CN112088164A - 表达膜结合IL-10的遗传重编程的Treg - Google Patents
表达膜结合IL-10的遗传重编程的Treg Download PDFInfo
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Abstract
提供了核酸分子,其包含编码任选地通过柔性铰链连接至跨膜‑胞内区段的同型二聚体IL‑10的核苷酸序列,以及包含和表达该核酸分子的哺乳动物调节性T细胞(Treg)及其用途。
Description
发明领域
本发明通常涉及表达膜结合IL10的遗传重编程的调节性T细胞以及它们在增加全身性免疫抑制和治疗表现为免疫***过度活性的疾病中的用途。
发明背景
利用CD4调节性T细胞(Treg)抑制局部炎症并恢复免疫平衡在治疗多种不同病理学情况中具有广阔的前景,包括自身免疫疾病、炎性肠疾病、过敏、动脉粥样硬化、移植排斥,移植物抗宿主病等。然而,天然(nTreg)或诱导(iTreg)Treg在整个人CD4 T细胞群体中均仅形成很小的部分。因此,迫切需要开发基于Treg的疗法以募集、诱导或工程化足够数量和稳定表型的自体或同种异体Treg,这对临床疗效和治疗安全性是至关重要的。
发明内容
在一个方面,本发明提供分离的核酸分子,其包含编码任选地通过柔性铰链连接至跨膜-胞内区段的同型二聚体IL-10(本文中称为mem-IL10)的核苷酸序列。
在不同的方面,本发明提供包含核酸分子的组合物,核酸分子包含编码如本文所定义的连接至跨膜-胞内区段的同型二聚体IL-10的核苷酸序列。
在进一步的方面,本发明提供包含任何一种核酸分子的病毒载体,该任何一种核酸分子包含编码如上定义的连接至跨膜-胞内区段的同型二聚体IL-10的核苷酸序列。
在另一个方面,本发明提供包含如上定义的病毒载体的组合物。
在另一个方面,本发明提供哺乳动物调节性T细胞(Treg),其包含如上定义的任何一种核酸分子或如上定义的病毒载体。
在其他方面,本发明提供制备具有稳定的Tr1表型的同种异体或自体Treg的方法,方法包括使CD4 T细胞与包含编码如上定义的同型二聚体IL-10的核苷酸序列的核酸分子或包含它的病毒载体接触,从而赋予所述CD4 T细胞稳定的Tr1表型,并因此制备具有稳定的Tr1的Treg。
在其他方面,本发明提供在有需要的受试者中增加免疫抑制的方法,包括施用哺乳动物Treg给所述受试者,该Treg在其表面表达如上定义的同型二聚体的膜结合IL-10。
在某些实施方案中,本发明提供治疗或预防受试者中疾病、病症或病况的方法,包括施用在其表面表达如上定义的同型二聚体IL-10的哺乳动物Treg给所述受试者,其中所述疾病、病症或病况表现为免疫***的过度的或其他不想要的活性,例如自身免疫疾病、过敏、哮喘以及器官和骨髓移植。
附图简要说明
图1描绘了膜锚定的同型二聚体IL-10的示意图。
图2A-2D显示对T细胞中memIL-10表达及其在IL-10受体(IL-10R)和CD49b上的影响的分析。用10μg编码人或小鼠memIL-10的体外转录的mRNA分别对人Jurkat或衍生自原代的、外周血淋巴细胞的CD4 T细胞(A、B)和小鼠B3Z或NOD脾CD4 T细胞(C、D)进行电穿孔。转染后24小时(A-C)或48小时(D,左和右),利用流式细胞术分析细胞。利用对相应的人或小鼠蛋白特异的单克隆抗体分别分析人或小鼠memIL-10和IL-10R以及人CD49b。
图3A-D描绘了结合其细胞表面受体的天然IL-10同型二聚体(A)和IL-10的三种膜锚定的衍生物(mem-IL10)的示意图:(B)具有短接头的mem-IL10;(C)具有长接头的mem-IL10;和(D)连接至IL-10Rβ的mem-IL10(IL-10Rβ融合)。
图4显示mRNA电穿孔后24小时,Jurkat细胞中的三种memIL-10衍生物的细胞表面表达。用10μg的每种指定的mRNA对人Jurkat CD4 T细胞进行电穿孔(sL和lL分别代表短接头和长接头)。利用流式细胞术分析细胞的IL-10表面表达二十四小时。
图5A-C显示CD4 T细胞中的memIL-10表达诱导STAT3的自发磷酸化。用无关mRNA(Irr.mRNA)、编码短接头memIL-10的mRNA(sLmemIL-10)、编码长接头memIL-10的mRNA(lLmemIL-10)的mRNA或连接至IL-10Rβ链的IL-10的mRNA(memIL-10Rβ)对小鼠CD4 T细胞进行电穿孔,或使用20ng/ml的可溶的重组IL-10(sIL-10)处理小鼠CD4 T细胞。二十四小时后,将细胞进行表面IL-10(A)、表面IL-10Rα链(B)或细胞内地磷酸化STAT3(pSTAT3)(C)的流式细胞术分析。
图6A-B显示对表达memIL-10的逆转录病毒转导的小鼠CD4 T细胞的分析。对转导后48小时(A)和6天(B)的短接头memIL-10-转导(memIL-10-ransduced)的小鼠CD4 T细胞(v-memlL-10)进行表型分析。对在同一细胞培养中生长的memIL-10(+)和memlL-10(-)细胞平行地进行分析,针对LAG-3、CD49b和PD-1染色。作为阳性对照,用可溶的IL-10(sIL-10)处理非转导的细胞。模拟,使用与逆转录病毒转导的细胞相同但不暴露于病毒颗粒的规程处理的细胞。
图7显示活化的memIL-10转导的小鼠CD4 T细胞分泌IL-10。用抗TCR-CD3 mAb(2C11)刺激来自与图6中相同实验的细胞,且将他们的生长培养基进行IL-10ELISA。模拟-和GFP-转导的T细胞作为阴性对照。
图8A-C显示memIL-10转导的人CD4 T细胞的表型特征化。利用磁珠从由健康供体的血液样品制备的外周血单核细胞中分离CD4 T细胞。细胞在抗CD3和抗CD28抗体以及IL-2的存在下生长至所需数量,并用编码memIL-10或无关基因(Irr.)的重组逆转录病毒转导,或用可溶的IL-10(sIL-10)处理。细胞在IL-2的存在下生长,并在第1天(A)、第5天(B)和第18天(C)取样,用于对指定细胞表面标记的流式细胞术分析。在第18天,将非转导的Treg加入分析中,以比较细胞表面标记。在每个时间点,将表达memIL-10的细胞(Pos,实框)与来自相同培养而不表达IL-10的细胞(Neg,虚框)并排分析。
图9显示表型化memIL-10转导的人CD4 T细胞的第二实验。制备细胞并用memIL-10转导,并在4天后分析图8说明中所述的指定标记。非转导的(未经免疫的)和模拟-转导的(模拟)CD4细胞作为阴性对照。将MemIL-10阳性细胞与来自相同培养的memIL-10阴性细胞以及在50、100或300ng/ml sIL-10的存在下生长的未经免疫的CD4 T细胞进行比较。显示的是每个样品中阳性染色细胞的%。双pos,对LAG-3和CD49b染色呈阳性的细胞的%。
具体实施方式
根据本发明,已发现遗传重编程T细胞以组成型表达膜结合IL-10赋予T细胞稳定的Tr1表型。
所选Treg细胞的类型对于成功的临床实施至关重要。Tr1细胞是CD4(+)FoxP3(+/-)Treg的亚群,其在IL-10存在下慢性暴露于树突细胞上的抗原时,以TCR特异和抗原特异的方式在外周被诱导(1,2)。这些细胞的特征在于非增殖的(无活动力的)状态、高产IL-10和TGF-β但仅有最少量的IL-2并且没有IL-4或IL-17,以及以细胞间不依赖接触的方式抑制效应T细胞(Teff)的能力。Andolfi等人证明,由慢病毒转导实现的人CD4 T细胞中IL-10的强制表达足以以自分泌方式赋予这些细胞稳定的Tr1表型(3)。该研究还显示,将这些细胞暴露于IL-2可暂时逆转这些IL-10诱导的Tr1细胞的无活动力状态。重要的是,已识别出两种细胞表面标记CD49b和LAG-3,其在人(和小鼠)Tr1细胞上稳定且选择性地共表达,且允许他们的分离和用于细胞群纯度的流式细胞术分析(4)。
