CN113574168A - 基于细胞因子的免疫细胞及其免疫治疗用途 - Google Patents
基于细胞因子的免疫细胞及其免疫治疗用途 Download PDFInfo
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Abstract
本申请涉及基于细胞因子的免疫细胞及其免疫治疗用途,并且根据一个方面的免疫细胞被设计为这样的形式,即细胞因子经由连接子连接至细胞表面,并且因此细胞因子连续刺激免疫细胞,从而诱导增殖和活化,并且细胞因子不影响周围细胞,从而可以最小化副作用。
Description
技术领域
本申请涉及基于细胞因子的免疫细胞及其免疫治疗用途。
背景技术
使用免疫细胞的抗癌治疗具有非常少的副作用问题,例如由现有的第一代抗癌治疗剂引起的全身毒性或第二代抗癌治疗剂复发的风险,与现有的治疗剂相比,其在抗癌效果方面是优越的,因此是近来受到许多关注的领域。
其中,使用NK细胞的免疫细胞治疗是被称为第四抗癌治疗的抗癌治疗疗法之一,并且具有作为能够使用其它的免疫细胞而没有副作用的唯一细胞治疗的优点。在各种免疫细胞中,与T细胞不同,即使当自然杀伤细胞不是患者自身的细胞时,自然杀伤细胞也可作为细胞治疗剂施用。因此,可以以相对低的成本开发并用作治疗剂。此外,由于它们的高细胞毒性,天然杀伤细胞不仅可用于治疗已被证实使用T细胞有效的血液癌症,而且可用于治疗实体癌,因此具有作为用于治疗更多各种类型癌症的细胞治疗剂的巨大潜力。
在过去十年,使用患者免疫系统的肿瘤免疫治疗已经持续发展,并且使用该治疗的细胞治疗剂也已经商业化。最近,已经开发了通过从健康正常人的血液中分离NK细胞、培养NK细胞并将培养的NK细胞注射到患有癌症的患者体内来治疗癌症的细胞治疗剂,并且已经积极地研究了细胞治疗剂的大规模培养方法等。特别地,在相关技术中已经使用细胞因子如白介素-2增殖和活化天然杀伤细胞。由于天然杀伤细胞在不存在白细胞介素-2时死亡,通过将白细胞介素-2基因导入天然杀伤细胞以允许白细胞介素-2分泌,或从外部提供白细胞介素-2,从而使天然杀伤细胞增殖和活化。
然而,在这种方法中,高浓度的白细胞介素-2可诱导炎症反应,分泌白细胞介素-2的细胞影响局部部位的周围细胞,从而存在副作用的可能性。
因此,需要开发基于细胞因子的天然杀伤细胞,其在使用细胞因子用于天然杀伤细胞的增殖和活化时防止副作用。
发明概述
[技术问题]
一个方面是提供经基因工程改造的免疫细胞,其包括:跨膜结构域;细胞因子;以及用于将细胞因子连接到跨膜结构域的肽连接子。
另一方面是提供包含免疫细胞或其细胞群作为活性成分的细胞治疗剂。
又一方面是提供一种用于预防或治疗癌症的药物组合物,包括作为活性成分的免疫细胞或其细胞群。
又一方面是提供一种用于预防或治疗感染性疾病的药物组合物,包括作为活性成分的免疫细胞或其细胞群。
又一方面是提供预防或治疗癌症或感染性疾病的方法,该方法包括将免疫细胞或其细胞群施用于需要其的个体。
另一方面是提供免疫细胞或其细胞群在制备用于预防或治疗癌症或感染性疾病的药物中的用途。
[技术方案]
一个方面提供了经基因工程改造的免疫细胞,其包括:跨膜结构域;细胞因子;以及用于将细胞因子连接到跨膜结构域的肽连接子。
如本文所用,术语“跨膜结构域”是指蛋白质中穿透细胞膜的区域,所述蛋白质穿过细胞膜并存在于细胞膜中,并且已知大多数跨膜结构域包括具有α-螺旋结构的疏水性氨基酸。跨膜结构域可用于通过将细胞因子固定在靶细胞的细胞膜或质膜上并在靶细胞的表面上展示与其结合的细胞因子或将细胞因子结合到靶细胞的细胞膜受体上来实现持续的刺激。跨膜结构域可以是受体酪氨酸激酶(RTK)的跨膜结构域。更具体地,受体酪氨酸激酶的跨膜结构域可以是选自以下的任一种受体的跨膜结构域:表皮生长因子受体、胰岛素受体,血小板衍生生长因子受体、血管内皮生长因子受体、成纤维细胞生长因子受体、胆囊收缩素(CCK)受体、神经营养因子(NGF)受体、肝细胞生长因子(HGF)受体、肝配蛋白(Eph)受体、血管生成素受体以及与受体酪氨酸激酶相关(RYK)的受体。
如本文所用,术语“细胞因子”可指在信号转导中起作用的蛋白质(约5至20kDa)。细胞因子由细胞释放,并影响释放细胞因子的细胞和/或其它细胞的行为。细胞因子的非限制性实例包括趋化因子、干扰素、白细胞介素、淋巴因子、肿瘤坏死因子、单核因子和集落刺激因子。细胞因子可由多种细胞产生,包括(但不限于)免疫细胞,例如巨噬细胞、B淋巴细胞、T淋巴细胞、肥大细胞和单核细胞、内皮细胞、成纤维细胞和基质细胞。细胞因子可以由一种或多种类型的细胞产生。细胞因子通过受体起作用,在免疫系统中尤其重要,其调节体液和基于细胞的免疫应答之间的平衡,并调节细胞群的成熟、生长和应答。本说明书的细胞因子可以是天然存在的细胞因子或天然存在的细胞因子的突变形式。本文所用的“天然存在的”也可称为野生型,其包括等位基因变体。天然存在的细胞因子的突变形式或“突变体”是指对天然存在的序列进行的特定突变,以改变细胞因子的功能、活性和/或特异性。在一个具体实例中,突变可以改善细胞因子的功能、活性和/或特异性。在另一个具体实例中,突变可降低细胞因子的功能、活性和/或特异性。突变可包括细胞因子的一个或多个氨基酸残基的缺失或添加。
细胞因子可以是选自以下中的任一种:骨形态发生蛋白(BMP)家族、趋化因子配体(CCL)家族、含CKLF样MARVEL跨膜结构域成员(CMTM)家族、C-X-C基序配体(CXCL)家族、生长/分化因子(GDF)家族、生长激素、干扰素(IFN)家族、白介素(IL)家族、肿瘤坏死因子(TNF)超家族、糖磷脂酰肌醇(GPI)、分泌的Ly-6/uPAR-相关蛋白1(SLUPR-1)、分泌的Ly-6/uPAR-相关蛋白2(SLUPR-2)及它们的组合。
