CN113366023A - 用于刺激自然杀伤细胞的组合物和方法 - Google Patents
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Abstract
描述了用于刺激NK细胞扩增和细胞毒性的组合物和方法。描述了使用扩增和刺激的NK细胞的治疗性组合物和方法。
Description
本申请要求2019年1月24日提交的美国临时申请第62/796,575号的权益,所述申请以全文引用的方式并入本文中。
技术领域
本公开涉及用于刺激自然杀伤(NK)细胞的组合物和方法。
背景技术
自然杀伤(NK)细胞疗法正在成为癌症的治疗方法和其它疾病的潜在治疗方法。充分发挥出NK细胞疗法的临床潜力的挑战包括获得大量稳健、健康的展现出高肿瘤细胞毒性的NK细胞;使NK细胞靶向疾病标靶的能力;并且一旦被引入患者体内,使NK细胞充分地持续存在于体内以实现治疗效果。这一挑战部分归因于以下事实:NK细胞活性受到激活受体与抑制受体(包括免疫检查点)的平衡的严格调节。举例来说,用于激活NK细胞受体的配体仅在受应激、经转型或被病毒感染的细胞上表达,以使得NK细胞的细胞毒性活性靶向所述细胞并不伤害正常、健康组织。NK细胞的细胞毒性活性进一步受到于“自身”细胞上表达的抑制配体的限制。同时,控制NK细胞的细胞毒性的抑制调节机制可以是肿瘤细胞的攻击途径,所述肿瘤细胞利用多种免疫抑制相互作用来防止免疫攻击。NK细胞如何抵抗肿瘤免疫抑制的一个实例是标记有用于在NK细胞中引发抗体依赖性细胞毒性(ADCC)的抗体的靶细胞的接合。因此,许多更新型的抗肿瘤抗体的成效取决于患者体内是否存在大量健康NK细胞以支持抗肿瘤活性。总而言之,NK细胞疗法领域中仍然需要获得大量健康NK细胞和刺激NK细胞以获得更高的细胞毒性和/或更好的ADCC功能的方法。
发明内容
在本公开的各个方面中存在包含至少一种饲养细胞的饲养细胞组合物,所述至少一种饲养细胞包含与饲养细胞的外表面结合的片段可结晶(Fc)结构域。在一些方面中,至少一种饲养细胞进一步包含一种或多种NK细胞效应剂。在某些方面中,至少一种饲养细胞包含至少一种NK细胞效应剂,其中NK细胞效应剂是IL-21。在另一个方面中,至少一种饲养细胞进一步包含至少两种NK细胞效应剂,其中至少两种NK细胞效应剂中的一种是IL-21。
本文还公开了不含饲养细胞的NK细胞扩增组合物,所述组合物包含工程化颗粒,所述工程化颗粒包含与任一个前述方面的工程化颗粒的外表面结合的Fc结构域。在一些方面中,工程化颗粒进一步包含一种或多种NK细胞效应剂。在一些方面中,工程化颗粒进一步包含至少一种NK细胞效应剂,其中NK细胞效应剂是IL-21。在另一个方面中,工程化颗粒进一步包含至少两种NK细胞效应剂,其中至少两种NK细胞效应剂中的一种是IL-21。
在本公开的一个方面中存在治疗剂量的包含多个体外扩增的NK细胞的NK细胞与NK细胞扩增组合物的组合,所述组合物不含饲养细胞并包含至少一种工程化颗粒,所述至少一种工程化颗粒包含与工程化颗粒的外表面结合的Fc结构域。在一些方面中,工程化颗粒进一步包含一种或多种NK细胞效应剂。在一些方面中,工程化颗粒进一步包含至少一种NK细胞效应剂,其中NK细胞效应剂是IL-21。在另一个方面中,工程化颗粒进一步包含至少两种NK细胞效应剂,其中至少两种NK细胞效应剂中的一种是IL-21。
在本公开的一个方面中存在体外暴露于NK细胞扩增组合物的扩增的NK细胞群,所述组合物不含饲养细胞并包含至少一种本文所公开的工程化细胞质膜(PM)颗粒。在本公开的另一个方面中存在体外暴露于NK细胞扩增组合物的扩增的NK细胞群,所述组合物包含至少一种饲养细胞,所述至少一种饲养细胞包含与本文所公开的饲养细胞的外表面结合的Fc结构域。所述方法任选地进一步包含使NK细胞暴露于一种或多种NK细胞效应剂。一种或多种细胞效应剂可以处于含溶液的细胞培养基中,和/或与本文所公开的Fc结合饲养细胞或工程化PM颗粒的表面结合。
本文还公开了治疗、改善、减轻和/或抑制癌症或癌转移或传染病的方法,所述方法包含向有需要的受试者施用有效量的任何所公开的NK细胞扩增组合物或任一个前述方面的NK细胞扩增输注制剂。在一个方面中,NK细胞扩增组合物或NK细胞扩增输注制剂可以与例如抗癌治疗剂或抗病毒剂或抗生素剂的治疗剂组合或同时施用。
