggcagcggca ccgacttcac cctgaccatc agcagactgg agcccgagga cttcgcggtg 660
tactactgtc agcaatacgg cagcagcaga ttcaccttcg gccccggcac caaggtggac 720
atcaag 726
<210> 15
<211> 651
<212> DNA
<213> Artificial Sequence
<400> 15
atggggtgga ttcgtggtcg gaggtctcga cacagctggg agatgagtga atttcataat 60
tataacttgg atctgaagaa gagtgatttt tcaacacgat ggcaaaagca aagatgtcca 120
gtagtcaaaa gcaaatgtag agaaaatgca tctccatttt ttttctgctg cttcatcgct 180
gtagccatgg gaatccgttt cattattatg gtagcaatat ggagtgctgt attcctaaac 240
tcattattca accaagaagt tcaaattccc ttgaccgaaa gttactgtgg cccatgtcct 300
aaaaactgga tatgttacaa aaataactgc taccaatttt ttgatgagag taaaaactgg 360
tatgagagcc aggcttcttg tatgtctcaa aatgccagcc ttctgaaagt atacagcaaa 420
gaggaccagg atttacttaa actggtgaag tcatatcatt ggatgggact agtacacatt 480
ccaacaaatg gatcttggca gtgggaagat ggctccattc tctcacccaa cctactaaca 540
ataattgaaa tgcagaaggg agactgtgca ctctatgcct cgagctttaa aggctatata 600
gaaaactgtt caactccaaa tacatacatc tgcatgcaaa ggactgtgta a 651
<210> 16
<211> 719
<212> DNA
<213> Artificial Sequence
<400> 16
atgtttactg ccacctccag agaagctcac tgctgaggtc ctaggaatca tttgcattgt 60
cctgatggcc actgtgttaa aaacaatagt tcttattcct tgtattggag tactggagca 120
gaacagtttt tccctgaata gaagaatgca gaaagcacgt cattgtggcc attgtcctga 180
ggagtggatt acatattcca acagttgtta ttacattggt aaggaaagaa aacttgggaa 240
gaaagagttt gctggcctgt gcttcgaaga actctgatct gctttctata gataatgagg 300
aagaaatgct actggggata aaggaaggag aaataagtca cctaaaattt gagcacctgc 360
taataggtat gtgtggggac ttccctggac ttctctggac cacagtcctc tgccagaccc 420
ctgccagacc ccagtccacc atgatccatc tgggtcacat cctcttcctg cttttgctcc 480
cagtggctgc agctcagacg actccaggag agagatcatc actccctgcc ttttaccctg 540
gcacttcagg ctcttgttcc ggatgtgggt ccctctctct gccgctcctg gcaggcctcg 600
tggctgctga tgcggtggca tcgctgctca tcgtgggggc ggtgttcctg tgcgcacgcc 660
cacgccgcag ccccgcccaa gatggcaaag tctacatcaa catgccaggc aggggctga 719
<210> 17
<211> 426
<212> DNA
<213> Artificial Sequence
<400> 17
tttttggtga tcatcgtgat tctaagcgca ctgttccttg gcacccttgc ctgcttctgt 60
gtgtggagga gaaagaggaa ggagaagcag tcagagacca gtcccaagga atttttgaca 120
atttacgaag atgtcaagga tctgaaaacc aggagaaatc acgagcagga gcagactttt 180
cctggagggg ggagcaccat ctactctatg atccagtccc agtcttctgc tcccacgtca 240
caagaacctg catatacatt atattcatta attcagcctt ccaggaagtc tggatccagg 300
aagaggaacc acagcccttc cttcaatagc actatctatg aagtgattgg aaagagtcaa 360
cctaaagccc agaaccctgc tcgattgagc cgcaaagagc tggagaactt tgatgtttat 420
tcctag 426
<210> 18
<211> 126
<212> DNA
<213> Artificial Sequence
<400> 18
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
tcctga 126
<210> 19
<211> 126
<212> DNA
<213> Artificial Sequence
<400> 19
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaactg 126
<210> 20
<211> 336
<212> DNA
<213> Artificial Sequence
<400> 20
agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc 60
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
tacgacgccc ttcacatgca ggccctgccc cctcgc 336
<210> 21
<211> 45
<212> DNA
<213> Artificial Sequence
<400> 21
ggcggagggg gttcaggtgg aggaggctct ggcggtggcg gaagc 45
<210> 22
<211> 12
<212> DNA
<213> Artificial Sequence
<400> 22
tacaggcacc ag 12
<210> 23
<211> 33
<212> DNA
<213> Artificial Sequence
<400> 23
cttatggaca atgcctactt ctgtgaggca gat 33
<210> 24
<211> 1989
<212> DNA
<213> Artificial Sequence
<400> 24
gccttaccag tgaccgcctt gctcctgccg ctggccttgc tgctccacgc cgccaggccg 60
caagtgcagc tggtgcagag cggcgccgag gtgaagaagc ccggcagcag cgtgaaggtg 120
agctgcaagg acagcggcgg caccttcagc agctacgcca tcagctgggt gagacaagcc 180
cccggccaag gcctggagtg gatgggcggc atcatcccca tcttcggcac caccaactac 240
gctcagcagt tccaaggcag agtgaccatc accgccgacg agagcacaag caccgcctac 300
