CN111670246A - 5%人白蛋白在洗涤和收获培养基中的用途 - Google Patents
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Abstract
Description
相关申请
本申请要求于2018年1月31日提交的美国临时专利申请第62/624,624号的优先权。出于所有目的,该临时申请的内容通过引用整体合并于此。
背景技术
自然杀伤(NK)细胞是细胞毒性淋巴细胞,其构成先天免疫系统的主要成分。通常占到循环淋巴细胞的约10-15%的NK细胞结合并杀死所靶向的细胞,包括病毒感染的细胞和许多恶性细胞,对于抗原而言是非特异性的,并且没有事先的免疫致敏。Herberman等,Science 214:24(1981)。通过诱导细胞裂解来杀死靶细胞。用于该目的的NK细胞从受试者的血液的外周血淋巴细胞(“PBL”)部分中分离,在细胞培养物中扩增以获得足够数量的细胞,然后将其重新注入受试者中。已经显示NK细胞在离体治疗和体内治疗中都有些有效。然而,由于并非所有的NK细胞都具有细胞溶解作用的事实,这种疗法变得复杂化,并且该疗法对所治疗的患者是特异性的。
NK-细胞先前已被评估为治疗某些癌症的治疗剂。与NK细胞不同,NK-是一种细胞溶解性癌细胞系,其是在患有非霍奇金淋巴瘤的受试者的血液中发现的,然后在体外永生化。NK-细胞缺乏正常NK细胞所表现出的主要抑制性受体,但保留了大多数活化性受体。然而,NK-细胞不攻击正常细胞,它们在人体中也不会引发不可接受的免疫排斥反应。NK-细胞系的表征公开于,例如,WO 1998/49268和美国专利8,034,332号中。
然而,细胞收获效率低下仍然是产生足够的NK-细胞用于各种治疗应用的重大挑战。常规的收获程序通常包括从细胞培养基收获细胞,和在缓冲液如PBS中洗涤细胞。在PBS中的多次洗涤导致细胞损失的存活力的显著降低。在一些情况下,细胞在诸如X-VIVOTM10的培养基中洗涤;这也是不理想的,因为最终产品制剂需要两个额外的步骤,包括离心去除X-VIVOTM10。这些步骤增加了处理时间,并且由于需要重复的离心步骤而导致细胞应激和细胞损失。
发明内容
本文提供了收获NK-细胞的方法,其包括从细胞培养物收集NK-细胞,并通过包含1-5%白蛋白的缓冲液洗涤收集的NK-细胞。NK-细胞可以是经修饰以表达一种或多种转基因的那些细胞,例如,NK-细胞可以进行修饰以表达细胞因子、Fc受体、嵌合抗原受体或其组合。
任选地,收集NK-细胞包括离心细胞培养物中的NK-细胞。任选地,该方法进一步包括将洗涤的NK-细胞置于输液袋中。任选地,通过离心细胞和然后将细胞重悬于洗涤缓冲液中来进行洗涤。任选地,洗涤进行至少3次,例如4至6次。任选地,该方法回收至少80%的NK-细胞。任选地,收获的细胞的存活力为至少90%。
任选地,已经收获的NK-细胞具有与未收获的对照NK-细胞基本相同的细胞毒性和/或存活力。任选地,已经收获的NK-细胞具有与收获前的NK-细胞基本相同的细胞毒性和/或存活力。任选地,已收获的NK-细胞对K562细胞具有80-100%的细胞毒性。任选地,缓冲液包含2-5%白蛋白,例如3-5%白蛋白或5%白蛋白。任选地,缓冲液缺乏糖。任选地,缓冲液缺乏右旋糖酐。任选地,离心是通过连续离心进行的。任选地,白蛋白是人血浆白蛋白或人血清白蛋白。任选地,NK-细胞表达细胞因子、Fc受体、嵌合抗原受体或其组合。
前面的一般描述和下面的详细描述是示例性和说明性的,并且旨在提供对本公开的进一步说明。对于本领域技术人员而言,其他目的、优点和新颖特征将是清楚的。
附图说明
当结合附图考虑以下公开时,将更容易地理解目的、特征和优点。
具体实施方式
本文提供了使用含有1-5%白蛋白,任选地5%人类白蛋白的缓冲液收获NK-细胞的方法。洗涤后,这些细胞可直接用于治疗应用(例如,输液)而无需进一步的处理步骤或配制。这有利地减少了处理时间并使细胞损失和细胞应激最小化。
在阅读了该说明书之后,对于本领域技术人员而言,如何实施各种可选的实施方式和可选的应用将变得显而易见。然而,本文中未描述所有实施方式。应理解的是,本文提出的实施方式仅是以示例性的而不是限制性的方式提出的。因此,各种可选实施方式的这种详细描述不应被解释为限制本文所阐述的本公开的范围或广度。应当理解,下面描述的方面不限于特定的组合物、制备这种组合物的方法或它们的用途,因为它们可能会有所变化。
术语
除非另有定义,否则本文中使用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同含义。
在本说明书和随后的权利要求中,将引用许多术语,这些术语应被定义为具有以下含义:
本文所使用的术语仅出于描述特定实施方式的目的,而无意于进行限制。如本文所使用的,单数形式的“一”、“一个”和“该”也旨在包含复数形式,除非上下文另外明确指出。因此,例如,提及“一个自然杀伤细胞”包括多个自然杀伤细胞。
所有数字指定,例如pH值、温度、时间、浓度、量和分子量,包括范围,都是近似值,其在适当的情况下以0.1或1.0的增量(+)或(-)变化。应当理解,尽管并非总是明确地陈述,但是所有数字指定可以以术语“约”前置。
如本领域技术人员将理解的,出于任何和所有目的,特别是在提供书面说明方面,本文公开的所有范围也涵盖任何和所有可能的子范围及其子范围的组合。任何列出的范围都可以容易地认可为充分描述该范围,并且可以将该范围分解为至少相等的两等份、三等份、四等份、五等份、十等份等。作为非限制性示例,本文讨论的各个范围可以容易地分解为下三分之一、中三分之一和上三分之一,等。如本领域的技术人员还应理解的,如“最多”、“至少”、“大于”、“小于”等等的所有语言包含所陈述的数字并指代随后可如上所述细分为子范围的范围。最后,如本领域技术人员将理解的,范围包含各单个成员。因此,例如,具有1-3个细胞的组是指具有1、2或3个细胞的组。类似地,具有1-5个细胞的组是指具有1、2、3、4或5个细胞的组,依此类推。
还应理解,尽管并非总是明确指出,本文所述的试剂仅是示例性的,其等同物是本领域已知的。
“任选的”或“任选地”是指随后描述的事件或情况可能发生或可能不发生,并且该描述包括其中事件或情况发生的情况以及其中事件或情况没有发生的情况。