在一个具体实例中,细胞因子是白介素或其突变体。许多白细胞介素由单核细胞、巨噬细胞和内皮细胞以及辅助CD4T淋巴细胞合成。白细胞介素可促进T、B淋巴细胞和造血细胞的发育和分化。白细胞介素的非限制性实例包括IL1、IL2、IL3、IL4、IL5、IL6、IL7、IL8(CXCL8)、IL9、IL10、IL11、IL12、IL13、IL14、IL15、IL16、IL17、IL18、IL19、IL20、IL21、IL22、IL23、IL24、IL25、IL26、IL27、IL28、IL29、IL30、IL31、IL32、IL33、IL35或IL36。因此,在某些示例性实施方案中,细胞因子是白介素或其突变体,其包括(但不限于)IL1、IL2、IL3、IL4、IL5、IL6、IL7、IL8(CXCL8)、IL9、IL10、IL11、IL12、IL13、IL14、IL15、IL16、IL17、IL18、IL19、IL20、IL21、IL22、IL23、IL24、IL25、IL26、IL27、IL28、IL29、IL30、IL31、IL32、IL33、IL35或IL36的野生型或突变型。在一个特定的具体实例中,细胞因子是IL2或其突变体。IL2是诱导应答性T细胞增殖的淋巴因子。此外,IL2通过受体特异性结合作用于一些B细胞,作为生长因子和抗体产生刺激物。IL2蛋白作为单糖基化多肽被分泌,并且信号序列的切割对于其活性是必需的。IL-2的结构包括一束4个螺旋(命名为A-D),其侧翼是两个较短的螺旋和数个分界较差的环。螺旋A中的残基以及螺旋A和B之间的环区中的残基对于受体结合是重要的。二级结构分析表明与IL4和粒细胞-巨噬细胞集落刺激因子(GMCSF)相似。在一个特定的具体实例中,本发明组合物的细胞因子是IL2或其变体。变体可以是截短的或突变的IL2。
在另一个具体实例中,细胞因子是干扰素亚家族或其突变体。基于干扰素转导信号的受体类型,人干扰素被分为三种主要类型:I型IFN、II型IFN和III型IFN。I型IFN结合被称为IFN-α/β受体(IFNAR)的特定细胞表面受体复合物,其由IFNAR1和IFNAR2链组成。存在于人中的I型干扰素的非限制性实例包括IFN-α、IFN-β、IFN-ε、IFN-γ和IFN-ω。因此,在某些示例性实施方案中,细胞因子是I型IFN细胞因子或其突变体,包括(但不限于)野生型和突变体形式的IFN-α、IFN-β、IFN-ε、IFN-κ和IFN-ω。II型IFN与由IFNGR1和IFNGR2链组成的IFNGR结合。存在于人中的II型干扰素的非限制性实例包括IFN-γ。因此,在某些示例性实施方案中,细胞因子是II型IFN细胞因子或其突变体,其包括(但不限于)IFN-γ的野生型和突变型。III型IFN通过由IL10R2(也称为CRF2-4)和IFNLR1(也称为CRF2-12)组成的受体复合物转导信号。III型干扰素的非限制性实例包括IFN-λ1、IFN-λ2和IFN-λ3(也分别称为IL29、IL28A和IL28B)。因此,在某些示例性实施方案中,本发明组合物的细胞因子是III型IFN细胞因子或其突变体,其包括(但不限于)IFN-λ1、IFN-λ2和IFN-λ3的野生型和突变型。
在另一个具体实例中,细胞因子是肿瘤坏死因子超家族(TNFSF)的成员,或其突变体。TNFSF的成员诱导炎性病症并用促炎细胞因子刺激免疫细胞功能,所述促炎细胞因子主要由免疫细胞表达。存在至少18种TNFSF同系物,其包括(但不限于)TNF(TNFα)、CD40L(TNFSF5)、CD70(TNFSF7;CD27L)、EDA、FASL(TNFSF6;Fas配体)、LTA(TNFSF1;淋巴毒素-α)、LTB(TNFSF3;淋巴毒素-β)、TNFSF4(OX40L)、TNFSF8(CD153)、TNFSF9(4-1BBL)、TNFSF10(TRAIL)、TNFSF11(RANKL;NF核因子κB配体的受体激活剂)、TNFSF12(TWEAK)、TNFSF13、TNFSF13B、TNFSF14、TNFSF15、TNFSF18。因此,在某些示例性实施方案中,本发明组合物的细胞因子是肿瘤坏死因子超家族(TNFSF)的成员,其包括TNF(TNFα)、CD40L(TNFSF5)、CD70(TNFSF7;CD27L)、EDA、FASL(TNFSF6)、LTA(TNFSF1)、LTB(TNFSF3)、TNFSF4(OX40L)、TNFSF8(CD153)、TNFSF9(4-1BBL)、TNFSF10(TRAIL)、TNFSF11(RANKL)、TNFSF12(TWEAK)、TNFSF13、TNFSF13B、TNFSF14、TNFSF15、TNFSF18或它们的突变体(但不限于此)。
在另一个具体实例中,CXCL可以是CXCL1、CXCL2、CXCL5、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、CXCL14、CXCL16或CXCL17。
在另一个具体实例中,趋化因子(c-c基序)配体(CCL)可以是CCL1、CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CCL8、CCL9、CCL10、CCL11、CCL12、CCL13、CCL14、CCL15、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、CCL23、CCL24、CCL25、CCL26、CCL27或CCL28。
在另一个具体实例中,BMP可以是BMP1、BMP2、BMP3、BMP4、BMP5、BMP6、BMP7、BMP8、BMP9、BMP10、BMP11、BMP12、BMP13、BMP14或BMP15。