在本公开的一个方面中存在在干细胞移植之前或之后预防、减轻、缓解和/或抑制癌症复发或癌转移的方法,所述方法包含向有需要的受试者施用有效量的任何所公开的扩增的NK细胞群,所述扩增的NK细胞群已经体外暴露于NK细胞扩增组合物或NK细胞刺激组合物或任何所公开的NK细胞刺激或扩增输注制剂。任何所公开的NK细胞刺激或扩增组合物或制剂都可以与干细胞移植组合或分开施用。
在本公开的一个方面中存在调节T细胞库的方法,所述方法包含向有需要的受试者施用有效量的任何所公开的已经体外暴露于NK细胞扩增组合物的扩增的NK细胞群或任何所公开的NK细胞扩增输注制剂。
在本公开的一个方面中存在预防、抑制、减轻或缓解急性或慢性移植物抗宿主疾病的方法,所述方法包含向有需要的受试者施用有效量的任何所公开的已经体外暴露于NK细胞扩增组合物的扩增的NK细胞群、或NK细胞扩增组合物、或任何所公开的NK细胞扩增输注制剂。
本公开的其它方面和特点在下文详述。
附图说明
图1A和1B显示了包含未裂解的信号锚的膜结合免疫细胞靶向配体的构筑。图1A显示了I型和II型整合膜蛋白的结构,所述蛋白质就其N末端和C末端来说不同之处在于定向。图1B显示了用作膜结合免疫细胞靶向配体的NA-Fc嵌合蛋白的结构,所述NA-Fc嵌合蛋白由充当膜锚的神经氨酸酶跨膜结构域、茎区和人类IgG'Fc区组成。
图2显示了膜结合免疫细胞靶向配体的替代构筑,所述配体包含有包含神经氨酸酶(NA)信号锚和增加的NA茎长的Fc结构域。
图3显示了膜结合免疫细胞靶向配体序列(SEQ ID NO:13)的实例,其中NA信号锚通过RS接头与IgG Fc结构域融合。
图4是NK细胞的Fc刺激的示意图。
图5显示了通过Fc区进行的CD16接合在第14天后增强了增殖率。使用CSTX002(开符号)或CSTX002-Fc细胞系(闭符号)作为饲养细胞从源自两个供体[L54(圆圈)或L44(正方形)]的PBMC扩增NK细胞。CD16接合允许增加NK细胞增殖。来自两个供体的NK细胞在用单独IL21(CSTX2)或IL21和Fc(CSTX2-Fc)刺激后以相同速率扩增直到第14天,此时Fc刺激的培养物与仅IL-21相比以增加的速率分裂。
图6呈现了两个图,每个图都显示了从获自不同供体的初始PBMC群扩增的NK细胞的细胞毒性。使用CSTX002(·)或CSTX002-Fc(■)细胞系作为饲养细胞从PBMC扩增NK细胞。发现用CSTX002-Fc从两个不同供体扩增的NK细胞对SKOV3细胞具有增加的细胞毒性。
图7显示了用Fc结合饲养细胞扩增的来自反应不佳的供体的NK细胞对表达膜结合Fc的肿瘤标靶具有增加的细胞毒性以模拟包覆抗体的肿瘤细胞,所述肿瘤细胞将接合抗体依赖性细胞毒性(ADCC)。使用CSTX002(·)或CSTX002-Fc(■)细胞系作为饲养细胞从PBMC扩增NK细胞。发现用CSTX002-Fc扩增的NK细胞对SKOV3-Fc细胞具有增加的细胞毒性。
图8是一系列六(6)个图,每个图都显示了通过NK细胞进行的比较受体表达,所述NK细胞用具有(CSTX002-Fc)并且不具有(CSTX-002)膜结合Fc的CSTX002饲养细胞扩增。使用CSTX002或CSTX002-Fc细胞系作为饲养细胞从源自两个供体L43(·)或L44(■)的PBMC扩增NK细胞。分析扩增的NK细胞的受体表达,所述受体被认为对细胞毒性功能和归巢至关重要。用CSTX002-Fc扩增的NK细胞具有更高的CD16、NKp46和CD62L表达。
实施方式
本公开提供了包含NK细胞刺激剂的组合物和制剂,并且使其使用方法涉及NK细胞刺激和下文进一步详细描述的各种治疗。
在NK细胞上接合CD16受体(FcγRIIIa受体(CD16a)和FcγRIIIb受体(CD16b))潜在地是非常强效的NK细胞刺激机制。抗体的Fc(片段可结晶区)结构域被CD16识别,并且Fc结构域与CD16的结合引发抗体依赖性细胞毒性(ADCC)。本公开描述了用于改进NK细胞扩增并增强NK细胞的细胞毒性的通过CD16接合对NK细胞进行的工程化刺激。换个说法,本公开考虑使用抗体的Fc结构域刺激NK细胞,其中Fc结构域能够胜任在NK细胞上激动CD16并呈递给NK细胞,其中Fc结构域与饲养细胞、细胞质膜(PM)颗粒、外泌体(EX)或固体载体结合。Fc结合饲养细胞、PM颗粒、外泌体和固体载体可以进一步包含呈各种形式的其它NK细胞刺激因子以及对应的信号传导路径或与其等组合,所述形式例如是膜结合或可溶性IL-15、IL-21、4-1BBL、其它细胞因子或同时接合其它刺激或抑制受体的其它化学部分。根据本文所公开的方法和使用本文所公开的组合物扩增的NK细胞可以展现出更高的细胞毒性、更高的CD16表达和/或改进的ADCC功能。所述NK细胞适用于用以治疗包括多种类型的癌症的人类疾病和病况的治疗组合物和方法。