术语“包含”旨在表示所述组合物和方法包括所列举的元素,但不排除其他元素。当用于定义组合物和方法时,“基本上由……组成”应表示排除对该组合具有任何实质意义的其他元素。例如,基本上由本文所定义的元素组成的组合物不排除不会实质上影响权利要求的基本和新颖特征的其他元素。“由...组成”是指排除多于痕量的其他成分和实质性方法步骤。由这些过渡术语中的每一个限定的实施方式在本公开的范围内。
如本文所用,“自然杀伤(NK)细胞”是免疫系统的细胞,其在没有特异性抗原刺激并且没有根据主要组织相容性复合物(MHC)类别的限制的情况下杀死靶细胞。靶细胞可以是癌细胞或肿瘤细胞。NK细胞的特征在于存在CD56和不存在CD3表面标志物。
为了本发明的目的,且除非另有说明,术语“NK-”或“NK-”意指原始的NK-细胞系以及NK-细胞系、NK-细胞克隆和已被修饰(例如,通过引入外源基因)的NK-细胞。NK-细胞及其示例性和非限制性的修饰描述于美国专利号7,618,817;8,034,332;8,313,943;9,181,322;9,150,636;和公开的10/008,955号美国申请中,其全部内容通过引用整体并入本文,且包括野生型NK-NK--CD16、NK--CD16-γ、NK--CD16-ζ、NK--CD16(F176V)、NK-MI和NK-CI。NK-细胞是本领域普通技术人员已知的,此类细胞可容易地从NantKwest,Inc.获得。
如本文所用,术语“taNK细胞”是指已被工程化以表达对癌症特异性抗原、癌症相关抗原或肿瘤特异性抗原具有亲和力的嵌合抗原受体(CAR)的NK-细胞。在一些实施方式中,肿瘤特异性抗原是HER-2,例如,人HER-2,并且这些NK-细胞被称为HER-2 taNK细胞。
如本文所用,术语“t-haNK细胞”是指已被工程化以表达对癌症特异性抗原、癌症相关抗原或肿瘤特异性抗原具有亲和力的嵌合抗原受体(CAR)并表达Fc受体的NK-细胞。在一些实施方式中,肿瘤特异性抗原是CD19,例如,人CD19,并且这些NK-细胞被称为CD19 t-haNK细胞。在一些实施方式中,肿瘤特异性抗原是PD-L1。在一些实施方式中,t-haNK细胞表达具有SEQ ID NO:5的序列的嵌合抗原受体PD-L1 CAR。在一些实施方式中,t-haNK细胞表达具有SEQ ID NO:6的序列的嵌合抗原受体CD19 CAR。在一些实施方式中,t-haNK细胞表达具有SEQ ID NO:7的序列的嵌合抗原受体HER2 CAR。
术语“Fc受体”是指在某些细胞(例如,自然杀伤细胞)的表面上发现的蛋白质,其通过结合至称为Fc区的抗体的部分而促进免疫细胞的保护性功能。抗体的Fc区与细胞的Fc受体(FcR)的结合通过抗体介导的吞噬作用或抗体依赖性细胞介导的细胞毒性(ADCC)刺激细胞的吞噬或细胞毒性活性。FcR根据其识别的抗体类型进行分类。例如,Fc-γ受体(FcγR)与IgG类的抗体结合。FcγRIII-A(也称为CD16)是与IgG抗体结合并激活ADCC的低亲和力Fc受体。FcγRIII-A通常在NK细胞上发现。NK-细胞不表达FcγRIII-A。
如本文所用,术语“嵌合抗原受体”(CAR)是指与细胞内信号传导结构域融合的细胞外抗原结合结构域。CAR可以在T细胞或NK细胞中表达以增加细胞毒性。通常,细胞外抗原结合结构域是对在目的细胞上发现的抗原具有特异性的scFv。基于scFv结构域的特异性,表达CAR的NK-细胞靶向于在细胞表面表达某些抗原的细胞。scFv结构域可以进行工程化以识别任何抗原,包含肿瘤特异性抗原。
术语“多核苷酸”、“核酸”和“寡核苷酸”可互换使用,并指任何长度的核苷酸的聚合形式,脱氧核糖核苷酸或核糖核苷酸或其类似物。多核苷酸可以具有任何三维结构,并且可以执行任何已知或未知的功能。以下是多核苷酸的非限制性实例:基因或基因片段(例如,探针、引物、EST或SAGE标签)、外显子、内含子、信使RNA(mRNA)、转运RNA、核糖体RNA、核酶、cDNA、重组多核苷酸、分支多核苷酸、质粒、载体、任何序列的分离的DNA、任何序列的分离的RNA、核酸探针和引物。多核苷酸可以包含修饰的核苷酸,例如甲基化的核苷酸和核苷酸类似物。如果存在,可以在多核苷酸组装之前或之后赋予对核苷酸结构的修饰。核苷酸的序列可以被非核苷酸成分打断。多核苷酸可在聚合后进一步修饰,例如通过与标记组分缀合。该术语还指双链和单链分子。除非另有说明或要求,否则多核苷酸包含双链形式以及已知或预测组成双链形式的两个互补单链形式的每一个。
术语“表达”是指基因产物的产生。当涉及表达时,术语“瞬时”是指多核苷酸未并入细胞的基因组中。
术语“细胞因子”或“多个细胞因子”是指影响免疫系统细胞的生物分子的大类。示例性细胞因子包括但不限于,干扰素和白介素(IL),特别是IL-2、IL-12、IL-15、IL-18和IL-21。在优选的实施方式中,细胞因子是IL-2。
如本文所用,术语“载体”是指包含完整复制子的非染色体核酸,使得当置于允许的细胞内(例如,通过转化过程)时,载体可以复制。载体可以在一种细胞类型(例如,细菌)中复制,但是在另一种细胞(例如,哺乳动物细胞)中复制的能力有限。载体可以是病毒的或非病毒的。用于递送核酸的示例性非病毒载体包括裸DNA;与阳离子脂质(单独或与阳离子聚合物结合)复合的DNA;阴离子和阳离子脂质体;DNA-蛋白质复合物和包含与阳离子聚合物(如异质聚赖氨酸、确定长度的寡肽和聚乙烯亚胺)凝聚的,在某些情况下包含在脂质体中的DNA的颗粒;以及包含病毒和聚赖氨酸-DNA的三元复合物的使用。
如本文所用,当涉及细胞毒性、存活力或细胞回收率时,术语“基本上相同”与术语“相当的”或“相似的”互换使用,是指对细胞毒性、存活力或细胞回收率的两个测量彼此的差异不超过15%、不超过10%、不超过8%或不超过5%。
如本文所用,术语“细胞毒性”当用于描述效应细胞如NK细胞的活性时,是指通过多种生物学、生物化学或生物物理机制中的任一种杀灭靶细胞。
如本文所用,术语“收获”是指从其培养基中分离和收集细胞并制备细胞用于治疗应用。收获包括用合适的缓冲液,例如5%白蛋白洗涤细胞,以及任选地将细胞重悬于适合于预期应用(例如,输注)的缓冲液中。
如本文所用,术语“回收率”是指与进入收获过程的细胞数量相比,在收获过程完成之后获得的细胞的相对量。在某些情况下,回收率以百分比表示,例如,当使用连续离心作为收获细胞的手段时,回收率可以表示为以下方程式:
回收率=从连续离心中回收的细胞量/进入连续离心的细胞量。