连接子不仅可用于将细胞因子连接到跨膜结构域,而且可用于根据连接子的柔性将细胞因子暴露在靶细胞的表面。作为连接物,例如,可以应用柔性连接物。此外,连接子可以具有对蛋白水解酶的抗性(蛋白酶抗性),并且可以通过根据细胞因子或靶细胞适当地改变其类型和/或长度来使用连接子。例如,连接子可以是由任何1-400、1-200或2-200个氨基酸组成的多肽。肽连接子可包括Gly、Asn和Ser残基,也可包括中性氨基酸如Thr和Ala。适用于肽连接子的氨基酸序列是本领域已知的。此外,拷贝数“n”可以参考连接子的优化来调整,以实现功能部分之间的适当分离或保持基本的部分间相互作用。其它柔性连接子是本领域已知的,并且例如,可以存在G和S连接子,其中添加氨基酸残基如T和A以保持柔性,以及添加极性氨基酸残基以改善水溶性。因此,在一个示例性实施方案中,连接子可以是包括G、S和/或T残基的柔性连接子。连接基可具有选自(GpSs)n和(SpGs)n的通式,并且在这种情况下,p独立地为1至10的整数,s为0或0至10的整数,p+s为20或更小的整数,并且n为1至20的整数。更具体地,连接子的实例包括(GGGGS)n(SEQ ID NO:1)、(SGGGG)n(SEQ ID NO:2)、(SRSSG)n(SEQ ID NO:3)、(SGSSC)n(SEQ ID NO:4)、(GKSSGSGSESKS)n(SEQ ID NO:5)、(RPPPPC)n(SEQ ID NO:6)、(SSPPPPC)n(SEQ ID NO:7)、(GSTSGSGKSSEGKG)n(SEQ ID NO:8)、(GSTSGSGKSSEGSGSTKG)n(SEQ ID NO:9)、(GSTSGSGKPGSGEGSTKG)n(SEQ ID NO:10)或(EGKSSGSGSESKEF)n(SEQ ID NO:11),并且n是1至20或1至10的整数。
在具体实例中,免疫细胞的非限制性实例包括巨噬细胞、B淋巴细胞、T淋巴细胞、肥大细胞、单核细胞、树突细胞、嗜酸性粒细胞、天然杀伤细胞、嗜碱性粒细胞和嗜中性粒细胞。因此,在某些示例性实施方案中,免疫细胞可以是选自巨噬细胞、B淋巴细胞、T淋巴细胞(CD8+CTL)、肥大细胞、单核细胞、树突细胞、嗜酸性粒细胞、自然杀伤细胞、嗜碱性粒细胞和嗜中性粒细胞中的任一种。在某些具体实例中,免疫细胞可以是天然杀伤细胞或T淋巴细胞。
如本文所用,术语“天然杀伤细胞”或“NK细胞”被定义为作为细胞毒性淋巴细胞的大颗粒淋巴细胞(LGL),其构成先天免疫系统的主要成分,并产生共同的淋巴祖细胞(CLP),并构成从B和T淋巴细胞分化的第三细胞。“天然杀伤细胞”或“NK细胞”包括没有来自任何组织来源的额外修饰的天然杀伤细胞,并且不仅可以包括成熟的天然杀伤细胞,还可以包括天然杀伤祖细胞。天然杀伤细胞通过对干扰素或巨噬细胞衍生的细胞因子的应答而被激活,并且天然杀伤细胞包括两种类型的表面受体,其用“激活受体”和“抑制受体”标记并控制细胞的细胞毒性活性。天然杀伤细胞可以从任何来源产生,例如来自胎盘组织、胎盘灌注液、脐带血、胎盘血、外周血、脾、肝等的造血细胞,例如,造血干细胞和祖细胞。
在一个具体的例子中,天然杀伤细胞可以是活化的天然杀伤细胞。活化的天然杀伤细胞可以是指与亲代细胞(例如造血细胞或天然杀伤祖细胞)相比,天然杀伤细胞的细胞毒性或原始免疫调节能力被活化的细胞。在具体的示例性实施方案中,活化的天然杀伤细胞是CD3-CD56+。在具体的示例性实施方案中,活化的天然杀伤细胞是CD3-CD56+CD16-。在其它具体的示例性实施方案中,活化的天然杀伤细胞另外是CD94+CD117+。在其它具体的示例性实施方案中,活化的天然杀伤细胞另外是CD161-。在其它具体的示例性实施方案中,活化的天然杀伤细胞另外是NKG2D+。在其它具体的示例性实施方案中,活化的天然杀伤细胞另外是NKp46+。在其它具体的示例性实施方案中,活化的天然杀伤细胞另外是CD226+。在某些示例性实施方案中,超过50%、60%、70%、80%、90%、92%、94%、96%或98%的活化的天然杀伤细胞是CD56+和CD16-。在其它示例性实施方案中,至少50%、60%、70%、80%、82%、84%、86%、88%或90%的活化的天然杀伤细胞是CD3-和CD56+。在其它示例性实施方案中,至少50%、52%、54%、56%、58%或60%的活化的天然杀伤细胞是NKG2D+。在其它示例性实施方案中,30%、20%、10%、9%、8%、7%、6%、5%、4%或3%的活化的天然杀伤细胞是NKB1+。在某些其它示例性实施方案中,少于30%、20%、10%、8%、6%、4%或2%的活化的天然杀伤细胞是NKAT2+。在某些其它示例性实施方案中,少于30%、20%、10%、8%、6%、4%或2%的活化的天然杀伤细胞是CD56+和CD16+。在更具体的示例性实施方案中,至少10%、20%、25%、30%、35%、40%、50%、55%、60%、65%或70%的CD3-,CD56+活化的天然杀伤细胞是NKp46+。在其它更具体的示例性实施方案中,至少10%、20%、25%、30%、35%、40%、50%、55%、60%、65%、70%、75%、80%或85%的CD3-,CD56+活化的天然杀伤细胞是CD117+。在其它更具体的示例性实施方案中,至少10%、20%、25%、30%、35%、40%、45%或50%的CD3-,CD56+活化的天然杀伤细胞是CD94+。在其它更具体的示例性实施方案中,至少10%、20%、25%、30%、35%、40%、45%或50%的CD3-,CD56+活化的天然杀伤细胞是CD161-。在其它更具体的示例性实施方案中,至少10%、12%、14%、16%、18%或20%的CD3-,CD56+活化的天然杀伤细胞是CD226+。在其它更具体的示例性实施方案中,至少20%、25%、30%、35%或40%的CD3-,CD56+活化的天然杀伤细胞是CD7+。在其它更具体的示例性实施方案中,至少30%、35%、40%、45%、50%、55%或60%的CD3-,CD56+活化的天然杀伤细胞是CD5+。
在一个具体实例中,活化的天然杀伤细胞或活化的天然杀伤细胞富集群体可以通过检测一种或多种功能相关标记物来评估,例如CD94、CD161、NKp44、DNAM-1、2B4、NKp46、CD94、KIR和NKG2活化受体家族(例如NKG2D)。