本发明提供编码IL-10的膜锚定衍生物(mem-IL10)的基因。天然IL-10为同型二聚体(5,6),且本文中发现,给其膜锚定形式赋予功能性同型二聚体构型提供了IL-10驱动的安全锁定,其保证Tr1表型的持久保存,同时在无抗原刺激时避免IL-10分泌。从安全角度考虑,由于IL-10不信号传导T细胞增殖,IL-10信号传导途径的自发激活与不受控制的细胞生长风险不相关。
在本发明中,通过修饰Treg以表达膜IL-10,我们首次实现了用于施加免疫抑制的抗炎效果。此外,由于IL-10不诱导T细胞增殖,可通过稳定的病毒转导来组成型表达IL-10,而没有诱导自发细胞增殖和细胞转化的风险。
在一个方面,本发明提供分离的核酸分子,其包含编码任选地通过柔性铰链连接至跨膜-胞内区段的同型二聚体IL-10(本文中称为mem-IL10)的核苷酸序列。
在某些实施方案中,分离的核酸分子不包含编码除mem-IL-10之外的额外的不同蛋白的核苷酸序列,但可包含额外的控制元件,例如启动子和终止子。
在某些实施方案中,同型二聚体IL-10包含以单链构型连接使得第一IL-10单体的C-末端经由第一柔性接头连接至第二IL-10单体的N-末端的第一IL-10单体和第二IL-10单体,。
柔性肽接头是本领域中公知的。由研究人员设计的经验性接头通常根据他们的结构分为三类:柔性接头、刚性接头和体内可裂解的接头,如例如(7-9)中定义的,其每一个都通过引用并入本文,如同在本文中完全公开。
如上所述,第一接头为柔性接头,且其结构选自(7-9)中公开的接头的任何一种。原则上,为提供柔性,接头通常由小的、非极性(例如Gly)或极性(例如Ser或Thr)氨基酸组成,例如交替的Gly和Ser残基的基础序列。可通过包含带电荷的残基增强接头和相关同型二聚体IL-10的溶解性;例如两个带正电荷的残基(Lys)和一个带负电荷的残基(Glu)。接头可在2至31个氨基酸之间变化,针对每种情况进行优化以使接头不对长度例如介于12至18个残基的所连接配偶体的构型或相互作用施加任何限制。
在某些实施方案中,第一柔性接头具有氨基酸序列GSTSGSGKPGSGEGSTKG(SEQ IDNO:1)。在某些实施方案中,第一柔性接头由例如SEQ ID NO:2中所示的核苷酸序列编码。
在某些实施方案中,柔性铰链包含多肽,其选自以下多肽或其变体:
·CD8α的铰链区,(例如,如SEQ ID NO:3所示;例如,由SEQ ID NO:4所示的核苷酸序列编码)
·IgG重链的铰链区(例如,如SEQ ID NO:5所示;例如,由SEQ ID NO:6所示的核苷酸序列编码)
·IgD重链的铰链区(例如,如SEQ ID NO:7所示;例如,由SEQ ID NO:8所示的核苷酸序列编码)。
·IL-10Rβ链的胞外区段(如SEQ ID NO:9所示;例如,由SEQ ID NO:10所示的核苷酸序列编码);和
·第二柔性接头,其包含多达28个氨基酸的氨基酸序列,氨基酸序列包含至少一个Gly4Ser(Gly3Ser)2序列,例如,包含一个Gly4Ser(Gly3Ser)序列(SEQ ID NO:11;例如,由SEQ ID NO:12所示的核苷酸序列编码),或两个Gly4Ser(Gly3Ser)序列,具有在其间***的一个或两个Ser残基。
在某些实施方案中,第二柔性接头包含21个氨基酸的序列,其包含氨基酸序列Gly4Ser(Gly3Ser)2(本文中称为“短接头”;SEQ ID NO:13;例如,由SEQ ID NO:14所示的核苷酸序列编码)。
在某些实施方案中,第二柔性接头由28个氨基酸的间隔物和SEQ ID NO:16的连接肽组成,间隔物包含氨基酸序列Gly4Ser(Gly3Ser)2Ser2(Gly3Ser)3(本文中称为“长接头”;SEQ ID NO:15;例如,由SEQ ID NO:22所示的核苷酸序列编码)。
在某些实施方案中,以上实施方案任一项的第二柔性接头进一步包含序列为SSQPTIPI的8氨基酸桥(本文中称为“连接肽”;SEQ ID NO:17;例如,由SEQ ID NO:18所示的核苷酸序列编码),其衍生自HLA-A2的连接肽的膜近端部分。
在某些实施方案中,mem-IL10的跨膜-胞内区段衍生自人I类MHC分子的重链,人I类MHC分子选自HLA-A、HLA-B或HLA-C分子,优选HLA-A2(如SEQ ID NO:19所示;例如,由SEQID NO:20所示的核苷酸序列编码);人CD28(如SEQ ID NO:21所示;例如,由SEQ ID NO:22所示的核苷酸序列编码);或人IL-10Rβ链(如SEQ ID NO:23所示;例如,由SEQ ID NO:24所示的核苷酸序列编码)。
在某些实施方案中,完整mem-IL10的氨基酸序列包含经由短的第二柔性接头和连接肽连接至HLA-A2的跨膜-胞内区段的同型二聚体IL-10或基本上由其组成,如SEQ ID NO:25所示;例如,由SEQ ID NO:26所示的核苷酸序列编码。
在某些实施方案中,完整mem-IL10的氨基酸序列包含经由长的第二柔性接头和连接肽连接至HLA-A2的跨膜-胞内片段的同型二聚体IL-10或基本上由其组成,如SEQ ID NO:27所示;例如,由SEQ ID NO:28所示的核苷酸序列编码)。
在某些实施方案中,mem-IL-10经由第二柔性接头与IL-10Rβ胞外域(例如,如SEQID NO:9所示)融合,且任选地进一步与IL-10Rβ跨膜域和胞质域(例如,如SEQ ID NO:23所示)融合。
在某些实施方案中,mem-IL-10经由短接头与基本上完整的IL-10Rβ链的N-末端融合(如SEQ ID NO:29所示;例如,由SEQ ID NO:23所示的核苷酸序列编码)。
组成由本发明的核酸分子编码的本发明的mem-IL10的多肽不限于本文中通过特定氨基酸序列定义的那些,而是还可为这些寡肽的变体或具有与以上公开的那些实质上同一的氨基酸序列。如本文所用,“实质上同一”的氨基酸序列指与参考序列相差一个或多个保守或非保守的氨基酸取代、缺失或***的序列,特别是当这样一个取代发生在非分子的活性位点的位点时,并且条件是该多肽基本上保留其功能性质。例如,一个保守的氨基酸取代是用另一个相同类别的氨基酸取代一个氨基酸被,例如,一个疏水性氨基酸被另一个疏水性氨基酸取代,一个极性氨基酸被另一个极性氨基酸取代,一个碱性氨基酸被另一个碱性氨基酸取代和一个酸性氨基酸被另一个酸性氨基酸取代。可从肽中缺失一个或多个氨基酸,从而获得其片段而不显著改变其生物活性。
在某些实施方案中,如上所述的完整膜结合IL-10或膜结合IL-10的各亚区域的每个的氨基酸序列(即同型二聚体IL-10,其中第一和第二IL-10单体经由第一柔性接头以单链构型连接;第一柔性接头本身,柔性铰链;和跨膜-胞内区段)与SEQ ID NO:1、3、5、7、9、11、13、15、17、19、21、23、25、27或29的同一性为至少70%、至少71%、至少72%、至少73%、至少74%、至少75%、至少76%、至少77%、至少78%、至少79%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%或至少98%。
在某些实施方案中,如上所述的完整膜结合IL-10或膜结合IL-10的各亚区域的每个的氨基酸序列(即同型二聚体IL-10,其中第一和第二IL-10单体经由第一柔性接头以单链构型连接;第一柔性接头本身,柔性铰链;和跨膜-胞内区段,以及整个构建体)与SEQ IDNO:1、3、5、7、9、11、13、15、17、19、21、23、25、27或29的同一性为70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98或99%。