为了方便读者,可以在说明书中使用标题或副标题,其不意在影响本公开的范围。另外,在下面更具体地定义本说明书中使用的一些术语。
白蛋白
白蛋白是细胞培养物中的蛋白质补充剂,用于将未酯化的脂肪酸递送到细胞中或从细胞中释放;白蛋白可以源自人或非人类来源,例如人或牛。人白蛋白可以源自人血清(“人血清白蛋白”)或人血浆(“人血浆白蛋白”),或者可以在体外合成,例如通过表达编码人白蛋白的基因(例如,NM_000477的序列)。迄今为止,白蛋白,特别是源自人的白蛋白尚未用于在收获期间洗涤细胞,因为与其他洗涤缓冲液(如PBS或生长培养基,如X VIVOTM10)相比,白蛋白的成本相对较高。人白蛋白可以商业购得,例如,从CSL Behring。
生长NK-细胞通常开始于解冻冷冻的NK-细胞和将其接种在具有合适培养基的容器中。使细胞恢复直至细胞存活力达到某个值,例如大于85%。然后在例如G-Rex烧瓶的容器中细胞扩增至所需的细胞密度,例如等于或小于1.2×106细胞/mL的密度。然后收集来自容器的细胞培养物,并用于接种一个或多个更大的培养容器。通常使用的这种较大的培养容器包括Xuri袋,其容积可以为至少2升、至少10升或至少50升。细胞在不同容器之间的转移可以使用本领域众所周知的方式进行,例如使用泵或重力进料,其在无菌条件下进行。
可以通过离心收获如此产生的NK-细胞。任选地,在连续离心机中进行离心,该连续离心机无菌连接到在扩增过程末端的培养容器,例如Xuri袋。连续离心是指持续时间45-60分钟的离心,取决于细胞培养体积,以浓缩细胞,随后进行至少1分钟、至少3分钟或至少5分钟的细胞洗涤。然后除去培养物上清液,并将细胞重悬在包含1-5%白蛋白,例如2-5%、3-5%或4-5%,优选5%白蛋白的洗涤缓冲液中。任选地,该洗涤可以重复至少两次、至少三次,例如4-6次。最后洗涤后,可以再次将含有细胞和洗涤缓冲液的混合物离心,且收集细胞并进行处理以用于治疗应用。
除白蛋白外,洗涤缓冲液还可包含1-10mg/mL的钠,例如3-5mg/mL的钠或3.2mg/mL的钠。任选地,洗涤缓冲液缺乏糖,例如右旋糖酐。任选地,洗涤缓冲液缺乏右旋糖酐-40。
收获方法可以回收80至100%的NK-细胞,例如85-99%或89-99%的NK-细胞。可以使用标准细胞计数程序,例如台盼蓝染料-排除法或Nucleocounter NC-200方法,评估收获的产率。任选地,使用本文公开的方法的收获方法可以回收与使用X-VIVOTM10培养基的收获方法基本相同量的NK-细胞。
如本文所公开的使用1-5%白蛋白收获的NK-细胞可以具有与在相同条件下生长但未收获的对照NK-细胞基本相同的细胞毒性。对照细胞可以是例如来自G-Rex烧瓶的NK-细胞。使用本文公开的方法收获的NK-细胞也可以具有与已经在X-VIVOTM10培养基中收获的NK-细胞基本相同的细胞毒性。使用本文公开的方法收获的NK-细胞可以具有与收获前的NK-细胞基本相同的细胞毒性。参见表2。
NK-细胞的细胞毒性可以通过其直接细胞毒性或ADCC来反映。产生的NK-细胞的直接细胞毒性,靶向和杀伤异常细胞(例如病毒感染和致瘤性细胞)的能力可以通过本领域众所周知的方法进行评估,例如51Cr释放测定法(Gong等(1994)),使用Klingemann等(1994)所描述的程序(Cancer Immunol.Immunother.33:395-397(1991))。简而言之,将51Cr标记的靶细胞与NK-细胞混合并裂解。可以基于释放的51Cr量计算特异性细胞毒性的百分比。参见专利公开号US20020068044。
可选地,也可以使用钙黄绿素释放测定法评估产生的NK-细胞的直接细胞毒性。例如,可以将NK-细胞(该测定中称为效应细胞)与装载钙黄绿素的靶细胞(该测定中称为靶细胞)以一定比率混合。孵育一段时间后,可以例如通过荧光平板阅读仪评估从靶细胞释放的钙黄绿素。测定中使用的效应与靶的比率可以变化,任选地,效应:靶标比率可以为20:1、15:1、10:1、8:1或5:1;优选地,效应:靶比率为10:1。靶细胞可以是表达可以被NK-细胞识别的MHC分子的任何细胞,例如K562细胞或BT-474细胞。NK-细胞的细胞毒性值可能根据所用靶细胞的类型以及效应:靶的比率有所不同。通常,使用本文所述方法产生的NK-细胞可具有60-100%,例如70-100%或80-100%的细胞毒性。在某些情况下,当使用K562细胞作为靶细胞时,通过钙黄绿素释放测定法,aNK细胞可具有80-100%的细胞毒性,例如82-100%、85-100%、87-100%、88-100%或89-100%。
任选地,评估的NK-细胞(例如haNK细胞)的细胞毒性是抗体依赖性细胞毒性(ADCC)。用于测量NK-细胞的ADCC的方法与上述测量直接细胞毒性的方法类似,不同之处在于添加了可以识别靶细胞的抗体。NK细胞的Fc受体识别细胞结合的抗体,并触发溶细胞反应并杀死靶细胞。在一个说明性实例中,haNK细胞可以与Rituxan(抗体)和Ramos(靶细胞)一起孵育,并且可以通过靶细胞内部组分(例如51Cr或钙黄绿素)的释放来测量Ramos细胞的杀伤,如上所述。
NK-细胞系是一种独特的细胞系,其被发现在白介素2(IL-2)的存在下增殖。Gong等,Leukemia 8:652-658(1994)。这些细胞具有针对多种癌症的高细胞溶解活性。NK-细胞系是具有广泛的抗肿瘤细胞毒性的均一癌性NK细胞群体,其具有可预测的扩增后产率。一期临床试验已证实其安全性特征。NK-在患有非霍奇金淋巴瘤的受试者的血液中发现,和然后离体永生化。NK-细胞源自NK细胞,但缺乏正常NK细胞所表现出的主要抑制性受体,同时保留了大多数活化性受体。但是,NK-细胞不攻击正常细胞,也不会在人体中引发不可接受的免疫排斥反应。在WO 1998/49268和美国专利申请公开号2002-0068044中公开了NK-细胞系的表征。
据发现NK-细胞系表现出CD56bright、CD2、CD7、CD11a、CD28、CD45和CD54表面标志物。此外,它不呈现CD1、CD3、CD4、CD5、CD8、CD10、CD14、CD16、CD19、CD20、CD23和CD34标志物。NK-细胞在培养中的生长依赖于重组白介素2(rIL-2)的存在,低至1IU/mL的剂量足以维持增殖。IL-7和IL-12不支持长期生长,其他测试的细胞因子(包括IL-1α、IL-6、肿瘤坏死因子α、干扰素α和干扰素γ)也不支持长期生长。NK-即使在1:1的低效应:靶(E:T)比率下也具有高的细胞毒性。Gong等,同上。NK-细胞保藏在美国典型培养物保藏中心(American Type Culture Collection,ATCC),保藏号为CRL-2407。