在一个具体的实例中,活化的天然杀伤细胞可以由上述造血细胞产生。在某些示例性实施方案中,活化的天然杀伤细胞可以获自增殖的造血细胞,例如造血干细胞和/或造血祖细胞。在具体的示例性实施方案中,造血细胞在不使用饲养细胞的第一培养基中连续增殖和分化。然后,在饲养细胞存在下,在第二培养基中培养细胞。这种分离(隔离)、增殖和分化可以在中心设备中进行,该中心设备提供增殖的造血细胞,用于在使用点增殖和分化,例如在医院等。
在一个具体的实例中,活化的天然杀伤细胞的产生包括增殖造血细胞群。在细胞增殖过程中,造血细胞群中的多个造血细胞分化为自然杀伤细胞。
如本文所用,术语“天然杀伤祖细胞”或“NK祖细胞”或其细胞群可指包括天然杀伤细胞系细胞的细胞或其群,其尚未发育成成熟的天然杀伤细胞,例如,如由一种或多种表型标记(诸如CD56、CD16和KIR)的表达水平所指示。在一个示例性实施方案中,天然杀伤祖细胞群包括具有低CD16和高CD56的细胞。例如,天然杀伤祖细胞群包括约5%、10%、15%、20%、25%、30%、35%、40%、45%或50%的CD3-CD56+细胞。在其它具体的示例性实施方案中,天然杀伤祖细胞群包括5%、10%、15%、20%、25%、30%、35%、40%、45%或50%的CD3-CD56+细胞或更少。在其它具体的示例性实施方案中,天然杀伤祖细胞群包括0%至5%、5%至10%、10%至15%、15%至20%、20%至25%、25%至30%、30%至35%、35%至40%、40%至45%,或45%至50%的CD3-CD56+细胞。
在一个具体的实例中,在天然杀伤祖细胞群中,CD3-CD56+细胞另外是CD117+。在具体的示例性实施方案中,在天然杀伤祖细胞群中,约65%、70%、75%、80%、85%、90%、95%、98%或99%的CD3-CD56+细胞是CD117+。在其它具体的示例性实施方案中,在天然杀伤祖细胞群中,65%、70%、75%、80%、85%、90%、95%、98%或99%或更多的CD3-CD56+细胞是CD117+。在其它具体的示例性实施方案中,在天然杀伤祖细胞群中,65%至70%、70%至75%、75%至80%、80%至85%、85%至90%、90%至95%或95%至99%的CD3-CD56+细胞是CD117+。
在另一个具体实例中,在天然杀伤祖细胞群中,CD3-CD56+细胞另外是CD161+。在具体的示例性实施方案中,在天然杀伤祖细胞群中,约40%、45%、50%、55%、60%、65%、70%或75%的CD3-CD56+细胞是CD161+。在其它具体的示例性实施方案中,在天然杀伤祖细胞群中,40%、45%、50%、55%、60%、65%、70%或75%或更多的CD3-CD56+细胞是CD161+。在其它具体的示例性实施方案中,在天然杀伤祖细胞群中,40%至45%、45%至50%、50%至55%、55%至60%、60%至65%、65%至70%或70%至75%的CD3-CD56+细胞是CD161+。
在另一个具体实例中,在天然杀伤祖细胞群中,CD3-CD56+细胞另外是NKp46+。在具体的示例性实施方案中,在天然杀伤祖细胞群中,约25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或更多的CD3-CD56+细胞是NKp46+。在其它具体的示例性实施方案中,在天然杀伤祖细胞群中,约25%、30%、35%、40%、45%、50%或55%的CD3-CD56+细胞是NKp46+。在其它具体的示例性实施方案中,在天然杀伤祖细胞群中,25%、30%、35%、40%、45%、50%或55%或更少的CD3-CD56+细胞是NKp46+。在其它具体的示例性实施方案中,在天然杀伤祖细胞群中,25%至30%、30%至35%、35%至40%、40%至45%、45%至50%、50%至55%、55%至60%、60%至65%、65%至70%、70%至75%、75%至80%、80%至85%、85%至90%或更多的CD3-CD56+细胞是NKp46+。在更具体的示例性实施方案中,在天然杀伤祖细胞群中,25%至30%、30%至35%、35%至40%、40%至45%、45%至50%或50%至55%的CD3-CD56+细胞是NKp46+。
此外,例如,天然杀伤祖细胞群是如上文针对CD52+、CD16+、CD244+、CD94+所述,或是CD94+。
在本说明书中,免疫细胞(例如,天然杀伤细胞)可以是遗传修饰的或工程改造的。
本文所用的“基因修饰”或“基因工程”包括人工改变细胞中遗传物质的组成或结构。
在一个具体的实例中,免疫细胞(例如,天然杀伤细胞)可以被遗传修饰以提高靶特异性和/或归巢特异性。
在一个具体实例中,遗传修饰的免疫细胞(例如,天然杀伤细胞)是包括嵌合抗原受体(CAR)的天然杀伤细胞。CAR是人工膜结合蛋白,其诱导针对抗原的免疫细胞(例如T淋巴细胞),并通过刺激免疫细胞杀死显示抗原的细胞。CAR包括与抗原(例如,细胞上的抗原)结合的细胞外结构域、跨膜结构域以及将初级活化信号传递给免疫细胞和/或共刺激结构域的细胞内(细胞质)信号传导结构域(即细胞内刺激结构域)。当满足所有其它条件时,CAR在例如T淋巴细胞如初级T淋巴细胞的表面上表达,并且CAR的细胞外结构域与抗原结合,细胞外信号传导结构域通过向T淋巴细胞传递信号而激活和/或增殖T淋巴细胞,并且当抗原存在于细胞表面上时杀死表达抗原的细胞。一些免疫细胞,例如T淋巴细胞和天然杀伤细胞,需要两个用于最大活化的信号,即初级活化信号和共刺激信号,并且CAR还可以包括共刺激结构域,使得与细胞外结构域的结合引起初级活化信号和共刺激信号的传输。
在另一个具体实例中,遗传修饰的免疫细胞(例如,天然杀伤细胞)可以是包括归巢受体的免疫细胞(例如,天然杀伤细胞)。这允许包括归巢受体的细胞停留在特定的解剖区域,特别是组织或特定类型的细胞,例如淋巴结,胃肠道或皮肤的B细胞区域。
在另一个具体实例中,遗传修饰的免疫细胞(例如,天然杀伤细胞)是包括CAR和归巢受体的免疫细胞,如本文所述。