atggagctga gcagcctgag aagcgaggac accgctgttt actactgcgc ccgggaggcg 360
gttgcggccg attggctcga tccctggggg caaggcaccc tggttaccgt tagcagcggt 420
ggaggcggca gcggcggtgg aggctcgggt ggtgggggat ctgagatcgt gctgacacag 480
tcgcccggca ccctaagcct gtcgcccggc gaaagagcca ccctgagctg cagagcttct 540
cagagcgtga gcagcagcta cctggcctgg tatcagcaga agcccggcca agcccctaga 600
ctgctgatct acggcgctag cagcagagcc accggcatcc ccgacagatt cagcggcagc 660
ggcagcggca ccgacttcac cctgaccatc agcagactgg agcccgagga cttcgcggtg 720
tactactgtc agcaatacgg cagcagcaga ttcaccttcg gccccggcac caaggtggac 780
atcaagatgg ggtggattcg tggtcggagg tctcgacaca gctgggagat gagtgaattt 840
cataattata acttggatct gaagaagagt gatttttcaa cacgatggca aaagcaaaga 900
tgtccagtag tcaaaagcaa atgtagagaa aatgcatctc catttttttt ctgctgcttc 960
atcgctgtag ccatgggaat ccgtttcatt attatggtag caatatggag tgctgtattc 1020
ctaaactcat tattcaacca agaagttcaa attcccttga ccgaaagtta ctgtggccca 1080
tgtcctaaaa actggatatg ttacaaaaat aactgctacc aattttttga tgagagtaaa 1140
aactggtatg agagccaggc ttcttgtatg tctcaaaatg ccagccttct gaaagtatac 1200
agcaaagagg accaggattt acttaaactg gtgaagtcat atcattggat gggactagta 1260
cacattccaa caaatggatc ttggcagtgg gaagatggct ccattctctc acccaaccta 1320
ctaacaataa ttgaaatgca gaagggagac tgtgcactct atgcctcgag ctttaaaggc 1380
tatatagaaa actgttcaac tccaaataca tacatctgca tgcaaaggac tgtgtaaaaa 1440
cggggcagaa agaaactcct gtatatattc aaacaaccat ttatgagacc agtacaaact 1500
actcaagagg aagatggctg tagctgccga tttccagaag aagaagaagg aggatgtgaa 1560
ctgagagtga agttcagcag gagcgcagac gcccccgcgt acaagcaggg ccagaaccag 1620
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 1680
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 1740
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 1800
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 1860
acctacgacg cccttcacat gcaggccctg ccccctcgct acaggcacca gggcggaggg 1920
ggttcaggtg gaggaggctc tggcggtggc ggaagcctta tggacaatgc ctacttctgt 1980
gaggcagat 1989
Claims (10)
1.一种携带STAT结合基序的嵌合抗原受体分子,其特征在于,所述嵌合抗原受体分子包括:从N-末端到C-末端依次为
(1)识别靶抗原的抗体单链可变区;
(2)跨膜结构域;
(3)共刺激结构域;
(4)信号转导结构域;
(5)STAT结合基序。
2.如权利要求1所述的携带STAT结合基序的嵌合抗原受体分子,其特征在于,所述STAT结合基序为至少一个或多个至少重复一次的Stat3结合基序和/或Stat5结合基序。
3.如权利要求2所述的携带STAT结合基序的嵌合抗原受体分子,其特征在于,相邻所述结合基序之间通过(G4S)3连接。
4.如权利要求1所述的携带STAT结合基序的嵌合抗原受体分子,其特征在于,所述抗原选自如下:CD19、CD20、CD22、CD33、CD123、CEA、GPC3和GD2。
5.如权利要求1所述的携带STAT结合基序的嵌合抗原受体分子,其特征在于,所述共刺激结构域选自CD28、4-1BB、CD137和OX40。
6.如权利要求1所述的携带STAT结合基序的嵌合抗原受体分子,其特征在于,所述信号转导结构域为CD3ζ。
7.如权利要求1所述的携带STAT结合基序的嵌合抗原受体分子,其特征在于,所述嵌合抗原受体分子为CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5,其嵌合抗原受体分子的氨基酸序列如SEQ ID NO:12所示。
8.如权利要求7所述的携带STAT结合基序的嵌合抗原受体分子,其特征在于,所述嵌合抗原受体分子为CD19ScFV-NKG2D-CD137-CD3ζ-Stat3(G4S)3-Stat5,与所述嵌合抗原受体分子的每个肽片段中具有95%同源性的蛋白质。
9.编码权利要求1所述的携带STAT结合基序的嵌合抗原受体分子的核酸分子。
10.表达权利要求1所述的嵌合抗原受体分子的NK细胞。
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CN114106203A (zh) * | 2021-11-26 | 2022-03-01 | 杭州乾合细胞生物科技有限公司 | 一种含有靶向Her-2 CAR序列的核酸构建体及其应用 |
CN114149510A (zh) * | 2021-10-29 | 2022-03-08 | 上海鑫湾生物科技有限公司 | 一种条件控制的可剪接嵌合抗原受体分子及其应用 |
CN115947869A (zh) * | 2022-11-28 | 2023-04-11 | 广州佰芮慷生物科技有限公司 | 一种靶向人巨细胞病毒的嵌合抗原受体、car-nk细胞及用途 |
CN116656614A (zh) * | 2022-02-17 | 2023-08-29 | 杭州乾合细胞生物科技有限公司 | 一种靶向Her-2的CAR-NK细胞及其应用 |
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CN114149510B (zh) * | 2021-10-29 | 2024-01-30 | 上海鑫湾生物科技有限公司 | 一种条件控制的可剪接嵌合抗原受体分子及其应用 |
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CN115947869A (zh) * | 2022-11-28 | 2023-04-11 | 广州佰芮慷生物科技有限公司 | 一种靶向人巨细胞病毒的嵌合抗原受体、car-nk细胞及用途 |
CN115947869B (zh) * | 2022-11-28 | 2023-12-12 | 广州佰芮慷生物科技有限公司 | 一种靶向人巨细胞病毒的嵌合抗原受体、car-nk细胞及用途 |
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