定义
除非另外定义,否则本文所使用的所有技术术语和科学术语均具有本发明所属领域的技术人员通常所理解的含义。以下参考文献为技术人员提供了本发明中使用的许多术语的一般定义:Singleton等人,《微生物学与分子生物学词典(Dictionary ofMicrobiology and Molecular Biology)》(第2版1994年);《剑桥科学与技术词典(TheCambridge Dictionary of Science and Technology)》(Walker编,1988年);《遗传学词汇表(The Glossary of Genetics)》,第5版,R.Rieger等人(编),施普林格(SpringerVerlag)(1991年);以及Hale和Marham,《哈珀柯林斯生物学词典(The Harper CollinsDictionary of Biology)》(1991年)。除非另外规定,否则如本文所使用的以下术语具有其被赋予的含义。
当介绍本公开或其一个或多个优选实施例的要素时,冠词“一个(a/an)”、“所述(the/said)”意图意味着存在所述要素中的一个或多个。术语“包含”、“包括”和“具有”意图是包括性的并且意味着除了列出的要素之外可能还存在额外要素。
范围在本文中可以表示为从“约”一个特定值开始和/或到“约”另一个特定值为止。当表示这类范围时,另一个实施例包括从一个特定值开始和/或到另一个特定值为止。类似地,当值表示为近似值时,先行词“约”的使用应理解为特定值形成另一个实施例。应进一步理解,每个范围的端点值与另一个端点值大大相关或与另一个端点值大大无关。还应理解,本文公开了多个值,并且除了值本身之外,每个值还在本文中公开为“约”所述特定值。举例来说,如果公开值“10”,则还公开“约10”。还应理解,如技术人员适当理解,当公开值时,“小于或等于”所述值、“大于或等于所述值”以及值之间的可能范围也被公开。举例来说,如果公开值“10”,则还公开“小于或等于10”以及“大于或等于10”。还应理解,在整个申请中,数据以多种不同的格式提供,并且这种数据表示端点值和起点值以及数据点的任何组合的范围。举例来说,如果公开了特定数据点“10”和特定数据点15,则应理解为认为公开了大于、大于或等于、小于、小于或等于以及等于10和15以及在10与15之间。还应理解,还公开了在两个特定单元之间的每个单元。举例来说,如果公开了10和15,那么也会公开11、12、13和14。
如本文所使用,术语“任选的”或“任选地”意味着随后描述的事件或情况可能会发生或可能不会发生,并且所述描述包括所述事件或情况发生的情形和不发生的情形。
如本文所使用,“N末端侧”或“氨基末端”是指肽、多肽或蛋白质的方向性并且可能不指N末端。在一些方面中,在讨论嵌合或融合肽、多肽或蛋白质的情况下,N末端侧可以仅指嵌合或融合肽、多肽或蛋白质的组分而不指整个结构。举例来说,在讨论Fc结构域并且将Fc结构域描述为与其细胞内面向的氨基末端或N末端侧融合的情况下,本文考虑嵌合或融合肽、多肽或蛋白质,其中信号锚处于嵌合或融合构筑体的N末端并且实际上跨越细胞膜。因此,在这类嵌合体中,跨膜锚与Fc结构域的氨基末端侧连接,其中Fc结构域的方向性使N末端侧面向细胞,N末端侧在典型B细胞上相对于Fc结构域倒置,典型B细胞通常具有跨越细胞膜的羧基末端和延伸到细胞外基质的氨基末端。
术语“肽”、“多肽”和“蛋白质”可互换用于指氨基酸残基的聚合物。