包括CAR和/或归巢受体的免疫细胞(例如,天然杀伤细胞)可以通过本领域已知的任何方法产生。在一些示例性实施方案中,操纵包括CAR和/或归巢受体的免疫细胞(例如,天然杀伤细胞),以便通过将免疫细胞(例如,天然杀伤细胞)引入(例如,通过转染)一个或多个载体(包括编码CAR和/或归巢受体的核酸序列)来表达CAR和/或归巢受体。在一些示例性实施方案中,可以通过首先引入(例如,通过转染)一种或多种载体(包括编码CAR和/或归巢受体的核酸序列)来操纵其中可以产生免疫细胞(例如,天然杀伤细胞)的细胞(例如,CD34+造血干细胞)以表达CAR和/或归巢受体。然后,可以通过上述方法诱导包括CAR和/或归巢受体的免疫细胞(例如,天然杀伤细胞)。
在一个具体的实例中,CAR的细胞外结构域是抗原结合结构域。在具体的示例性实施方案中,抗原结合结构域是scFv结构域。在某些示例性实施方案中,抗原结合结构域特异性结合TAA。在具体的示例性实施方案中,TAA选自CD123、CLL-1、CD38、CD20和CS-1。在更具体的示例性实施方案中,抗原结合结构域包括单链Fv(scFv)或衍生自结合CS-1的抗体的抗原结合片段。在更具体的示例性实施方案中,抗原结合结构域包括依洛珠单抗的单链和/或依洛珠单抗的抗原结合片段。在具体的示例性实施方案中,抗原结合结构域包括单链Fv(scFv)或衍生自结合CD20的抗体的抗原结合片段。
在一个具体的实例中,CAR的细胞内刺激结构域是CD3ζ信号传导结构域。
在一个具体实例中,CAR的共刺激结构域包括CD28、4-1BB、PD-1、OX40、CTLA-4、NKp46、NKp44、NKp30、DAP10或DAP12的细胞内结构域。
在一个具体实例中,归巢受体是趋化受体。在具体的示例性实施方案中,趋化受体选自CXCR4、VEGFR2和CCR7。
在特定的具体实例中,天然杀伤细胞可以是NK-92细胞。
在一个具体的实例中,细胞因子可以与存在于免疫细胞表面上的细胞因子受体结合以连续刺激细胞。
如本文所用,术语“免疫细胞(例如,天然杀伤细胞)的刺激”可意指活性增加,例如,免疫细胞(例如,天然杀伤细胞)在体外或体内的细胞毒性活性增加,或活化的免疫细胞(例如,天然杀伤细胞)产生、增加或增殖。
根据具体实例的免疫细胞(例如,天然杀伤细胞),细胞因子不影响周围细胞,从而可诱导增殖和活化,同时使副作用最小化。
在一个具体实例中,免疫细胞可以用包含编码融合蛋白的多核苷酸的载体转化,所述融合蛋白包括:跨膜结构域;细胞因子;以及用于将细胞因子连接到跨膜结构域的肽连接子。具体地,免疫细胞可以是包括载体的免疫细胞。因此,如本文所用,术语“基因工程免疫细胞”可指包括用载体转化的免疫细胞。
术语“多核苷酸”是指以单链或双链形式存在的脱氧核糖核苷酸或核糖核苷酸的聚合物。所述多核苷酸包括RNA基因组序列、DNA(gDNA和cDNA)以及由其转录的RNA序列,并且不仅包括天然多核苷酸,而且包括它们的具有修饰的糖或碱基位点的类似物,除非另有具体说明。在一个具体的实例中,多核苷酸是单链多核苷酸。
本文所用的术语“载体”是指包含调节元件的基因构建体,所述调节元件可操作地连接以表达作为能够在合适的宿主细胞中表达靶蛋白的载体的基因插入物。根据一个实例的载体可以包括表达调控元件,例如启动子、操纵子、起始密码子、终止密码子、聚腺苷酸化信号和/或增强子,并且载体的启动子可以是组成型的或诱导型的。此外,载体可以是能够在宿主细胞中稳定表达融合蛋白的表达载体。作为表达载体,可以使用本领域用于在植物、动物或微生物中表达外源蛋白的典型载体。重组载体可以通过本领域已知的各种方法构建。例如,载体可以包括用于选择含有载体的宿主细胞的选择性标记,并且在可复制载体的情况下,载体可以包括复制起点。此外,载体可以是自我复制的或导入宿主DNA,载体可以选自质粒、慢病毒、腺病毒、腺相关病毒、逆转录病毒、单纯疱疹病毒和痘苗病毒。
载体包括在动物细胞,例如哺乳动物细胞中可操作的启动子。根据一个实例的合适的启动子包括衍生自哺乳动物病毒的启动子和衍生自哺乳动物细胞基因组的启动子,并且可以包括,例如,巨细胞病毒(CMV)启动子、U6启动子和H1启动子、鼠白血病病毒(MLV)的长末端重复(LTR)启动子、腺病毒早期启动子、腺病毒晚期启动子、痘苗病毒7.5K启动子、SV40启动子、HSV的tk启动子、RSV启动子、EF1α启动子、金属硫蛋白启动子、β-肌动蛋白启动子、人IL-2基因的启动子、人IFN基因的启动子、人IL-4基因的启动子、人淋巴毒素基因的启动子、人GM-CSF基因的启动子、人磷酸甘油酸激酶(PGK)启动子、小鼠磷酸甘油酸激酶(PGK)启动子和存活素启动子。
此外,在载体中,编码上述融合蛋白的多核苷酸序列可以与启动子可操作地连接。如本文所用,术语“可操作地连接”是指核酸表达调节序列(例如:启动子、信号序列和转录调节因子结合位点的阵列)与不同核酸序列之间的功能性连接,因此,调节序列调节不同核酸序列的转录和/或翻译。
另一方面提供了包含免疫细胞或其细胞群作为活性成分的细胞治疗剂。
又一方面提供了用于预防或治疗癌症或感染性疾病的药物组合物,包括作为活性成分的免疫细胞或其细胞群。
又一方面提供免疫细胞或其细胞群用于制备药物的用途。
又一方面提供了治疗疾病的方法,该方法包括将免疫细胞或其细胞群施用于个体。
如本文所用,术语“疾病”可指一种病理状况,特别是癌症、感染性疾病、炎性疾病、代谢性疾病、自身免疫性疾病、退行性疾病、细胞凋亡相关疾病和移植物排斥。
如本文所用,术语“治疗”是指减轻、进展抑制或预防疾病、病症或病状或者它们的一种或多种症状,并且“活性成分”或“药物有效量”可以是指在实施本文提供的方法中所使用的足以减轻或抑制疾病、病症或病状或者它们的一种或多种症状的进展或预防疾病、病症或病状或者它们的一种或多种症状的组合物的任何量。