迄今为止,对内源性NK细胞的研究表明,IL-2(1000 IU/mL)对于运输过程中NK细胞的活化至关重要,但是不必将细胞维持在37℃和5%的二氧化碳中。Koepsell等,Transfusion 53:398-403(2013)。
修饰的NK-细胞是已知的,并包括但不限于在例如,美国专利号7,618,817、8,034,332和8,313,943,美国专利申请公开号2013/0040386中描述的那些,其全部内容的全文通过引用并入本文,例如,野生型NK-NK--CD16、NK--CD16-γ、NK--CD16-ζ、NK--CD16(F157V)、NK-mi和NK-ci。
尽管NK-细胞保留了几乎所有活化性受体和与NK细胞相关的细胞溶解途径,但它们在其细胞表面上不表达CD16。CD16是识别并结合抗体的Fc部分以激活NK细胞的抗体依赖性细胞毒性(ADCC)的Fc受体。由于缺乏CD16受体,NK-细胞无法通过ADCC机制裂解靶细胞,并因此无法增强内源性或外源性抗体(即,利妥昔单抗和赫赛汀)的抗肿瘤作用。
对内源性NK细胞的研究表明,IL-2(1000IU/mL)对于运输过程中的NK细胞活化至关重要,但是不必将细胞维持在37℃和5%的二氧化碳中。Koepsell等,Transfusion 53:398-403(2013)。但是,内源性NK细胞与NK-细胞显著不同,很大程度上是因为它们的来源不同:NK-是癌症衍生的细胞系,而内源性NK细胞从供体(或患者)收获并进行处理以注入患者体内。内源性NK细胞制剂是异质细胞群体,而NK-细胞是同质的克隆细胞系。NK-细胞在保持细胞毒性的同时很容易在培养物中增殖,而内源性NK细胞则不能。另外,内源性NK细胞的异质群体不会以高密度聚集。此外,内源性NK细胞表达Fc受体,包括NK-细胞不表达的CD-16受体。
Fc受体
Fc受体结合抗体的Fc部分。几种Fc受体是已知的,并且根据它们优选的配体、亲和力、表达和与抗体结合后的作用而不同。
表1.说明性Fc受体
在一些实施方式中,Fc受体是CD16。编码CD16的代表性氨基酸序列示于SEQ IDNO:2中。编码CD16的代表性多核苷酸序列示于SEQ ID NO:1中。在一些实施方式中,NK-细胞通过引入与编码全长(包含信号肽)的天然存在的CD16(其在全长CD16的位置176处具有苯丙氨酸)的多核苷酸序列具有至少约70%多核苷酸序列同一性的编码CD16多肽的多核苷酸来修饰。在一些实施方式中,编码CD16多肽的多核苷酸与编码在176位具有缬氨酸的全长(包含信号肽)的天然存在的CD16的多核苷酸序列具有至少约70%的多核苷酸序列同一性。
同源多核苷酸序列包括对编码CD16变体的多肽序列进行编码的那些序列。在一些实施方式中,同源CD16多核苷酸的长度可以是约150至约700、约750或约800多核苷酸,尽管具有超过700至800多核苷酸的CD16变体在本公开的范围内。
在其他实例中,具有改变CD16氨基酸序列的多态性的cDNA序列用于修饰NK-细胞,例如,在CD16基因中表现出遗传多态性的个体之间的等位基因变异。在其他实例中,使用来自其他物种的具有与人CD16的序列不同的多核苷酸序列的CD16基因来修饰NK-细胞。
在实例中,使用本领域已知的方法例如寡核苷酸介导的(定点)诱变、丙氨酸扫描和PCR诱变来制备变体多肽。可以对克隆的DNA进行定点诱变(Carter,1986;Zoller和Smith,1987)、盒式诱变、限制性选择诱变(Wells等,1985)或其他已知技术以产生CD16变体(Ausubel,2002;Sambrook和Russell,2001)。
人CD16多肽的氨基酸序列中的保守置换,其中一个类别的氨基酸被相同类别的另一氨基酸取代落入所公开的CD16变体的范围内,只要该置换没有实质性地改变多肽的活性。保守置换是本领域技术人员众所周知的。影响(1)多肽主链的结构如β-折叠或α-螺旋构象,(2)电荷,(3)疏水性或(4)靶位点的侧链的体积的非保守置换可以修饰CD16多肽的功能或免疫学特性。非保守置换需要将这些类别中一个的成员交换为另一个类别。可以将置换引入保守置换位点中或更优选引入非保守位点中。
在一些实施方式中,CD16多肽变体的长度为至少200个氨基酸,并且与SEQ ID NO:1或SEQ ID NO:2具有至少70%的氨基酸序列同一性,或至少80%或至少90%的同一性。在一些实施方式中,CD16多肽变体的长度为至少225个氨基酸,并且与SEQ ID NO:1或SEQ IDNO:2具有至少70%的氨基酸序列同一性,或至少80%或至少90%的同一性。
在一些实施方式中,编码CD16多肽的核酸可以编码CD16融合蛋白。CD16融合多肽包含与非CD16多肽融合的CD16的任何部分或整个CD16。在一些实施方式中,可以产生其中异源多肽序列与CD16的C末端融合或位于CD16内部的融合多肽。通常,最多约30%的CD16胞质结构域可以被替换。这样的修饰可以增强表达或增强细胞毒性(例如,ADCC响应性)。在其他实例中,嵌合蛋白,例如来自其他淋巴细胞活化受体的结构域,包括但不限于Ig-a、Ig-B、CD3-e、CD3-d、DAP-12和DAP-10,取代了一部分CD16细胞质结构域。
融合基因可以通过常规技术合成,包括自动DNA合成仪和使用锚定引物的PCR扩增,其在两个连续的基因片段之间产生互补的突出端,随后可以对其进行退火和重新扩增以产生嵌合基因序列(Ausubel,2002)。许多载体是可商购的,其有助于将CD16框内亚克隆到融合部分。
嵌合抗原受体
如本文所述,将NK-细胞进一步工程化以在细胞表面上表达嵌合抗原受体(CAR)。任选地,CAR对肿瘤特异性抗原具有特异性。通过非限制性实例,在US 2013/0189268;WO 1999024566 A1;US 7098008;和WO 2000020460 A1中描述了肿瘤特异性抗原,其每一个通过引用将其全部内容并入本文。肿瘤特异性抗原包括但不限于,NKG2D、CS1、GD2、CD138、EpCAM、EBNA3C、GPA7、CD244、CA-125、ETA、MAGE、CAGE、BAGE、HAGE、LAGE、PAGE、NY-SEO-1、GAGE、CEA、CD52、CD30、MUC5AC、c-Met、EGFR、FAB、WT-1、PSMA、NY-ESO1、AFP、CEA、CTAG1B、CD19和CD33。其他非限制性的肿瘤相关性抗原以及与之相关的恶性肿瘤可以在表2中找到。