如本文所使用,术语“序列一致性”指示长度基本上相等的两个序列之间的一致性程度的定量量度。两个序列(无论是核酸序列还是氨基酸序列)的一致性百分比是两个比对序列之间的精确匹配的数量除以较短序列的长度再乘以100。Smith和Waterman,《应用数学进展(Advances in Applied Mathematics)》2:482-489(1981年)的局部同源性算法提供了核酸序列的近似比对。这种算法可以通过使用以下研发的评分矩阵来应用于氨基酸序列:Dayhoff,《蛋白质序列和结构地图集(Atlas of Protein Sequences and Structure)》,M.O.Dayhoff编,5增刊3:353-358,美国华盛顿特区的国家生物医学研究基金会(NationalBiomedical Research Foundation,Washington,D.C.,USA),并且通过以下标准化:Gribskov,《核酸研究(Nucl.Acids Res.)》14(6):6745-6763(1986年)。遗传学计算机组(Genetics Computer Group)(威斯康星州麦迪逊(Madison,Wis.))在“BestFit”实用应用程序中提供了这种算法用于测定序列的一致性百分比的示例性实施方案。用于计算序列之间的一致性或类似性百分比的其它合适程序是所属领域中公知的,举例来说,另一种比对程序是BLAST,所述程序均与默认参数一起使用。举例来说,可以使用以下默认参数使用BLASTN和BLASTP:遗传密码=标准;过滤器=无;链=两者;截止值=60;期望值=10;矩阵=BLOSUM62;描述=50个序列;排序依据=高分;数据库=非冗余,GenBank+EMBL+DDBJ+PDB+GenBank CDS翻译+Swiss蛋白+Spupdate+PIR。这些程序的细节可以在GenBank网站上找到。一般来说,取代是保守氨基酸取代:限于以下成员内的交换:第1组:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;第2组:丝氨酸、半胱氨酸、苏氨酸和甲硫氨酸;第3组:脯氨酸;第4组:苯丙氨酸、酪氨酸和色氨酸;第5组:天冬氨酸、谷氨酸、天冬酰胺酸和谷氨酰胺酸。
用于测定核酸和氨基酸序列一致性的技术是所属领域中已知的。通常,所述技术包括测定基因的mRNA核苷酸序列和/或测定其所编码的氨基酸序列,并将这些序列与第二核苷酸或氨基酸序列进行比较。也可以以这种方式测定和比较基因组序列。一般来说,一致性分别是指两个多核苷酸或多肽序列的精确核苷酸与核苷酸或氨基酸与氨基酸的对应关系。可以通过测定两个或更多个序列(多核苷酸或氨基酸)的一致性百分比来对其进行比较。
由于可以在不脱离本发明范围的情况下对上述细胞和方法作出各种改变,因此预期上文描述和下文给出的实例中所含有的所有内容都应被解释为说明性的而不在限制性意义上解释。
“增加”可以指导致更大量的症状、疾病、组成、病况或活动的任何变化。增加可以是病况、症状、活动、组成以统计学上显著的量的任何单独、中值或平均增加。因此,增加可以是1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%增加,只要增加是统计学上显著的即可。
“减少”可以指引起更少量的症状、疾病、组成、病况或活动的任何变化。当具有一种物质的基因产物的遗传输出相对于不具有所述物质的基因产物的输出来说较低时,所述物质也被理解为减少基因的遗传输出。此外,举例来说,减少可以是病症症状的变化以使得症状比以前观察到的要少。减少可以是病况、症状、活动、组成以统计学上显著的量的任何单独、中值或平均减少。因此,减少可以是1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%减少,只要减少是统计学上显著的即可。
“抑制(inhibit/inhibiting/inhibition)”意指减少活动、反应、病况、疾病或其它生物学参数。这可以包括但不限于活动、反应、病况或疾病的完全消除。这还可以包括例如与天然或对照水平相比活动、反应、病况或疾病减少10%。因此,与天然或对照水平相比,减少可以是10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或其间的任何量的减少。
“减少(reduce)”或所述词的其它形式例如“减少(reducing/reduction)”意指减少事件或特征(例如肿瘤生长)。应理解,这通常与某个标准或预期值有关,换句话说,其是相对的,但并不总是需要参考标准值或相对值。举例来说,“减少肿瘤生长”意指相对于标准或对照来说降低肿瘤生长速率。