如本文所用,术语“施用”、“引入”和“移植”可互换使用,并且可以指根据具体实例的组合物在个体内通过用于引起根据具体实例的组合物在所需部位的至少部分定位的方法或途径的处置。根据具体实例的组合物的至少一些细胞或细胞组分可以通过将组合物递送至活个体内的所需位置的任何合适的途径施用。施用于个体后细胞的存活时间可以短至数小时,例如24小时至数天或长至数年。
如本文所用,术语“分离的细胞”,如“分离的免疫细胞”是指基本上从细胞起源的组织中分离的细胞,例如造血细胞。
本发明的组合物可用于治疗或识别肿瘤或源自肿瘤的癌症的方法。肿瘤可以是恶性的或良性的,癌症可以是原发的或转移的,并且肿瘤或癌症可以是早期的或晚期的。可治疗的肿瘤或癌症的非限制性实例包括急性成淋巴细胞性白血病、急性髓细胞性白血病、肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、肛门癌、阑尾癌、星形细胞瘤(儿科小脑或大脑)、基底细胞癌、胆管癌、膀胱癌、骨肿瘤、脑干神经胶质瘤、脑肿瘤(小脑星形细胞瘤、脑星形细胞瘤/恶性神经胶质瘤、室管膜神经胶质瘤、成神经管细胞瘤、幕上原始神经外胚层肿瘤、视觉通路和下丘脑神经胶质瘤)、乳腺癌、支气管腺瘤/类癌、伯基特淋巴瘤、类癌瘤(儿科、胃肠)、未知原发性癌、中枢神经系统淋巴瘤(原发性)、小脑星形细胞瘤、脑星形细胞瘤/恶性神经胶质瘤、宫颈癌、儿科癌症、慢性淋巴细胞白血病、慢性骨髓性白血病、慢性骨髓增生性疾病、结肠癌、皮肤T细胞淋巴瘤、绒毛膜小圆细胞肿瘤、子宫内膜癌、室管膜神经胶质瘤、食道癌、尤因瘤家族的尤因肉瘤、颅外生殖细胞肿瘤(儿科)、性腺外生殖细胞肿瘤、肝外胆管癌、眼癌(眼内黑色素瘤、成视网膜细胞瘤)、胆囊癌、胃部(胃)癌、胃肠类癌瘤、胃肠间质瘤、生殖细胞肿瘤(儿科颅外、性腺外、卵巢)、妊娠滋养细胞瘤、神经胶质瘤(成人、儿科脑星形细胞瘤、儿科视觉通路和下丘脑)、胃类癌、毛细胞白血病、头颈癌、肝细胞(肝)癌、霍奇金淋巴瘤、下咽癌、下丘脑和视觉通路神经胶质瘤(儿科)、眼内黑素瘤、胰岛细胞癌、卡波西肉瘤、肾癌(肾细胞癌)、喉癌、白血病(急性淋巴母细胞、急性骨髓性、慢性淋巴细胞性、慢性骨髓性、毛细胞)、唇和口腔癌、肝癌(原发性)、肺癌(非小细胞、小细胞)、淋巴瘤(AIDS相关的、伯基特(Burkitt)、皮肤T细胞、霍奇金(Hodgkin)、非霍奇金(non-Hodgkin)、原发性中枢神经系统)、巨球蛋白血症(Waldenstrom)、骨恶性纤维组织细胞瘤/骨肉瘤、成神经管细胞瘤(儿科)、黑色素瘤、眼内黑色素瘤、Merkel细胞癌、间皮瘤(成人恶性、儿科)、转移性鳞状头颈癌伴隐匿性原发性口腔癌、多发性内分泌瘤综合征(儿科)、多发性骨髓瘤/浆细胞瘤、蕈样真菌病、骨髓增生异常综合征、骨髓增生异常/骨髓增生性病症、骨髓性白血病(慢性)、骨髓性白血病(成人急性、儿科急性)、多发性骨髓瘤、骨髓增生性病症(慢性)、鼻腔和鼻窦癌、鼻咽癌、成神经细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口腔癌、口咽癌、骨肉瘤/骨的恶性纤维组织细胞瘤、卵巢癌、卵巢上皮癌(表面上皮-间质肿瘤)、卵巢生殖细胞肿瘤、卵巢低恶性潜能肿瘤、胰腺癌、胰腺癌(胰岛细胞)、鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、喉癌、嗜铬细胞瘤、松果体星形细胞瘤、松果体生殖细胞瘤、松果体细胞瘤和幕上原始神经外胚层肿瘤(儿科)、垂体腺瘤、浆细胞瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞癌(肾癌)、肾盂和输尿管移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤(儿科)、唾液腺癌、肉瘤(尤因家族肿瘤、卡波西、软组织、子宫管)、塞兹里综合征、皮肤癌(非黑素瘤、黑素瘤)、皮肤癌(Merkel细胞)、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、(转移性)鳞状头颈癌伴隐匿性原发性胃癌、幕上原始神经外胚层肿瘤(儿科)、T细胞淋巴瘤(皮肤)、睾丸癌、喉咽癌、胸腺瘤(儿科)、胸腺瘤和胸腺癌、甲状腺癌、甲状腺癌(儿科)、肾盂和输尿管的移行细胞癌、滋养细胞瘤形成(妊娠)、未知的原发部位(成人、儿科)、输尿管和肾盆移行细胞癌;尿道癌、输卵管癌(子宫内膜)、输卵管肉瘤、阴道癌、视觉通路和下丘脑神经胶质瘤(儿科)、外阴癌、瓦尔登斯特伦巨球蛋白血症和威尔姆斯瘤(儿科)。在某些具体实例中,肿瘤或癌症可以选自黑素瘤、肾细胞癌、肺癌和血液癌。在一个具体实例中,肿瘤是黑素瘤。在另一个具体实例中,肿瘤是肾细胞癌。在一个具体实例中,肿瘤是肺癌(例如,NSCLC)。在另一个具体实例中,肿瘤是本申请中描述的血液癌。本申请中使用的“血液癌”是影响血液、骨髓和淋巴系统的癌症。血液癌有三大组:白血病、淋巴瘤和骨髓瘤。四大类白血病如下:急性淋巴细胞白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性骨髓性白血病(CML)。淋巴瘤可分为两类:霍奇金淋巴瘤和非霍奇金淋巴瘤。大多数非霍奇金淋巴瘤是快速生长(高级别)或逐渐生长(低级别)的B细胞淋巴瘤。有14种类型的B细胞非霍奇金淋巴瘤。其它的是不同的白细胞癌,或命名为淋巴细胞的T细胞的淋巴瘤。骨髓瘤经常被称为多发性骨髓瘤,因为其经常发生在骨髓的许多部位。在一些具体实例中,这些方法包括施用本申请提供的组合疗法。在一些具体实例中,组合疗法包括PD-1抑制剂。在其它具体实例中,PD-1抑制剂是抗PD-1抗体。在一些具体实例中,组合疗法包括PD-L1抑制剂。在其它具体实例中,PD-L1抑制剂是抗PD-L1抗体。
如本文所用,术语“感染性疾病”包括在受试者内或受试者上存在病原体,其中当病原体的生长被抑制时受试者受益。除了指病原体的存在之外,此类术语“感染”还指不利的正常细菌组。如本文所用,术语“病原体”是指能够引起疾病的感染性材料。感染性材料的非限制性实例包括在受试者中诱导疾病的病毒、细菌、朊病毒、真菌、类病毒或寄生虫。在一个特定的具体实例中,感染是由病原体引起的,例如细菌或病毒。在某些具体实例中,感染是细胞内感染。在一个具体实例中,感染是病毒感染。