表2:肿瘤特异性抗原和相关的恶性肿瘤
在一些实施方式中,CAR靶向CD19、CD33或CSPG-4。
在实例中,使用本领域已知的方法例如寡核苷酸介导的(定点)诱变、丙氨酸扫描和PCR诱变来制备变体多肽。可以对克隆的DNA进行定点诱变(Carter,1986;Zoller和Smith,1987)、盒式诱变、限制性选择诱变(Wells等,1985)或其他已知技术以产生CD16变体(Ausubel,2002;Sambrook和Russell,2001)。
任选地,CAR靶向与特定癌症类型相关的抗原。任选地,所述癌症选自于白血病(包括急性白血病(例如,急性淋巴细胞性白血病、急性髓细胞性白血病(包括成髓细胞性、早幼粒细胞性、骨髓单核细胞性、单核细胞性和红细胞性白血病))和慢性白血病(例如,慢性髓细胞性(粒细胞性)白血病和慢性淋巴细胞性白血病)、真性红细胞增多症、淋巴瘤(例如,霍奇金病和非霍奇金病)、多发性骨髓瘤、沃尔登斯特伦巨球蛋白血症、重链病、实体肿瘤包括但不限于肉瘤和癌瘤,如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨源性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内膜肉瘤、滑膜瘤、间皮瘤、尤因氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔姆氏肿瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、血管瘤、黑色素瘤、神经母细胞瘤和视网膜母细胞瘤。
在一些实施方式中,编码CAR的多核苷酸突变以改变编码CAR的氨基酸序列,而不改变CAR的功能。例如,可以在以上公开的CAR中进行导致“非必需”氨基酸残基处的氨基酸置换的多核苷酸置换。可以按照例如在专利公开号WO 2014039523;US 20140242701;US20140274909;US 20130280285;和WO 2014099671中描述的对CAR工程化,其每一个通过引用整体并入本文。任选地,该CAR是CD19 CAR、CD33 CAR或CSPG-4 CAR。
另外的修饰-细胞因子
NK-细胞的细胞毒性取决于细胞因子(例如白介素-2(IL-2))的存在。在商业规模的培养中使用外源添加的IL-2维持和扩增NK-细胞的成本是可观的。向人类受试者施用足够量的IL-2以继续激活NK-细胞会引起不利的副作用。
在一些实施方式中,表达FcR的NK-细胞被进一步修饰以表达至少一种细胞因子和自杀基因。在具体的实施方式中,该至少一种细胞因子是IL-2、IL-12、IL-15、IL-18、IL-21或其变体。在优选的实施方式中,该细胞因子是IL-2。SEQ ID NO:3中显示了编码IL-2的代表性核酸,和SEQ ID NO:4中显示了IL-2的代表性多肽。在某些实施方式中,IL-2是靶向于内质网的变体。
在一个实施方式中,表达具有将IL-2引导至内质网的信号序列的IL-2。不受理论的束缚,但是将IL-2引导至内质网允许以足以自分泌激活的水平表达IL-2,但不会细胞外释放IL-2。参见Konstantinidis等“Targeting IL-2 to the endoplasmic reticulumconfines autocrine growth stimulation to NK-cells”Exp Hematol.2005Feb;33(2):159-64。可以例如通过自杀基因的存在来阻止表达FcR的NK-细胞的连续激活。
另外的修饰-自杀基因
术语“自杀基因”是允许细胞的负向选择的一种基因。自杀基因被用作安全系统,从而允许表达该基因的细胞通过引入选择剂而被杀死。在重组基因引起导致不受控制的细胞生长的突变的情况中,这是理想的。已经确定了许多自杀基因系统,包括单纯疱疹病毒胸苷激酶(TK)基因、胞嘧啶脱氨酶基因、水痘带状疱疹病毒胸苷激酶基因、硝基还原酶基因、大肠杆菌gpt基因和大肠杆菌Deo基因(另请参见,例如,Yazawa K,Fisher WE,BrunicardiFC:Current progress in suicide gene therapy for cancer.World J.Surg.2002年7月;26(7):783-9)。如本文所用,自杀基因在NK-细胞中具有活性。通常,自杀基因编码的蛋白质对细胞没有不良影响,但是在存在特定化合物的情况下会杀死细胞。因此,自杀基因通常是系统的一部分。
在一个实施方式中,自杀基因是胸苷激酶(TK)基因。TK基因可以是野生型或突变TK基因(例如,tk30、tk75、sr39tk)。可以使用更昔洛韦(ganciclovir)杀死表达TK蛋白的细胞。
在另一个实施方式中,自杀基因是胞嘧啶脱氨酶,其在5-氟胞嘧啶存在下对细胞是毒性的。Garcia-Sanchez等,“Cytosine deaminase adenoviral vector and 5-fluorocytosine selectively reduce breast cancer cells 1 million-fold whenthey contaminate hematopoietic cells:a potential purging method forautologous transplantation.”Blood 1998年7月15日;92(2):672-82。
在另一个实施方式中,自杀基因是在异环磷酰胺或环磷酰胺存在下毒性的细胞色素P450。参见,例如,Touati等,“A suicide gene therapy combining the improvementof cyclophosphamide tumor cytotoxicity and the development of an anti-tumorimmune response.”Curr Gene Ther.2014;14(3):236-46。