在某些实施方案中,分离的核酸分子包含编码如上所述的完整膜结合IL-10或膜结合IL-10的各亚区域中的每个(即同型二聚体IL-10,其中第一和第二IL-10单体经由第一柔性接头以单链构型连接;第一柔性接头本身,柔性铰链;和跨膜-胞内区段,以及整个构建体)的多核苷酸序列与SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28或30之一的同一性为至少70%、至少71%、至少72%、至少73%、至少74%、至少75%、至少76%、至少77%、至少78%、至少79%、至少80%、至少81%、至少82%、至少83%、至少84%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%或至少98%。
在某些实施方案中,分离的核酸分子包含编码如上所述的完整膜结合IL-10或膜结合IL-10的各亚区域中的每个(即同型二聚体IL-10,其中第一和第二IL-10单体经由第一柔性接头以单链构型连接;第一柔性接头本身,柔性铰链;和跨膜-胞内区段,以及整个构建体)的多核苷酸序列与SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28或30之一的同一性为70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。
在某些实施方案中,分离的核酸分子包含如SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28或30之一所示的编码如上所述的完整膜结合IL-10或膜结合IL-10的各亚区域中的每个(即同型二聚体IL-10,其中第一和第二IL-10单体经由第一柔性接头以单链构型连接;柔性接头本身,柔性铰链;和跨膜-胞内区段,以及整个构建体)的多核苷酸序列。
在不同的方面,本发明提供包含核酸分子的组合物,核酸分子包含如以上实施方案任一项所定义的编码连接至跨膜-胞内区段的同型二聚体IL-10的核苷酸序列。
在某些实施方案中,核酸分子是组合物中唯一的核酸分子,即组合物不包含额外的核酸分子,额外的核酸分子包含编码额外的不同蛋白的核苷酸序列。
为了使用本领域中任何公知的方法赋予稳定的Tr1表型的目的,将本发明的核酸分子递送到T细胞中:例如,Matuskova和Durinikova(10)中教导,有两种***用于将转基因递送至细胞-病毒的和非病毒的。非病毒的方法的代表为聚合物纳米颗粒、脂质、磷酸钙、电穿孔/核转染或DNA包被的微粒的生物弹道(biolistic)递送。
取决于DNA是否被整合到宿主细胞的染色质中,根据本发明可使用两种主要类型的载体。逆转录病毒载体,如衍生自γ逆转录病毒或慢病毒的那些,以整合的原病毒形式固存于细胞核中,并随细胞***而增殖。其他类型的载体(例如,衍生自疱疹病毒或腺病毒的那些)以游离形式保留在细胞中。
因此,在进一步的方面,本发明提供包含任何核酸分子的病毒载体,该核酸分子包含编码如上定义的连接至跨膜-胞内区段的同型二聚体IL-10的核苷酸序列。
在某些实施方案中,病毒载体选自衍生自病毒的修饰的病毒,所述病毒选自由逆转录病毒、慢病毒、γ病毒(gammavirus)、腺病毒、腺伴随病毒、痘病毒、α病毒(alphavirus)和疱疹病毒组成的组。
在具体实施方案中,载体为逆转录病毒,如修饰的γ病毒、慢病毒、鼠干细胞病毒、莫洛尼鼠白血病病毒(moloney murine leukemia virus)、牛白血病病毒、劳斯肉瘤病毒和泡沫病毒属。实际上,在(11)中所列的在实体瘤中评估CAR-T细胞的52个临床试验中,24个使用逆转录病毒载体,且9个使用慢病毒载体。还应注意,两种FDA批准用于治疗B细胞恶性肿瘤的CAR产品为KymriahTM(慢病毒载体)和YescartaTM(γ逆转录病毒载体)。因此,本发明的病毒载体的良好候选者可为逆转录病毒载体、慢病毒载体和γ逆转录病毒载体。例如,逆转录病毒可衍生自莫洛尼鼠白血病病毒或鼠干细胞病毒序列(γ逆转录病毒载体)。
在某些实施方案中,核酸分子是由核苷酸序列编码的唯一的多肽,即病毒载体的核酸分子不编码额外的不同蛋白,但可包含额外的控制元件,例如启动子和终止子。
在另一个方面,本发明提供包含如上定义的病毒载体的组合物。
在另一个方面,本发明提供哺乳动物调节性T细胞(Treg),其包含任何一种如上定义的核酸分子或如上定义的病毒载体。
在某些实施方案中,哺乳动物Treg在其表面表达任选地经由柔性铰链连接至跨膜-胞内区段的同型二聚体IL-10。
在某些实施方案中,哺乳动物Treg为人Treg。
在某些实施方案中,哺乳动物Treg具有稳定的Tr1表型(即,不丧失其调节活性(12),显示细胞表面标记CD49b和LAG-3)。
在其他方面,本发明提供制备具有稳定的Tr1表型的同种异体或自体Treg的方法,方法包括使CD4 T细胞与包含编码如上定义的同型二聚体IL-10的核苷酸序列的核酸分子或包含它的病毒载体接触,从而赋予所述CD4 T细胞稳定的Tr1表型,并从而制备具有稳定的Tr1的Treg。
制备CD4 T细胞的方法是本领域中公知的,且可例如利用公开于以下实施例部分中的方法进行。
用于创制重组逆转录病毒和慢病毒载体并将其用于转导T细胞的方法也是本领域中公知的,且通常使用包含包装细胞、质粒和转染试剂的商业试剂盒进行,商业试剂盒由许多公司提供,包括Cell和许多其他公司。因此,方法用由商业试剂盒提供的指南进行。
简言之,根据Addgene的网站上的γ逆转录病毒指南教导的非限制性示例,需要以下组分:(a)编码目标转基因的γ逆转录病毒转移质粒:转基因序列侧翼为长末端重复(LTR)序列,其促进转移质粒序列整合到宿主基因组中。通常这是其间的序列,并包括在病毒转导时整合到宿主基因组中的LTR;(b)包装基因(病毒Gag-Pol):Gag为前体结构蛋白,且Pol为聚合酶;和(c)包膜基因(可被假型化以改变感染性)。
作为非限制性示例,上述三个组分(包膜、包装和转移)由三种类型的质粒提供,其被共转染到293T包装细胞系中。该***提供最大的灵活性以使用不同的包膜假型化γ逆转录病毒以修饰向性。简言之,不同的包膜质粒可指导产生具有各种向性的病毒。用于重组逆转录病毒原种的制备和人CD4T细胞的逆转录病毒转导的方法的详细非限制性实例发现于以下实施例部分中。
在其他方面,本发明提供在有需要的受试者中增加免疫抑制的方法,包括施用哺乳动物Treg给所述受试者,哺乳动物Treg在其表面表达如上定义的同型二聚体的膜结合IL-10。
在某些实施方案中,因为由表现为免疫***的过度或不想要的活性的疾病、病症或病况引起的症状,受试者需要增强免疫抑制。
因此,在某些实施方案中,本发明提供了治疗或预防受试者中疾病、病症或病况的方法,包括施用哺乳动物Treg给所述受试者,哺乳动物Treg在其表面表达如上定义的同型二聚体IL-10,其中所述疾病、病症或病况表现为免疫***的过度或其他不想要的活性,如自身免疫疾病、过敏、哮喘以及器官和骨髓移植。
在另一个方面,本发明涉及在其表面表达如上定义的同型二聚体IL-10的哺乳动物Treg,其用于在有需要的受试者中增加免疫抑制。
在某些实施方案中,在其表面表达如上定义的同型二聚体IL-10的哺乳动物Treg用于治疗或预防表现为免疫***的过度或其他不想要的活性的疾病、病症或病况。
在某些实施方案中,哺乳动物Treg用于治疗人受试者,且哺乳动物Treg为人Treg。