在一个具体实例中,施用药物组合物的方法没有特别限制,但是药物组合物可以以静脉内、皮下、腹膜内、吸入或局部施用的方式肠胃外施用或口服施用,这取决于所需方法。剂量根据患者的体重、年龄、性别和健康状况、饮食、给药时间、给药方法、排泄率和疾病的严重程度而变化。日剂量是指足以治疗可通过向需要治疗的个体施用而减轻的疾病病况的根据一个方面的治疗材料的量。治疗材料的有效量根据具体化合物、疾病状况和其严重程度以及需要治疗的个体而变化,这通常可由本领域普通技术人员确定。作为非限制性实例,根据一个方面的用于人体的组合物的剂量可以根据患者的年龄、体重和性别、给药方式、健康状况和疾病程度而变化。基于体重为70kg的成年患者,根据一个方面的组合物可以以规则的时间间隔每天一次或以数个分开的剂量施用,例如,约1,000至10,000个细胞/次、1,000至100,000个细胞/次、1,000至1000,000个细胞/次、1,000至10,000,000个细胞/次、1,000至100,000,000个细胞/次、1,000至1,000,000,000个细胞/次。和1,000至10,000,000,000个细胞/次,并且可以以规则的时间间隔施用若干次。
“个体”是指需要治疗疾病的受试者,更具体地,是指哺乳动物,例如人或非人灵长类动物、小鼠、大鼠、狗、猫、马和牛。
根据具体实例的药物组合物可以包括药学上可接受的载体和/或添加剂。例如,药物组合物可以包括无菌水、盐水、常用的缓冲液(例如磷酸、柠檬酸和其它有机酸)、稳定剂、盐、抗氧化剂(例如抗坏血酸)、表面活性剂、悬浮剂、等渗剂、防腐剂等。对于局部给药,药物组合物可以与有机材料如生物聚合物,无机材料如羟基磷灰石,特别是胶原基质,聚乳酸聚合物或共聚物,聚乙二醇聚合物或共聚物及其化学衍生物等的组合进行组合。当根据具体实例的药物组合物制备成适于注射的剂型时,免疫细胞或增加其活性的材料可以溶解在药学上可接受的载体中或可以在溶解溶液的状态下冷冻。
根据具体实例的药物组合物根据给药方法或剂型可适当地包括悬浮剂、增溶剂、稳定剂、等渗剂、防腐剂、吸附阻断剂、表面活性剂、稀释剂、赋形剂、pH调节剂、止痛剂、缓冲剂、还原剂、抗氧化剂等,如果必要的话。适用于本申请的药学上可接受的载体和制剂,包括上文举例说明的那些,详细描述于文献[Remington's Pharmaceutical Sciences,第19版,1995]。根据具体实施例的药物组合物可以以单位剂量的形式制备,或者通过使用药学上可接受的载体和/或赋形剂根据本发明所属领域的普通技术人员可以容易地实施的方法配制而包含在多剂量容器中。在此类情况下,剂型可以是在油性或水性介质中的溶液、悬浮液或乳液的形式,或粉末、颗粒、片剂或胶囊的形式。
[有益效果]
根据一个方面的免疫细胞被设计为此类形式,即细胞因子通过连接子连接到细胞表面,并且因此细胞因子连续刺激免疫细胞,从而诱导增殖和活化,并且细胞因子不影响周围细胞,从而可以最小化副作用。
附图说明
图1是根据示例性实施方案的自然杀伤细胞的示意图。
图2是根据示例性实施方案的用于产生天然杀伤细胞的慢病毒载体的图解。
图3是显示根据示例性实施方案的天然杀伤细胞的增殖能力的图。
图4是显示根据示例性实施方案的天然杀伤细胞的生存力的图。
具体实施方式
在下文中,将通过实施例更详细地描述本发明。然而,提供这些实施例仅用于示例性地描述本发明,并且本发明的范围不受这些实施例的限制。
实施例1:制造其中细胞因子与连接子连接的天然杀伤细胞。
为了制备其中细胞因子与连接子连接的天然杀伤细胞,构建了包含跨膜结构域、连接子和编码细胞因子的多核苷酸的载体。
具体而言,设计PCR引物,使得每个cDNA可被引入到慢病毒载体pLV2-EF1a-MTA中与PCR扩增插入片段的每个末端相容的一对Sfil限制性酶识别位点中。在Sfil识别区被消化后,通过将插入片段分别连接到Sfil消化的慢病毒载体中,构建各种细胞因子的慢病毒细胞因子质粒。设计插入片段以包括[细胞因子-柔性连接子-跨膜结构域]的结构,并且质粒的特定结构如图2所示。
接下来,将HEK-293FT细胞与上述制备的慢病毒质粒以及pCMVD8.9和pVSVg病毒包装载体以1:1:1的比例共转染。细胞孵育过夜后,除去DNA脂质复合物,然后向细胞加入新鲜培养基。48小时后,收集含有病毒的上层液体,并使用0.22μm聚醚砜膜过滤器单元(Millipore)过滤收集的上清液。将从该程序获得的慢病毒颗粒加入到NK-92细胞(KCTC,韩国典型培养物保藏中心)中的含有8μg/mL聚凝胺的生长培养基中,并且可以使用1200×g速度的离心力感染90分钟。在37℃和5%CO2的条件下24小时后,在用新的培养基替换培养基后,将细胞孵育2天或更长时间。培养基购自Thermo Fisher Scientific(Waltham,USA)并使用。
通过上述方法生产的细胞因子的类型示于下述表1中。
[表1]
结果如图1所示,制备了天然杀伤细胞,其中细胞因子通过跨膜结构域经由连接子与天然杀伤细胞的质膜连接。细胞的增殖和活化可以通过将细胞因子与存在于天然杀伤细胞表面的细胞因子受体结合以连续刺激天然杀伤细胞来诱导。
实验性实施例1:通过连接子连接细胞因子的天然杀伤细胞的增殖能力和生存力分析。
为了分析被设计成经由连接子与实施例1的细胞因子IL-2连接的天然杀伤细胞的增殖能力和生存力,确认了在培养一段时间而不供应细胞因子后活细胞的比例。