在另一个实施方式中,自杀基因是iCas9。Di Stasi,(2011)“Inducibleapoptosis as a safety switch for adoptive cell therapy.”N Engl J Med 365:1673–1683。另见Morgan,“Live and Let Die:A New Suicide Gene Therapy Moves tothe Clinic”Molecular Therapy(2012);20:11–13。iCas9蛋白在小分子AP1903存在下诱导细胞凋亡。AP1903是生物学惰性的小分子,其在临床研究中已显示出是良好耐受的,并已用于过继性细胞治疗的情况中。
在一个实施方式中,在施用于患者之前,修饰的NK-细胞进行辐照。NK-细胞的辐照描述于,例如,美国专利号8,034,332中,其通过引用整体并入本文。在一个实施方式中,未工程化以表达自杀基因的经修饰的NK-细胞进行辐照。
转基因表达
可通过本领域技术人员已知的任何机制将转基因(例如,CD19CAR和CD16)工程化到表达载体中。可以将转基因工程化到相同的表达载体或不同的表达载体中。在优选的实施方式中,将转基因工程化到相同的载体中。
在一些实施方式中,载体允许将转基因整合至细胞的基因组中。在一些实施方式中,载体具有正向选择标记。正向选择标记包括允许细胞在将杀死不表达该基因的细胞的条件下生长的任何基因。非限制性实例包含抗生素抗性,例如,遗传霉素(来自Tn5的Neo基因)。
可以使用任何数量的载体来表达Fc受体和/或CAR。在一些实施方式中,载体是质粒。在一个实施方式中,载体是病毒载体。病毒载体包括但不限于,逆转录病毒载体、腺病毒载体、腺相关病毒载体、单纯疱疹病毒载体、痘病毒载体等等。
公开了可用于本公开的方法和组合物,可与本公开的方法和组合物结合使用,可用于制备本公开的方法和组合物的材料、组合物和组分,或者公开了本公开的方法和组合物的产物。在本文中公开了这些和其他材料,并且应当理解,当公开这些材料的组合、子集、相互作用、组等时,尽管这些化合物的各个单独的和集体的组合和排列的具体指示可能未明确公开,但其各自都在本文中特别考虑和描述。例如,如果公开并讨论了一种方法,并且讨论了可以对包括该方法的许多分子进行多种修饰,则该方法的各个和每种组合和排列以及可能的修饰都被特别考虑,除非特别指出相反。同样,这些的任何子集或组合也被特别考虑和公开。该概念适用于本公开的所有方面,包括但不限于使用所公开的组合物的方法中的步骤。因此,如果存在可以执行的多种附加步骤,则应理解,这些附加步骤中的每一个可以与所公开方法的任何特定方法步骤或方法步骤的组合来执行,并且每个这样的组合或组合的子集都特别考虑且应视为已公开。
实施例
以下实施例仅用于说明性目的,并且不应解释为限制。存在着本领域技术人员可以使用的多种替代技术和程序,它们将类似地允许人们成功地执行以下实施例。
实施例1:使用5%的人类白蛋白洗涤细胞提高细胞收获的效率
图1显示了使用X-VIVOTM10或5%HA(人白蛋白)从大型生物反应器收获修饰的NK-(HER2.taNK)细胞的过程。尽管细胞可以使用两种方法浓缩,但在X-VIVOTM10中进行收获还需要两个额外的步骤,这导致处理时间增加以及由离心导致的细胞应激和损失。在5%的人白蛋白中收获细胞简化工艺并提高收获效率。
将冷冻的修饰的NK-(HER2.taNK)细胞在37℃水浴中解冻。将100μL解冻的细胞分别添加到900μL X-VIVOTM10培养基、5%人类白蛋白和PBS中。使用Nucleocounter NC-200TM测量细胞存活力,并在表3中显示。
表3.在5%人白蛋白中解冻后的细胞存活力
结果表明,在5%人白蛋白中解冻的细胞具有86.5%的存活力,尽管不如X-VIVOTM10(94.4%)高,但显著高于在PBS中解冻的细胞的存活力(74.6%)。将在5%人白蛋白中解冻的细胞和在X-VIVOTM10中解冻的细胞分别转移至G-Rex烧瓶生长培养基中进行扩增,且分别在Xuri袋中的25L生长培养基和10L生长培养基中进一步扩增。
收集在Xuri袋中生长的修饰的NK-(HER2.taNK)细胞,并使用连续离心用X-VIVOTM10培养基或5%人白蛋白进行洗涤。对于每一组,对用于进料到连续离心的细胞(即未经过收获过程的细胞,称为收获前样品);离开连续离心机的细胞(即,完成收获过程的细胞,称为收获后样品);和未经过收获过程的用作对照细胞的来自G-rex烧瓶的细胞进行细胞毒性测定。为了评估细胞毒性,将细胞与负载钙黄绿素的靶细胞以10:1的效应:靶比率混合。共孵育3小时后,通过荧光平板阅读仪评估钙黄绿素的释放。使用钙黄绿素释放测定法测定细胞毒性,并表示为钙黄绿素释放的平均值±标准偏差百分比(%)。效应:靶比率为10:1,且样品一式三份地分析。
结果显示,使用5%人白蛋白作为洗涤缓冲液收获的修饰NK-(HER2.taNK)细胞的细胞毒性(为88±10%)与使用X-VIVOTM 10收获的HER2.taNK细胞的细胞毒性(90±4%)基本相同。用5%人白蛋白收获的HER2.taNK细胞的细胞毒性也与对照HER2.taNK细胞(即,G-Rex烧瓶中的细胞)的细胞毒性(为90±5%)基本相同。另外,使用5%人白蛋白作为细胞洗涤培养基不损害HER2.taNK细胞的细胞毒性,如收获前样品的细胞毒性和收获后样品的细胞毒性也基本相似所反映的。见表4。
表4.HER2.taNK细胞对BT-474靶细胞的细胞毒性
结果表明,使用5%白蛋白(人)作为洗涤缓冲液收获的修饰的NK-(CD19 t-haNK和PD-L1 t-haNK)细胞(收获后)对不同起源的肿瘤细胞的细胞毒性与直接取自生物反应器的细胞(收获前)以及参考对照细胞(即,G-Rex烧瓶中的细胞)的细胞毒性相当。参见表5。
结果显示,使用5%白蛋白(人)作为洗涤缓冲液收获的修饰的NK-(haNK,和CD19 t-haNK,和PD-L1 t-haNK)细胞(收获后)当与临床级别的不同治疗性抗体配合时,诱导肿瘤细胞的有效抗体依赖性细胞毒性(ADCC)。在参考样品、收获前样品和收获后样品之间观察到了相当的ADCC。参见表6。