被定义为自身免疫疾病的特定疾病是本领域中公知的;例如,如TheEncyclopedia of Autoimmune Diseases,Dana K.Cassell,Noel R.Rose,InfobasePublishing,2014年5月14日中所公开的,其全部内容通过引用并入本文,如同在本文中完全公开的。
在某些实施方案中,自身免疫疾病选自1型糖尿病;类风湿性关节炎;银屑病;银屑病关节炎;多发性硬化;***性红斑狼疮;炎性肠疾病,如克罗恩氏病和溃疡性结肠炎;阿狄森氏病(Addison’s diseases);格雷夫斯病(Graves’diseas);干燥综合征;桥本甲状腺炎;重症肌无力;血管炎;恶性贫血;乳糜泻和动脉粥样硬化。
在一些实施方案中,受试者为人,且所述哺乳动物Treg为人的。
在一些实施方案中,Treg为同种异体Treg。
本发明的稳定的Tr1细胞可用于增强免疫抑制和治疗表现为免疫***的过度或其他不想要的活性的疾病、病症或病况,而无需进一步的遗传操作,这从临床前研究可明显看出,所述临床前研究显示:纯化的CD4+CD25+Treg的过继转移可抑制或预防一系列自身免疫病模型内的疾病。这些包括,但不限于***性红斑狼疮、炎性肠疾病、自身免疫性脑脊髓炎、1型糖尿病、自身免疫性肝炎和胶原蛋白诱发的关节炎。此外,这些细胞的过继转移可保护免受同种异体造血干细胞移植诱发的同种异体移植排斥和移植物抗宿主病(13)。此外,数目不断增长的临床试验显示了这种方法的前景,这些临床试验评估离体扩增的、非抗原特异的Treg的过继转移在若干病况和疾病的免疫疗法中的安全性和有效性,病况和疾病包括移植物抗宿主病(GvHD)、同种异体移植排斥和1型糖尿病(参见综述(13))。
鉴于累积的证据,这些研究中观察到的有益的临床反应可被改善,所述证据证明经其内源TCR的Treg与抗原的参与增强免疫抑制(14-16)。
本发明的发明人设想了一种方法,其中操纵Tr1细胞以表达靶向组织的蛋白。例如,视黄酸(RA)诱导T细胞中肠道归巢受体(gut-homing receptor)整联蛋白α4β7和趋化因子受体CCR9的表达,并能在离体预温育后在体内发挥这种功能(17,18)。RA还是通过Treg的TGF-β介导的抑制的关键调节物,并促进Treg分化(19)。还已显示RA增强未经处理的CD4Teff细胞向诱导的Treg的转化(20,21),并在炎性环境中在存在IL-6时维持Treg稳定性和功能(18)。全反式RA的预温育成为对重编程的Tr1细胞配备肠道归巢能力的可行且简单的方法。因此,在施用给受试者前,将在如上定义的治疗疾病的方法中使用的Treg与视黄酸接触,以给重编程的Tr1细胞配备肠道归巢能力,并在炎性环境中在存在IL-6时维持Treg稳定性和功能。
有吸引力的替代方案利用已良好建立的能力以使用嵌合抗原受体或CAR将大量T细胞遗传重定向为针对所选细胞表面抗原(22)。
原则上,CAR也可用于重编程Treg。实际上,多个实验室最近已描述在不同实验环境中小鼠和人的功能性CAR-Treg的生成((23-29),并参见综述(13,16,30,31))。还报道了通过外源TCR基因的转移重定向Treg(32-34)。
本领域中最近的工作(28)已采用慢病毒转导以生成HLA-A2特异的人CAR-Treg,作为预防由HLA-A2+效应T细胞导致的免疫缺陷小鼠中的异种GvHD的手段。实际上,在体内,这些CAR-Treg在抑制GvHD上显著优于相同数量的具有无关特异性的CAR-Treg。在接受者小鼠的血液中可检测到的HLA-A2 CAR-Treg的数量在施用后一周达到峰值,在接下来一周保持稳定,然后在第三周结束时降至接近零。
最近已报道CAR-Treg的预期临床用途的另一个示例,其中已将逆转录病毒转导的人Treg重定向至凝血因子VIII(FVIII)处,以试图抑制血友病A替代疗法中的抗体应答(29)。通过使用异种的免疫活性小鼠模型,免疫后8周,抗体应答的强抑制是明显的,尽管在转移后2周,引入的CAR-Treg已检测不到。
因此,在其表面表达如本文定义的膜结合的同型二聚体IL-10并具有稳定的Tr1表型的哺乳动物Treg是增加免疫抑制和治疗表现为免疫***的过度或其他不想要的活性的疾病、病症或病况的有效试剂;且是可使用本领域中公知的增加有效性的技术容易地操纵的试剂。此外,采用离体扩增的、非抗原特异的以及重定向的抗原特异的Treg的过继转移的方法是免疫疗法领域中公知的。
定义
术语“Tr1细胞”在本文中与术语“iTreg”或“1型细胞”互换使用,且指具有以下特征的CD4 T细胞:两种细胞表面标记CD49b和LAG-3的表达,FoxP3低表达或不表达,非增殖的(无活动力的)状态,高产IL-10和TGF-β,但仅产最少量的IL-2并且不产IL-4或IL-17,和以细胞间不依赖接触的方式抑制效应T细胞(Teff)的能力。
如本文所用,术语“治疗”指获得期望的生理效应的手段。就部分或完全治愈疾病和/或归因于疾病的症状而言,效应可以是治疗性的。该术语指抑制疾病,即阻止其发展;或改善疾病,即导致疾病的消退。
如本文所用,术语“受试者”或“个体”或“动物”或“患者”或“哺乳动物”指希望对其进行诊断、预后或疗法的任何受试者,特别是哺乳动物受试者,例如,人。
可使用一种或多种生理学上可接受的载体或赋形剂以常规方式配制根据本发明使用的药物组合物。就与组合物的其他成分相容且不对其接受者有害的意义而言,一种或多种载体必须是“可接受的”。
列出载体、施用方式、剂型等的以下示例,作为由其选择用于本发明的载体、施用方式、剂型等的已知可能性。然而,本领域的普通技术人员将理解,应当首先测试所选的任何给定的制剂和施用方式,以确定其获得期望的结果。
施用方法包括但不限于胃肠道外的,例如,静脉内、腹膜内、肌肉内、皮下、经粘膜(例如,经口、鼻内、经颊、经***、经直肠、眼内)、鞘内、局部的和皮内的途径。施用可以是全身的或局部的。在某些实施方案中,药物组合物适于口服施用。
术语“载体”指活性剂与其一起施用的稀释剂、佐剂、赋形剂或媒介物。
如本文所用,术语“变体”指分别在一个或多个碱基对、密码子、内含子、外显子或氨基酸残基处修饰但仍保留具有天然存在序列的多肽的生物活性的多核苷酸或多肽。
除非另有所指,否则表达同一性或相似性或任何其他参数的所有数值在所有情况下均理解为由术语“约”修饰。因此,除非相反指明,否则在本说明书和所附权利要求书中提出的数值参数为近似值,取决于本发明寻求获得的期望性质,其最多可变化正或负10%。
现在将通过下列非限制性实施例阐明本发明。
实施例
材料和方法
人CD4 T细胞的分离
使用标准的Ficoll-Paque(Sigma)分离程序,从全血样品或血液成分提取法(pheresis)产品中制备外周血单核细胞(PBMC)。分离后(或细胞解冻后)二十四小时,在可溶的抗CD28和重组人IL-2的存在下,通过板结合的(plate-bound)抗CD3 Ab(OKT3)激活PBMC 72小时。然后使用利用磁珠(BD IMagTM)的阳性选择分离CD4 T细胞,然后在实验性使用前置于完全培养基中静置24小时。
重组逆转录病毒原液的制备
经由BamHI-EcoRI限制酶切位点,将memIL-10基因克隆到常用的MSGV1逆转录病毒载体中。根据制造商说明书使用转染试剂如Lipofectamine(Thermo Fisher)或Fugene将所得质粒与携带gag/pol的质粒和携带env的质粒一同共转染3×106HEK293T细胞,该细胞置于无抗生素的OptiMEMTM培养基(改良的伊戈尔氏最小必需培养基(modification of Eagle's Minimum Essential Media),用HEPES和碳酸氢钠缓冲,并补充有次黄嘌呤、胸苷、丙酮酸钠、L-谷氨酰胺、微量元素和生长因子)中的10cm多聚-D赖氨酸包被的板中。次日,将细胞移至含有抗生素的完全培养基中,在接下来的一天收集上清液,并将其等分冷冻或直接用于逆转录病毒转导。