具体地,使用流式细胞仪装置分离其中白细胞介素-2通过慢病毒感染经由连接子与质膜连接的天然杀伤细胞,并将这些细胞在通过将0.2mM的肌醇、0.1mM的2-巯基丙醇、0.02mM的叶酸、12.5%马血清和12.5%的FBS加入到MEMα培养基中并包括100U/mL白细胞介素-2培养一周而获得的培养基中培养。此后,将细胞因子未附着的NK-92细胞和白细胞介素-2附着的NK-92细胞分别用作对照组和实验组,并在将培养基更换为培养基(在此培养基中仅从相同培养基组合物中排除了白细胞介素-2)后培养一段时间,然后通过用锥虫蓝1:1染色确认活细胞的数目。培养基购自Thermo Fisher Scientific(Waltham,USA),待添加的材料购自Sigma Aldrich(St.Louis,USA)和BD(Franklin Lakes,USA)并使用。
通过计算用锥虫蓝染色为死细胞的细胞和计算未染色的细胞为活细胞来分析天然杀伤细胞的增殖能力和生存力,结果分别示于图3和图4。
图3是显示根据示例性实施方案的天然杀伤细胞的增殖能力的图。
图4是显示根据示例性实施方案的天然杀伤细胞的生存力的图。
如图3和图4所示,证实了根据具体实施例的天然杀伤细胞与没有遗传操作的对照天然杀伤细胞相比,在不存在外部细胞因子的环境中,其增殖增加了2倍或更多,并且也证实了细胞生存力增加了约1.6倍或更多。
这些结果意味着根据具体实施例与自然杀伤细胞的表面连接的细胞因子被增殖和活化,其通过刺激自身无需单独供应细胞因子且不影响其它细胞。
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Claims (17)
1.经基因工程改造的免疫细胞,其包含:跨膜结构域;细胞因子;以及用于将细胞因子连接到跨膜结构域的肽连接子。
2.如权利要求1所述的免疫细胞,其中所述跨膜结构域是受体酪氨酸激酶(RTK)的跨膜结构域。
3.如权利要求2所述的免疫细胞,其中受体酪氨酸激酶的跨膜结构域可以是选自以下的任一种受体的跨膜结构域:表皮生长因子受体、胰岛素受体,血小板衍生生长因子受体、血管内皮生长因子受体、成纤维细胞生长因子受体、胆囊收缩素(CCK)受体、神经营养因子(NGF)受体、肝细胞生长因子(HGF)受体、肝配蛋白(Eph)受体、血管生成素受体以及与受体酪氨酸激酶相关(RYK)的受体。
4.如权利要求1所述的免疫细胞,其中所述细胞因子是选自以下中的任一种:骨形态发生蛋白(BMP)家族、趋化因子配体(CCL)家族、含CKLF样MARVEL跨膜结构域成员(CMTM)家族、C-X-C基序配体(CXCL)家族、生长/分化因子(GDF)家族、生长激素、干扰素(IFN)家族、白介素(IL)家族、肿瘤坏死因子(TNF)超家族、糖磷脂酰肌醇(GPI)、分泌的Ly-6/uPAR-相关蛋白1(SLUPR-1)、分泌的Ly-6/uPAR-相关蛋白2(SLUPR-2)及它们的组合。
5.如权利要求4所述的免疫细胞,其中所述白介素是IL1、IL2、IL3、IL4、IL5、IL6、IL7、IL8(CXCL8)、IL9、IL10、IL11、IL12、IL13、IL14、IL15、IL16、IL17、IL18、IL19、IL20、IL21、IL22、IL23、IL24、IL25、IL26、IL27、IL28、IL29、IL30、IL31、IL32、IL33、IL35或IL36。
6.如权利要求4所述的免疫细胞,其中所述IFN家族是IFN-α、IFN-β、IFN-γ、IFN-ε、IFN-κ或IFN-ω。
7.如权利要求4所述的免疫细胞,其中所述TNFSF是TNF、CD40L(TNFSF5)、CD70(TNFSF7;CD27L)、EDA、FASL(TNFSF6)、LTA(TNFSF1)、LTB(TNFSF3)、TNFSF4(OX40L)、TNFSF8(CD153)、TNFSF9(4-1BBL)、TNFSF10(TRAIL)、TNFSF11(RANKL)、TNFSF12(TWEAK)、TNFSF13、TNFSF13B、TNFSF14、TNFSF15或TNFSF18。
8.如权利要求1所述的免疫细胞,其中所述肽连接子是柔性连接子,并且包含1至400个氨基酸残基。
9.如权利要求1所述的免疫细胞,其中所述肽连接子是(GGGGS)n(SEQ ID NO:1)、(SGGGG)n(SEQ ID NO:2)、(SRSSG)n(SEQ ID NO:3)、(SGSSC)n(SEQ ID NO:4)、(GKSSGSGSESKS)n(SEQ ID NO:5)、(RPPPPC)n(SEQ ID NO:6)、(SSPPPPC)n(SEQ ID NO:7)、(GSTSGSGKSSEGKG)n(SEQ ID NO:8)、(GSTSGSGKSSEGSGSTKG)n(SEQ ID NO:9)、(GSTSGSGKPGSGEGSTKG)n(SEQ ID NO:10)或(EGKSSGSGSESKEF)n(SEQ ID NO:11),并且n是1至20的整数。
10.如权利要求1所述的免疫细胞,其中所述免疫细胞用包含编码融合蛋白的多核苷酸的载体转化,所述融合蛋白包含:跨膜结构域;细胞因子;以及用于将细胞因子连接到跨膜结构域的肽连接子。
11.如权利要求10所述的免疫细胞,其中所述载体选自慢病毒、腺病毒、腺相关病毒、逆转录病毒、单纯疱疹病毒和痘苗病毒。
12.如权利要求1所述的免疫细胞,其中所述细胞因子结合存在于所述免疫细胞表面上的细胞因子受体,以连续刺激所述细胞。
13.如权利要求1所述的免疫细胞,其中所述免疫细胞是选自以下中的任一种:巨噬细胞、B淋巴细胞、T淋巴细胞、肥大细胞、单核细胞、树突细胞、嗜酸性粒细胞、天然杀伤细胞、嗜碱性粒细胞和嗜中性粒细胞。
14.如权利要求1所述的免疫细胞,其中所述免疫细胞是NK-92细胞。
15.细胞治疗剂,其包含作为活性成分的权利要求1所述的免疫细胞或其细胞群。
16.用于预防或治疗癌症的药物组合物,其包含作为活性成分的权利要求1所述的免疫细胞或其细胞群。
17.用于预防或治疗感染性疾病的药物组合物,其包含作为活性成分的权利要求1所述的免疫细胞或其细胞群。
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Application publication date: 20211029 |