使用在X-VIVOTM 10或5%白蛋白(人)中进行的连续离心收获修饰的NK-(HER2.taNK)细胞。使用Nucleocounter NC-200细胞计数方法和台盼蓝染料排除法检查收获前和收获后样品的细胞存活力。以从连续离心回收的细胞量/进入连续离心的细胞量来计算百分回收率。结果表明,从X-VIVOTM 10或5%白蛋白(人)收获的细胞的存活力相当,为96.7%和95.7%。此外,使用5%白蛋白(人)收获时的细胞百分回收率为91.9%,略高于使用X-VIVOTM 10的收获(其为89.9%)。此外,收获前样品和收获后样品的存活力也相当,这表明用5%白蛋白(人)洗涤细胞不会损害细胞存活力。见表7。
使用在5%白蛋白(人)中的连续离心来收获修饰的NK-细胞,并使用基于流式细胞术的方法检查样品的表面表达。表面标志物百分表达不受5%白蛋白(人)洗涤的影响,因为在收获后、收获前细胞以及参考细胞上观察到相似的表达量。见表8和表9。
表8.收获的CD19 t-haNK细胞的表型分型
1通过流式细胞术测定的细胞表面标志物阳性的CD19 t-haNK细胞的百分比(%)
1通过流式细胞术测定的CD19.CAR表达阳性的CD19 t-haNK细胞的百分比
应当理解,本文描述的实施例和实施方式仅用于说明性目的,并且鉴于其的各种修改或改变将是本领域技术人员容易想到的,并且将被包括在本申请的精神和范围以及所附权利要求的范围之内。本文引用的所有出版物、序列登录号、专利和专利申请出于所有目的通过引用整体并入本文。
非正式序列表
SEQ ID NO:1高亲和力变体免疫球蛋白γFc区受体III-A核酸序列(全长形式)。
ATGTGGCA GCTGCTGCTG CCTACAGCTC TCCTGCTGCT GGTGTCCGCC GGCATGAGAACCGAGGATCT GCCTAAGGCC GTGGTGTTCC TGGAACCCCA GTGGTACAGA GTGCTGGAAA AGGACAGCGTGACCCTGAAG TGCCAGGGCG CCTACAGCCC CGAGGACAAT AGCACCCAGT GGTTCCACAA CGAGAGCCTGATCAGCAGCC AGGCCAGCAG CTACTTCATCGACGCCGCCA CCGTGGACGA CAGCGGCGAG TATAGATGCCAGACCAACCT GAGCACCCTGAGCGACCCCG TGCAGCTGGA AGTGCACATC GGATGGCTGC TGCTGCAGGCCCCCAGATGG GTGTTCAAAG AAGAGGACCC CATCCACCTG AGATGCCACT CTTGGAAGAACACCGCCCTGCACAAAGTGA CCTACCTGCA GAACGGCAAG GGCAGAAAGT ACTTCCACCA CAACAGCGACTTCTACATCC CCAAGGCCAC CCTGAAGGAC TCCGGCTCCT ACTTCTGCAG AGGCCTCGTGGGCAGCAAGAACGTGTCCAG CGAGACAGTG AACATCACCA TCACCCAGGG CCTGGCCGTGTCTACCATCA GCAGCTTTTTCCCACCCGGC TACCAGGTGT CCTTCTGCCT CGTGATGGTG CTGCTGTTCG CCGTGGACAC CGGCCTGTACTTCAGCGTGA AAACAAACAT CAGAAGCAGC ACCCGGGACT GGAAGGACCA CAAGTTCAAG TGGCGGAAGGACCCCCAGGA CAAGTGA
SEQ ID NO:2高亲和力变体免疫球蛋白γFc区受体III-A氨基酸序列(全长形式)。位置176处的Val加下划线。
Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Leu Leu Leu Val Ser Ala GlyMet Arg Thr Glu Asp Leu Pro Lys Ala Val Val Phe Leu Glu Pro Gln Trp Tyr ArgVal Leu Glu Lys Asp Ser Val Thr Leu Lys Cys Gln Gly Ala Tyr Ser Pro Glu AspAsn Ser Thr Gln Trp Phe His Asn Glu Ser Leu Ile Ser Ser Gln Ala Ser Ser TyrPhe Ile Asp Ala Ala Thr Val Asp Asp Ser Gly Glu Tyr Arg Cys Gln Thr Asn LeuSer Thr Leu Ser Asp Pro Val Gln Leu Glu Val His Ile Gly Trp Leu Leu Leu GlnAla Pro Arg Trp Val Phe Lys Glu Glu Asp Pro Ile His Leu Arg Cys His Ser TrpLys Asn Thr Ala Leu His Lys Val Thr Tyr Leu Gln Asn Gly Lys Gly Arg Lys TyrPhe His His Asn Ser Asp Phe Tyr Ile Pro Lys Ala Thr Leu Lys Asp Ser Gly SerTyr Phe Cys Arg Gly Leu Val Gly Ser Lys Asn Val Ser Ser Glu Thr Val Asn IleThr Ile Thr Gln Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly TyrGln Val Ser Phe Cys Leu Val Met Val Leu Leu Phe Ala Val Asp Thr Gly Leu TyrPhe Ser Val Lys Thr Asn Ile Arg Ser Ser Thr Arg Asp Trp Lys Asp His Lys PheLys Trp Arg Lys Asp Pro Gln Asp Lys
SEQ ID NO:3 ER IL-2核酸序列