人CD4 T细胞的逆转录病毒转导
在无包被的6孔组织培养板中进行转导。用基因转导增强物(Retro )将孔包被过夜。Retro是重组人纤连蛋白片段(也称为rFN-CH-296)的63kD片段,其增强慢病毒介导的和逆转录病毒介导的基因转导效率。移出Retro并洗涤孔,用含2.5%无菌牛血清白蛋白(BSA)的磷酸盐缓冲盐水(PBS)封闭,并再次洗涤。稀释病毒上清液于含有转染试剂如聚凝胶的达尔伯克改良伊格尔氏培养基(Dulbecco's Modified Eagle's medium(DMEM))中,并以4ml/孔将其移至Retro包被的孔中。在32℃下将板以2000xg离心2小时,吸出上清液,并在每孔中加入在50/50AIM-V/RPMI培养基+300IU/ml重组IL-2中的5x105细胞/ml的4ml CD4 T细胞。将板以1000xg离心15分钟,并在37℃下孵育过夜。然后将CD4 T细胞移至新的包被的6孔组织培养板,并在每孔中加入1ml新鲜的50/50培养基+300IU/ml rIL-2。在随后的日子里,根据需要更换培养基并分板细胞。
实施例1:两个IL-10单体通过柔性接头串联在一起并经由短的铰链区连接至跨膜-胞内区段。
在此处使用的特定构建体中,两个IL-10单体通过序列为GSTSGSGKPGSGEGSTKG的柔性接头串联在一起,以创制同型二聚体,然后通过柔性铰链区将其连接至衍生自HLA-A2重链的跨膜-胞内区段,该柔性铰链区含有包括柔性接头的21氨基酸的间隔物。
Gly4Ser(Gly3Ser)2和序列为SSQPTIPI的另外的8氨基酸桥衍生自HLA-A2的连接肽的膜-近端部分(图1)。然后证实了人和小鼠CD4 T细胞上的memIL-10和IL-10R的表面表达(图2)。
(A)中可观察到CD49b整联蛋白的升高,且IL-10受体(IL-10R)的上调与重组IL-10(rIL-10,(B))诱导的类似。转染后48小时,小鼠memIL-10被清楚地表达(D,左),且如预期的,memlL-10阻断我们使用的抗小鼠IL-10R mAb的结合,这表明了顺式结合(35)。
实施例2:两个IL-10单体通过柔性接头串联在一起并经由长的铰链区或IL-10Rβ链连接至跨膜-胞内区段。
我们的起始memIL-10构建体(人的和小鼠的)被引入包含21氨基酸的柔性接头的铰链(除了8个氨基酸长的刚性间隔物之外,其现在在本文中称为SmemIL-10(S表示短接头,见下文)。
为了试图优化我们的memIL-10,我们工程化并克隆了该膜细胞因子的两个新版本:在首先克隆的一个中,我们给memIL-10提供更长的接头肽(具有30个氨基酸,称为LmemIL-10,代表长),以促进与IL-10R的最佳结合(图3,左下)。为创制另一种衍生物,我们将我们的二聚体IL-10融合到IL-10Rβ链的N-末端作为新的支架,其设计为赋予其直接接近位于IL-10Rα链上的IL-10结合位点,定名为memIL-10RB(图3,右下)。实际上,图4证实了人Jurkat细胞中三种产物的表面表达。值得注意的是,预料到memIL-10RB融合蛋白的表面表达水平取决于IL-10Rα链的可用性。为评估三种不同的memIL-10构型的表达和功能,用编码三种构建体的mRNA转染小鼠CD4 T细胞,并测定其表面表达(图5A)、表面IL-10R的下调(图5B)和STAT3的自发磷酸化(图5C)。实际上,与在Jurkat细胞中获得的结果一致,包含短和长接头的构建体的表达水平远高于memILL-10Rβ,并表现优越的功能,这从表面IL-10R的更大减少和pSTAT3的更强诱导可明显看出。由于在重复实验中短接头构建体(sLmemIL-10)在诱导pSTAT3的能力上也优于长接头构建体(lLmemIL-10)(未显示),选择短接头构建体用于进一步实验。
实施例4:逆转录病毒转导的小鼠CD4 T细胞中memIL-10的表达和特征化。
为了测试逆转录病毒转导的T细胞中memIL-10的表达和功能,我们首先使用以磁珠自C57BL/6(B6)小鼠纯化的脾CD4 T细胞。作为memIL-10转导细胞的阴性对照,我们使用模拟物转导的细胞(模拟)。在这些实验中使用可溶的IL-10(sIL-10)作为阳性对照。图6显示了转染后48小时和6天,转导细胞相对于在相同培养中生长的非转导细胞和模拟物转导的细胞的流式细胞术分析结果,模拟物转导的细胞用于表达三种与Tr1相关的标记LAG-3、CD49b和PD-1。实际上在第2天就已经可观察到3种标记的明显升高,其在第6天也持续存在,这指明了预期的表型。经由TCR介导的激活,转导的T细胞分泌IL-10的能力证实了Tr1样功能性质的获得(图7)。
实施例5:评估转导的细胞对T效应细胞的抑制作用。
为了检查转导的细胞对邻近的Teff细胞发挥其抑制作用的能力,设计了共培养环境,其将允许我们随意地选择性激活仅一个T细胞群体,而不激活其他T细胞群体(显然,抗TCR/CD3抗体将激活共培养中的所有T细胞)。为此,我们将利用我们已创制的两个基因,其编码嵌合的H-2Kb-CD3ζ(Kb-CD3ζ)和H-2Kd-CD3ζ(Kd-CD3ζ)MHC-I重链。我们已显示,在Ab介导的交联后,两个基因均以与TCR交联相当的量级选择性激活T细胞。在随后的一系列功能性实验中,采用这些工具来以不同比例混合mRNA转染的Tr1和Teff细胞3-4天,并使用CFSE稀释和胞内IFN-γ染色以评估激活的Tr1细胞(相对于非激活的或RFP+非Tr1细胞)的抑制激活的Teff的增殖和效应功能的能力。
实施例6:在人疾病小鼠模型中评估IL-10转导的细胞的体内持久性和抑制功能。
为了评估同基因(syngeneic)野生型小鼠中IL-10转导的NOD或B6 CD4T细胞的体内持久性及其表型的维持,使用我们最近建立于我们的T1D实验***中的方案(36)。简言之,将10×106个细胞注射入尾静脉。在注射后1、7和14天收获脾和外周***,并利用流式细胞术识别CD4+IL-10+LAG-3+CD49b+T细胞(与未注射小鼠的背景染色水平相比)。
然后测试体内生理条件下memIL-10转导的T细胞的实际抑制功能,其采用人疾病如T1D或IBD的小鼠模型。
实施例7:逆转录病毒转导的人CD4 T细胞中memIL-10的表达和特征化。
为了评估人CD4 T细胞的逆转录病毒转导的表型结果和功能结果,我们从通过以色列Blood Services Center of Magen David Adom获自健康供体的血液样品中分离CD4T细胞。两个独立离体实验中的第一个展示于图8中。在该实验中,转导后18天将细胞保持在培养中,并在转导后1、5和18天利用流式细胞术对标记LAG-3、CD49b、PD-1、4-1BB、CD25和IL-10Rα进行表型分析。我们的结果证实,与在整个实验期间生长于相同培养皿中的memIL-10阴性细胞相比,在表达memIL-10的细胞中,与预期的Tr1表型相关的所有这些细胞表面标记均显著增加。
在不同的血液样品上进行第二个实验,且针对LAG-3、CD49b和PD-1进行的流式细胞术(图9)与第一个实验中获得的结果一致。从这两个实验可总结出,人CD4 T细胞中经由逆转录病毒转导的memIL-10的长期表达赋予这些细胞TR-1样表型。
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序列表
<110> 加维什-加利里生物应用有限公司(GAVISH-GALILEE BIO APPLICATIONS LTD.)