ATGTACCGGATG CAGCTGCTGA GCTGTATCGC CCTGTCTCTG GCCCTCGTGA CCAACAGCGCCCCTACCAGC AGCAGCACCA AGAAAACCCA GCTGCAGCTG GAACATCTGC TGCTGGACCTGCAGATGATCCTGAACGGCA TCAACAACTA CAAGAACCCC AAGCTGACCC GGATGCTGACCTTCAAGTTC TACATGCCCAAGAAGGCCAC CGAACTGAAA CATCTGCAGT GCCTGGAAGAGGAACTGAAG CCCCTGGAAG AAGTGCTGAACCTGGCCCAG AGCAAGAACT TCCACCTGAG GCCCAGGGAC CTGATCAGCA ACATCAACGT GATCGTGCTGGAACTGAAAG GCAGCGAGACAACCTTCATG TGCGAGTACG CCGACGAGAC AGCTACCATC GTGGAATTTCTGAACCGGTGGATCACCTTC TGCCAGAGCA TCATCAGCAC CCTGACCGGC TCCGAGAAGG ACGAGCTGTGA
SEQ ID NO:4 ER IL-2(ER保留信号带下划线)氨基酸序列
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu ValThr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu HisLeu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro LysLeu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu LysHis Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu AlaGln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val IleVal Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu ThrAla Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile SerThr Leu Thr Gly Ser Glu Lys Asp Glu Leu
SEQ ID NO:5 PD-L1 CAR的氨基酸序列
SEQ ID NO:6 CD19 CAR的氨基酸序列
SEQ ID NO:7 Her2 CAR的氨基酸序列
MDWIWRILFLVGAATGAHSAQPADIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKSSGGGGSGGGGSGGGGSGGGGSGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS
权利要求书(按照条约第19条的修改)
4.如权利要求1所述的方法,其中所述洗涤通过离心所述细胞,和然后将所述细胞重悬浮于所述洗涤缓冲液中来进行。
5.如权利要求1所述的方法,其中所述洗涤至少进行三次。
6.如权利要求1所述的方法,其中所述洗涤进行4-6次。
8.如权利要求1所述的方法,其中所收获的细胞的存活力为至少90%。
12.如权利要求1所述的方法,其中所述缓冲液包含2-5%的白蛋白。
13.如权利要求1所述的方法,其中所述缓冲液包含3-5%的白蛋白。
14.如权利要求1所述的方法,其中所述缓冲液包含5%的白蛋白。
15.如权利要求1所述的方法,其中所述缓冲液缺乏糖。
16.如权利要求1所述的方法,其中所述缓冲液缺乏右旋糖酐。
17.如权利要求4所述的方法,其中所述离心是通过连续离心进行的。
18.如权利要求1所述的方法,其中所述白蛋白是人白蛋白,或者人血清来源的白蛋白,或人血浆来源的白蛋白。
20.如权利要求19所述的方法,其中所述嵌合抗原受体是HER2、CD19或PD-L1的受体。
21.如权利要求19所述的方法,其中所述嵌合抗原受体是表1中所列的任何肿瘤特异性抗原的受体。
Claims (21)
4.如权利要求1所述的方法,其中所述洗涤通过离心所述细胞,和然后将所述细胞重悬浮于所述洗涤缓冲液中来进行。
5.如权利要求1所述的方法,其中所述洗涤至少进行三次。
6.如权利要求1所述的方法,其中所述洗涤进行4-6次。
8.如权利要求1所述的方法,其中所收获的细胞的存活力为至少90%。
12.如权利要求1所述的方法,其中所述缓冲液包含2-5%的白蛋白。
13.如权利要求1所述的方法,其中所述缓冲液包含3-5%的白蛋白。
14.如权利要求1所述的方法,其中所述缓冲液包含5%的白蛋白。
15.如权利要求1所述的方法,其中所述缓冲液缺乏糖。
16.如权利要求1所述的方法,其中所述缓冲液缺乏右旋糖酐。
17.如权利要求4所述的方法,其中所述离心是通过连续离心进行的。
18.如权利要求1所述的方法,其中所述白蛋白是人白蛋白,或者人血清来源的白蛋白,或人血浆来源的白蛋白。
20.如权利要求19所述的方法,其中所述嵌合抗原受体是HER2、CD19或PD-L1的受体。
21.如权利要求19所述的方法,其中所述嵌合抗原受体是表1中所列的任何肿瘤特异性抗原的受体。
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CN112567024A (zh) * | 2018-10-31 | 2021-03-26 | 南克维斯特公司 | 表达pd-l1嵌合抗原受体的nk细胞消除pd-l1阳性恶性肿瘤 |
KR20200119892A (ko) * | 2018-10-31 | 2020-10-20 | 난트퀘스트, 인크. | Cd19-car 발현 nk 세포에 의한 cd19-양성 림프성 악성종양의 제거(elimination of cd19-positive lymphoid malignancies by cd19-car expressing nk cells) |
US11230699B2 (en) | 2020-01-28 | 2022-01-25 | Immunitybio, Inc. | Chimeric antigen receptor-modified NK-92 cells targeting EGFR super-family receptors |
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