G·格罗斯(GROSS, Gideon)
H·温斯坦-马罗姆(WEINSTEIN-MAROM, Hadas)
A·克罗纳(KRONER, Amit)
<120> 表达的遗传重编程的Treg
<130> GAVISH-099 PCT
<150> 62/647,084
<151> 2018-03-23
<160> 30
<170> PatentIn version 3.5
<210> 1
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 1
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 2
<211> 39
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 2
ggaggtggcg gatccggagg tggctccgga ggtggctcc 39
<210> 3
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<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 Ile
35 40 45
<210> 4
<211> 138
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 4
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgatatc 138
<210> 5
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 5
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly
20
<210> 6
<211> 66
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工序列(Artificial Sequence)
<400> 6
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 60
ggggga 66
<210> 7
<211> 64
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 7
Arg Trp Pro Glu Ser Pro Lys Ala Gln Ala Ser Ser Val Pro Thr Ala
1 5 10 15
Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala
20 25 30
Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys
35 40 45
Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro
50 55 60
<210> 8
<211> 192
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 8
cgctggccag agtctccaaa ggcacaggcc tcctcagtgc ccactgcaca accccaagca 60
gagggcagcc tcgccaaggc aaccacagcc ccagccacca cccgtaacac aggaagagga 120
ggagaagaga agaagaagga gaaggagaaa gaggaacaag aagagagaga gacaaagaca 180
ccagagtgtc cg 192
<210> 9
<211> 201
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 9
Met Val Pro Pro Pro Glu Asn Val Arg Met Asn Ser Val Asn Phe Lys
1 5 10 15
Asn Ile Leu Gln Trp Glu Ser Pro Ala Phe Ala Lys Gly Asn Leu Thr
20 25 30
Phe Thr Ala Gln Tyr Leu Ser Tyr Arg Ile Phe Gln Asp Lys Cys Met
35 40 45
Asn Thr Thr Leu Thr Glu Cys Asp Phe Ser Ser Leu Ser Lys Tyr Gly
50 55 60
Asp His Thr Leu Arg Val Arg Ala Glu Phe Ala Asp Glu His Ser Asp
65 70 75 80
Trp Val Asn Ile Thr Phe Cys Pro Val Asp Asp Thr Ile Ile Gly Pro
85 90 95
Pro Gly Met Gln Val Glu Val Leu Ala Asp Ser Leu His Met Arg Phe
100 105 110
Leu Ala Pro Lys Ile Glu Asn Glu Tyr Glu Thr Trp Thr Met Lys Asn
115 120 125
Val Tyr Asn Ser Trp Thr Tyr Asn Val Gln Tyr Trp Lys Asn Gly Thr
130 135 140
Asp Glu Lys Phe Gln Ile Thr Pro Gln Tyr Asp Phe Glu Val Leu Arg
145 150 155 160
Asn Leu Glu Pro Trp Thr Thr Tyr Cys Val Gln Val Arg Gly Phe Leu
165 170 175
Pro Asp Arg Asn Lys Ala Gly Glu Trp Ser Glu Pro Val Cys Glu Gln
180 185 190
Thr Thr His Asp Glu Thr Val Pro Ser
195 200
<210> 10
<211> 603
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 10
atggtaccac ctcccgaaaa tgtcagaatg aattctgtta atttcaagaa cattctacag 60
tgggagtcac ctgcttttgc caaagggaac ctgactttca cagctcagta cctaagttat 120
aggatattcc aagataaatg catgaatact accttgacgg aatgtgattt ctcaagtctt 180
tccaagtatg gtgaccacac cttgagagtc agggctgaat ttgcagatga gcattcagac 240
tgggtaaaca tcaccttctg tcctgtggat gacaccatta ttggaccccc tggaatgcaa 300
gtagaagtac ttgctgattc tttacatatg cgtttcttag cccctaaaat tgagaatgaa 360
tacgaaactt ggactatgaa gaatgtgtat aactcatgga cttataatgt gcaatactgg 420
aaaaacggta ctgatgaaaa gtttcaaatt actccccagt atgactttga ggtcctcaga 480
aacctggagc catggacaac ttattgtgtt caagttcgag ggtttcttcc tgatcggaac 540
aaagctgggg aatggagtga gcctgtctgt gagcaaacaa cccatgacga aacggtcccc 600
tcc 603
<210> 11
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 11
Gly Gly Gly Gly Ser Gly Gly Gly Ser
1 5
<210> 12
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 12
ggaggtggcg gatccggagg tggctcc 27
<210> 13
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 13
Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10
<210> 14
<211> 39
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 14
ggaggtggcg gatccggagg tggctccgga ggtggctcc 39
<210> 15
<211> 28
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 15
Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Ser Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
20 25
<210> 16
<211> 84
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 16
ggaggtggcg gatccggagg tggctccgga ggtggctcct cgagcggagg tggcggatcc 60
ggaggtggct ccggaggtgg ctcc 84
<210> 17
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 17
Ser Ser Gln Pro Thr Ile Pro Ile
1 5
<210> 18
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 18
tcgagccagc ccaccatccc catc 24
<210> 19
<211> 57
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 19
Val Gly Ile Ile Ala Gly Leu Val Leu Phe Gly Ala Val Ile Thr Gly
1 5 10 15
Ala Val Val Ala Ala Val Met Trp Arg Arg Lys Ser Ser Asp Arg Lys
20 25 30
Gly Gly Ser Tyr Ser Gln Ala Ala Ser Ser Asp Ser Ala Gln Gly Ser
35 40 45
Asp Val Ser Leu Thr Ala Cys Lys Val
50 55
<210> 20
<211> 174
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 20
gtgggcatca ttgctggcct ggttctcttt ggagctgtga tcactggagc tgtggtcgct 60
gctgtgatgt ggaggaggaa gagctcagat agaaaaggag ggagctactc tcaggctgca 120
agcagtgaca gtgcccaggg ctctgatgtg tctctcacag cttgtaaagt gtga 174
<210> 21
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 21
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
20 25
<210> 22
<211> 81
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 22
ttctgggtgt tggtcgttgt gggtggtgtc ctggcgtgtt attcactgtt ggttactgtg 60
gcttttataa ttttctgggt g 81
<210> 23
<211> 105
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 23
Trp Met Val Ala Val Ile Leu Met Ala Ser Val Phe Met Val Cys Leu
1 5 10 15
Ala Leu Leu Gly Cys Phe Ala Leu Leu Trp Cys Val Tyr Lys Lys Thr
20 25 30
Lys Tyr Ala Phe Ser Pro Arg Asn Ser Leu Pro Gln His Leu Lys Glu
35 40 45
Phe Leu Gly His Pro His His Asn Thr Leu Leu Phe Phe Ser Phe Pro
50 55 60
Leu Ser Asp Glu Asn Asp Val Phe Asp Lys Leu Ser Val Ile Ala Glu
65 70 75 80
Asp Ser Glu Ser Gly Lys Gln Asn Pro Gly Asp Ser Cys Ser Leu Gly
85 90 95
Thr Pro Pro Gly Gln Gly Pro Gln Ser
100 105
<210> 24
<211> 318
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 24
tggatggtgg ccgtcatcct catggcctcg gtcttcatgg tctgcctggc actcctcggc 60
tgcttcgcct tgctgtggtg cgtttacaag aagacaaagt acgccttctc ccctaggaat 120
tctcttccac agcacctgaa agagtttttg ggccatcctc atcataacac acttctgttt 180
ttctcctttc cattgtcgga tgagaatgat gtttttgaca agctaagtgt cattgcagaa 240
gactctgaga gcggcaagca gaatcctggt gacagctgca gcctcgggac cccgcctggg 300
caggggcccc aaagctag 318
<210> 25
<211> 434
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 25
Met His Ser Ser Ala Leu Leu Cys Cys Leu Val Leu Leu Thr Gly Val
1 5 10 15
Arg Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His
20 25 30
Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe
35 40 45
Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu
50 55 60
Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys
65 70 75 80
Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro
85 90 95
Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu
100 105 110
Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg
115 120 125
Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn
130 135 140
Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu
145 150 155 160
Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile
165 170 175
Arg Asn Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly
180 185 190
Ser Thr Lys Gly Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys
195 200 205
Thr His Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp
210 215 220
Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp
225 230 235 240
Asn Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu
245 250 255
Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val
260 265 270
Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn
275 280 285
Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys
290 295 300
His Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val
305 310 315 320
Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met
325 330 335
Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met
340 345 350
Lys Ile Arg Asn Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
355 360 365
Ser Ser Ser Gln Pro Thr Ile Pro Ile Val Gly Ile Ile Ala Gly Leu
370 375 380
Val Leu Phe Gly Ala Val Ile Thr Gly Ala Val Val Ala Ala Val Met
385 390 395 400
Trp Arg Arg Lys Ser Ser Asp Arg Lys Gly Gly Ser Tyr Ser Gln Ala
405 410 415
Ala Ser Ser Asp Ser Ala Gln Gly Ser Asp Val Ser Leu Thr Ala Cys
420 425 430
Lys Val
<210> 26
<211> 1305
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 26
atgcacagct cagcactgct ctgttgcctg gtcctcctga ctggggtgag ggccagccca 60
ggccagggca cccagtctga gaacagctgc acccacttcc caggcaacct gcctaacatg 120
cttcgagatc tccgagatgc cttcagcaga gtgaagactt tctttcaaat gaaggatcag 180
ctggacaact tgttgttaaa ggagtccttg ctggaggact ttaagggtta cctgggttgc 240
caagccttgt ctgagatgat ccagttttac ctggaggagg tgatgcccca agctgagaac 300
caagacccag acatcaaggc gcatgtgaac tccctggggg agaacctgaa gaccctcagg 360
ctgaggctac ggcgctgtca tcgatttctt ccctgtgaaa acaagagcaa ggccgtggag 420
caggtgaaga atgcctttaa taagctccaa gagaaaggca tctacaaagc catgagtgag 480
tttgacatct tcatcaacta catagaagcc tacatgacaa tgaagatacg aaacggcagt 540
acttcgggca gtggtaagcc cgggagtggt gagggtagta ctaagggtag cccaggccag 600
ggcacccagt ctgagaacag ctgcacccac ttcccaggca acctgcctaa catgcttcga 660
gatctccgag atgccttcag cagagtgaag actttctttc aaatgaagga tcagctggac 720
aacttgttgt taaaggagtc cttgctggag gactttaagg gttacctggg ttgccaagcc 780
ttgtctgaga tgatccagtt ttacctggag gaggtgatgc cccaagctga gaaccaagac 840
ccagacatca aggcgcatgt gaactccctg ggggagaacc tgaagaccct caggctgagg 900
ctacggcgct gtcatcgatt tcttccctgt gaaaacaaga gcaaggccgt ggagcaggtg 960
aagaatgcct ttaataagct ccaagagaaa ggcatctaca aagccatgag tgagtttgac 1020
atcttcatca actacataga agcctacatg acaatgaaga tacgaaacgg aggtggcgga 1080
tccggaggtg gctccggagg tggctcctcg agccagccca ccatccccat cgtgggcatc 1140
attgctggcc tggttctctt tggagctgtg atcactggag ctgtggtcgc tgctgtgatg 1200
tggaggagga agagctcaga tagaaaagga gggagctact ctcaggctgc aagcagtgac 1260
agtgcccagg gctctgatgt gtctctcaca gcttgtaaag tgtga 1305
<210> 27
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 27
Met His Ser Ser Ala Leu Leu Cys Cys Leu Val Leu Leu Thr Gly Val
1 5 10 15
Arg Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His
20 25 30
Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe
35 40 45
Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu
50 55 60
Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys
65 70 75 80
Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro
85 90 95
Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu
100 105 110
Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg
115 120 125
Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn
130 135 140
Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu
145 150 155 160
Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile
165 170 175
Arg Asn Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly
180 185 190
Ser Thr Lys Gly Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys
195 200 205
Thr His Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp
210 215 220
Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp
225 230 235 240
Asn Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu
245 250 255
Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val
260 265 270
Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn
275 280 285
Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys
290 295 300
His Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val
305 310 315 320
Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met
325 330 335
Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met
340 345 350
Lys Ile Arg Asn Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
355 360 365
Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
370 375 380
Ser Ser Gln Pro Thr Ile Pro Ile Val Gly Ile Ile Ala Gly Leu Val
385 390 395 400
Leu Phe Gly Ala Val Ile Thr Gly Ala Val Val Ala Ala Val Met Trp
405 410 415
Arg Arg Lys Ser Ser Asp Arg Lys Gly Gly Ser Tyr Ser Gln Ala Ala
420 425 430
Ser Ser Asp Ser Ala Gln Gly Ser Asp Val Ser Leu Thr Ala Cys Lys
435 440 445
<210> 28
<211> 1350
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 28
atgcacagct cagcactgct ctgttgcctg gtcctcctga ctggggtgag ggccagccca 60
ggccagggca cccagtctga gaacagctgc acccacttcc caggcaacct gcctaacatg 120
cttcgagatc tccgagatgc cttcagcaga gtgaagactt tctttcaaat gaaggatcag 180
ctggacaact tgttgttaaa ggagtccttg ctggaggact ttaagggtta cctgggttgc 240
caagccttgt ctgagatgat ccagttttac ctggaggagg tgatgcccca agctgagaac 300
caagacccag acatcaaggc gcatgtgaac tccctggggg agaacctgaa gaccctcagg 360
ctgaggctac ggcgctgtca tcgatttctt ccctgtgaaa acaagagcaa ggccgtggag 420
caggtgaaga atgcctttaa taagctccaa gagaaaggca tctacaaagc catgagtgag 480
tttgacatct tcatcaacta catagaagcc tacatgacaa tgaagatacg aaacggcagt 540
acttcgggca gtggtaagcc cgggagtggt gagggtagta ctaagggtag cccaggccag 600
ggcacccagt ctgagaacag ctgcacccac ttcccaggca acctgcctaa catgcttcga 660
gatctccgag atgccttcag cagagtgaag actttctttc aaatgaagga tcagctggac 720
aacttgttgt taaaggagtc cttgctggag gactttaagg gttacctggg ttgccaagcc 780
ttgtctgaga tgatccagtt ttacctggag gaggtgatgc cccaagctga gaaccaagac 840
ccagacatca aggcgcatgt gaactccctg ggggagaacc tgaagaccct caggctgagg 900
ctacggcgct gtcatcgatt tcttccctgt gaaaacaaga gcaaggccgt ggagcaggtg 960
aagaatgcct ttaataagct ccaagagaaa ggcatctaca aagccatgag tgagtttgac 1020
atcttcatca actacataga agcctacatg acaatgaaga tacgaaacgg aggtggcgga 1080
tccggaggtg gctccggagg tggctcctcg agcggaggtg gcggatccgg aggtggctcc 1140
ggaggtggct cctcgagcca gcccaccatc cccatcgtgg gcatcattgc tggcctggtt 1200
ctctttggag ctgtgatcac tggagctgtg gtcgctgctg tgatgtggag gaggaagagc 1260
tcagatagaa aaggagggag ctactctcag gctgcaagca gtgacagtgc ccagggctct 1320
gatgtgtctc tcacagcttg taaagtgtga 1350
<210> 29
<211> 677
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 29
Met His Ser Ser Ala Leu Leu Cys Cys Leu Val Leu Leu Thr Gly Val
1 5 10 15
Arg Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His
20 25 30
Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe
35 40 45
Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu
50 55 60
Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys
65 70 75 80
Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro
85 90 95
Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu
100 105 110
Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg
115 120 125
Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn
130 135 140
Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu
145 150 155 160
Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile
165 170 175
Arg Asn Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly
180 185 190
Ser Thr Lys Gly Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys
195 200 205
Thr His Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp
210 215 220
Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp
225 230 235 240
Asn Leu Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu
245 250 255
Gly Cys Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val
260 265 270
Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn
275 280 285
Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys
290 295 300
His Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val
305 310 315 320
Lys Asn Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met
325 330 335
Ser Glu Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met
340 345 350
Lys Ile Arg Asn Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
355 360 365
Ser Ser Ser Met Val Pro Pro Pro Glu Asn Val Arg Met Asn Ser Val
370 375 380
Asn Phe Lys Asn Ile Leu Gln Trp Glu Ser Pro Ala Phe Ala Lys Gly
385 390 395 400
Asn Leu Thr Phe Thr Ala Gln Tyr Leu Ser Tyr Arg Ile Phe Gln Asp
405 410 415
Lys Cys Met Asn Thr Thr Leu Thr Glu Cys Asp Phe Ser Ser Leu Ser
420 425 430
Lys Tyr Gly Asp His Thr Leu Arg Val Arg Ala Glu Phe Ala Asp Glu
435 440 445
His Ser Asp Trp Val Asn Ile Thr Phe Cys Pro Val Asp Asp Thr Ile
450 455 460
Ile Gly Pro Pro Gly Met Gln Val Glu Val Leu Ala Asp Ser Leu His
465 470 475 480
Met Arg Phe Leu Ala Pro Lys Ile Glu Asn Glu Tyr Glu Thr Trp Thr
485 490 495
Met Lys Asn Val Tyr Asn Ser Trp Thr Tyr Asn Val Gln Tyr Trp Lys
500 505 510
Asn Gly Thr Asp Glu Lys Phe Gln Ile Thr Pro Gln Tyr Asp Phe Glu
515 520 525
Val Leu Arg Asn Leu Glu Pro Trp Thr Thr Tyr Cys Val Gln Val Arg
530 535 540
Gly Phe Leu Pro Asp Arg Asn Lys Ala Gly Glu Trp Ser Glu Pro Val
545 550 555 560
Cys Glu Gln Thr Thr His Asp Glu Thr Val Pro Ser Trp Met Val Ala
565 570 575
Val Ile Leu Met Ala Ser Val Phe Met Val Cys Leu Ala Leu Leu Gly
580 585 590
Cys Phe Ala Leu Leu Trp Cys Val Tyr Lys Lys Thr Lys Tyr Ala Phe
595 600 605
Ser Pro Arg Asn Ser Leu Pro Gln His Leu Lys Glu Phe Leu Gly His
610 615 620
Pro His His Asn Thr Leu Leu Phe Phe Ser Phe Pro Leu Ser Asp Glu
625 630 635 640
Asn Asp Val Phe Asp Lys Leu Ser Val Ile Ala Glu Asp Ser Glu Ser
645 650 655
Gly Lys Gln Asn Pro Gly Asp Ser Cys Ser Leu Gly Thr Pro Pro Gly
660 665 670
Gln Gly Pro Gln Ser
675
<210> 30
<211> 2034
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成的
<400> 30
atgcacagct cagcactgct ctgttgcctg gtcctcctga ctggggtgag ggccagccca 60
ggccagggca cccagtctga gaacagctgc acccacttcc caggcaacct gcctaacatg 120
cttcgagatc tccgagatgc cttcagcaga gtgaagactt tctttcaaat gaaggatcag 180
ctggacaact tgttgttaaa ggagtccttg ctggaggact ttaagggtta cctgggttgc 240
caagccttgt ctgagatgat ccagttttac ctggaggagg tgatgcccca agctgagaac 300
caagacccag acatcaaggc gcatgtgaac tccctggggg agaacctgaa gaccctcagg 360
ctgaggctac ggcgctgtca tcgatttctt ccctgtgaaa acaagagcaa ggccgtggag 420
caggtgaaga atgcctttaa taagctccaa gagaaaggca tctacaaagc catgagtgag 480
tttgacatct tcatcaacta catagaagcc tacatgacaa tgaagatacg aaacggcagt 540
acttcgggca gtggtaagcc cgggagtggt gagggtagta ctaagggtag cccaggccag 600
ggcacccagt ctgagaacag ctgcacccac ttcccaggca acctgcctaa catgcttcga 660
gatctccgag atgccttcag cagagtgaag actttctttc aaatgaagga tcagctggac 720
aacttgttgt taaaggagtc cttgctggag gactttaagg gttacctggg ttgccaagcc 780
ttgtctgaga tgatccagtt ttacctggag gaggtgatgc cccaagctga gaaccaagac 840
ccagacatca aggcgcatgt gaactccctg ggggagaacc tgaagaccct caggctgagg 900
ctacggcgct gtcatcgatt tcttccctgt gaaaacaaga gcaaggccgt ggagcaggtg 960
aagaatgcct ttaataagct ccaagagaaa ggcatctaca aagccatgag tgagtttgac 1020
atcttcatca actacataga agcctacatg acaatgaaga tacgaaacgg aggtggcgga 1080
tccggaggtg gctccggagg tggctcctcg agcatggtac cacctcccga aaatgtcaga 1140
atgaattctg ttaatttcaa gaacattcta cagtgggagt cacctgcttt tgccaaaggg 1200
aacctgactt tcacagctca gtacctaagt tataggatat tccaagataa atgcatgaat 1260
actaccttga cggaatgtga tttctcaagt ctttccaagt atggtgacca caccttgaga 1320
gtcagggctg aatttgcaga tgagcattca gactgggtaa acatcacctt ctgtcctgtg 1380
gatgacacca ttattggacc ccctggaatg caagtagaag tacttgctga ttctttacat 1440
atgcgtttct tagcccctaa aattgagaat gaatacgaaa cttggactat gaagaatgtg 1500
tataactcat ggacttataa tgtgcaatac tggaaaaacg gtactgatga aaagtttcaa 1560
attactcccc agtatgactt tgaggtcctc agaaacctgg agccatggac aacttattgt 1620
gttcaagttc gagggtttct tcctgatcgg aacaaagctg gggaatggag tgagcctgtc 1680
tgtgagcaaa caacccatga cgaaacggtc ccctcctgga tggtggccgt catcctcatg 1740
gcctcggtct tcatggtctg cctggcactc ctcggctgct tcgccttgct gtggtgcgtt 1800
tacaagaaga caaagtacgc cttctcccct aggaattctc ttccacagca cctgaaagag 1860
tttttgggcc atcctcatca taacacactt ctgtttttct cctttccatt gtcggatgag 1920
aatgatgttt ttgacaagct aagtgtcatt gcagaagact ctgagagcgg caagcagaat 1980
cctggtgaca gctgcagcct cgggaccccg cctgggcagg ggccccaaag ctag 2034
Claims (28)
1.一种包含编码含有连接至跨膜-胞内区段的同型二聚体IL-10的膜结合的同型二聚体IL-10(mem-IL10)的核苷酸序列的核酸分子。
2.如权利要求1所述的核酸分子,其中所述同型二聚体IL-10通过柔性铰链连接至所述跨膜-胞内区段。
3.如权利要求1或2所述的核酸分子,其中所述同型二聚体IL-10包含以单链构型连接的第一和第二IL-10单体,使得第一IL-10单体的C-末端经由第一柔性接头连接至第二IL-10单体的N-末端。
4.如权利要求3所述的核酸分子,其中所述第一柔性接头具有氨基酸序列GSTSGSGKPGSGEGSTKG(SEQ ID NO:1)。
5.如权利要求2至4任一项所述的核酸分子,其中所述柔性铰链包含多肽,该多肽选自CD8α的铰链区、IgG重链的铰链区、IgD重链的铰链区;IL-10Rβ链的胞外区段;和第二柔性接头,该第二柔性接头包含含有至少一个Gly4Ser(Gly3Ser)2序列的多达28个氨基酸的氨基酸序列。
6.如权利要求5所述的核酸分子,其中所述第二柔性铰链包含含有氨基酸序列Gly4Ser(Gly3Ser)2的21个氨基酸的序列(本文中称为“短接头”;SEQ ID NO:13)。
7.如权利要求5所述的核酸分子,其中所述第二柔性接头包含含有氨基酸序列Gly4Ser(Gly3Ser)2Ser2(Gly3Ser)3的28个氨基酸的序列(本文中称为“长接头”;SEQ ID NO:15)。
8.如权利要求5至7任一项所述的核酸分子,其中所述多肽进一步包含具有序列SSQPTIPI(SEQ ID NO:17;)的氨基酸桥。
9.如权利要求1至8任一项所述的核酸分子,其中所述跨膜-胞内区段衍生自人I类MHC分子的重链,该人I类MHC分子选自HLA-A、HLA-B或HLA-C分子,优选为HLA-A2;人CD28;或人IL-10Rβ链。
10.如权利要求1至9任一项所述的核酸分子,其中完整mem-IL10的氨基酸序列包含经由短的第二柔性接头和连接肽连接至HLA-A2的跨膜-胞内区段的同型二聚体IL-10或基本上由其组成,如SEQ ID NO:25所示。
11.如权利要求1至9任一项所述的核酸分子,其中完整mem-IL10的氨基酸序列包含经由长的第二柔性接头和连接肽连接至HLA-A2的跨膜-胞内区段的同型二聚体IL-10或基本上由其组成,如SEQ ID NO:27所示。
12.如权利要求1至9任一项所述的核酸分子,其中该同型二聚体IL-10经由短接头连接至基本上完整的人IL-10Rβ链的N-末端,如SEQ ID NO:29所示,。
13.一种组合物,其包含权利要求1至12任一项所述的核酸分子。
14.一种病毒载体,其包含权利要求1至12任一项所述的核酸分子。
15.如权利要求14所述的病毒载体,其为衍生自病毒的经修饰病毒,该病毒选自逆转录病毒、慢病毒、γ病毒、腺病毒、腺伴随病毒、痘病毒、α病毒和疱疹病毒。
16.一种组合物,其包含权利要求14或15所述的病毒载体。
17.一种哺乳动物调节性T细胞(Treg),其包含权利要求1至12任一项所述的核酸分子或权利要求14或15所述的病毒载体。
18.如权利要求17所述的哺乳动物Treg,其在其表面表达连接至跨膜-胞内区段的同型二聚体IL-10。
19.如权利要求17或18所述的哺乳动物Treg,其为人Treg。
20.如权利要求17至19任一项所述的哺乳动物Treg,其具有表现细胞表面标记CD49b和LAG-3的稳定的Tr1表型。
21.如权利要求20所述的哺乳动物Treg,其进一步表现PD-1、4-1BB、CD25和IL-10Rα。
22.一种制备具有稳定的Tr1表型的同种异体或自体Treg的方法,该方法包括使CD4 T细胞与权利要求1至12任一项所述的核酸分子或包含它的病毒载体接触,从而赋予所述CD4T细胞稳定的Tr1表型,并从而制备具有稳定的Tr1表型的Treg。
23.如权利要求17至21任一项所述的哺乳动物Treg,其用于在其有需要的受试者中增强免疫抑制。
24.如权利要求23所述的哺乳动物Treg,其用于治疗或预防表现为免疫***的过度或不想要的活性的疾病、病症或病况。
25.如权利要求24所述的哺乳动物Treg,其中所述疾病、病症或病况选自自身免疫疾病、过敏、哮喘以及器官和骨髓移植。
26.如权利要求25所述的哺乳动物Treg,其中所述自身免疫疾病选自1型糖尿病;类风湿性关节炎;银屑病;银屑病关节炎;多发性硬化;***性红斑狼疮;炎性肠疾病,例如克罗恩氏病和溃疡性结肠炎;阿狄森氏病;格雷夫斯病;干燥综合征;桥本甲状腺炎;重症肌无力;血管炎;恶性贫血;乳糜泻;和动脉粥样硬化。
27.如权利要求23至26任一项所述的哺乳动物Treg,其中所述哺乳动物Treg为人Treg,且其用于治疗或预防人受试者中的所述疾病、病症或病况。
28.如权利要求27所述的哺乳动物Treg,其中所述人Treg为同种异体Treg。
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EP4289859A1 (en) * | 2022-06-10 | 2023-12-13 | Medizinische Hochschule Hannover | Fusion protein for maintenance of regulatory t-cells |
WO2023237774A1 (en) * | 2022-06-10 | 2023-12-14 | Medizinische Hochschule Hannover | Fusion protein for maintenance of regulatory t-cells |
WO2024028881A1 (en) * | 2022-08-03 | 2024-02-08 | Migal Galilee Research Institute Ltd. | Chimeric membrane-bound cytokines incorporating costimulatory elements for enhancing anti-inflammatory function |
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JP2024019533A (ja) | 2024-02-09 |
EP3768699A1 (en) | 2021-01-27 |
AU2019240370A1 (en) | 2020-11-19 |
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