“预防(prevent)”或所述词的其它形式例如“预防(preventing/prevention)”意在终止特定事件或特征,稳定或延迟特定事件或特征的发展或进展,或最大限度地减少特定事件或特征发生的机率。预防不需要与对照的比较,这是因为其通常比例如减少更绝对。如本文所使用,某些事情可以被减少但不可以被预防,但是某些被减少的事情也可以被预防。同样,某些事情可以被预防但不可以被减少,但是某些被预防的事情也可以被减少。应理解,在使用减少或预防的情况下,除非另外特定地指示,否则还明确地公开其它词的使用。
术语“受试者”是指作为施用或治疗目标的任何个体。受试者可以是脊椎动物,例如哺乳动物。在一个方面中,受试者可以是人类、非人类灵长类动物、牛、马、猪、犬或猫。受试者还可以是豚鼠、大鼠、仓鼠、兔子、小鼠或鼹鼠。因此,受试者可以是人类或兽类患者。术语“患者”是指处于临床医生例如医师的治疗下的受试者。
术语“治疗有效”是指所用组合物的量是足以改善疾病或病症的一种或多种病因或症状的量。所述改善仅需要减少或更改,而不一定需要消除。
术语“治疗”是指旨在治愈、改善、稳定或预防疾病、病理病况或病症的患者医学管理。这种术语包括积极治疗,即专门针对改善疾病、病理病况或病症的治疗,并且还包括病因治疗,即针对消除相关疾病、病理病况或病症的病因的治疗。另外,这种术语包括姑息治疗,即设计用于缓解症状而非治愈疾病、病理病况或病症的治疗;预防治疗,即针对最大限度地减少或部分或完全抑制相关疾病、病理病况或病症发展的治疗;和支持治疗,即用于补充另一种针对改善相关疾病、病理病况或病症的特定疗法的治疗。
向受试者“施用”包括向受试者引入或递送药剂的任何途径。施用可以通过任何合适的途径进行,所述途径包括口服、局部、静脉内、皮下、经皮(transcutaneous/transdermal)、肌肉内、关节内(intra-joint)、胃肠外、小动脉内、皮内、心室内、颅内、腹膜内、病灶内、鼻内、直肠、阴道、通过吸入、通过植入型药盒、胃肠外(例如皮下、静脉内、肌肉内、关节内(intra-articular)、滑膜内、胸骨内、鞘内、腹膜内、肝内、病灶内和颅内注射或输注技术)等等。如本文所使用,“同时施用(Concurrent administration)”、“组合施用”、“同时施用(simultaneous administration/administered simultaneously)”意味着化合物在同一时间点施用或基本上紧随彼此之后施用。在后一种情况下,两种化合物的施用时间足够接近以至于所观察到的结果与化合物在同一时间点施用时所实现的结果没有区别。“全身施用”是指通过将药剂引入或递送到受试者身体的广泛区域(例如大于身体的50%)的途径,例如通过进入循环系统或淋巴系统的入口来将药剂引入或递送到受试者。相比之下,“局部施用”是指通过将药剂引入或递送到所述区域或紧邻施用点的区域并且不以治疗显著量全身性地引入药剂的途径来将药剂引入或递送到受试者。举例来说,局部施用的药剂在施用点的局部附近可以容易地被检测到,但在受试者身体的远端部分检测不到或可检测到的量可忽略不计。施用包括自我施用和他人施用。
如本文所使用,“治疗(treat/treating/treatment)”和其语法变体包括以部分或完全预防、延迟、治愈、治愈、减轻、缓解、更改、补救、改善、改进、稳定、减弱和/或减少一种或多种疾病或病况、疾病或病况的症状、或疾病或病况的根本病因的强度或频率的意图或目的施用组合物。可以预防性、防治性、姑息性或补救性应用本发明的治疗。在发作之前(例如在癌症迹象显而易见之前)、在早期发作期间(例如在癌症的初始迹象和症状之后)或在确定癌症发展之后向受试者施用防治性治疗。防治性施用可以在疾病或感染症状显现之前进行数天到数年。
(I)Fc融合肽
在一个方面中,本文公开了工程化饲养细胞、工程化细胞质膜(PM)颗粒、工程化外泌体、工程化血小板(包括但不限于Fc结合血小板)和工程化淋巴细胞(例如工程化以表达Fc结构域来刺激NK细胞的淋巴细胞(例如T细胞)),以及包含膜结合Fc融合肽的固体载体(在本文中分别称为Fc结合饲养细胞、Fc结合PM颗粒、Fc结合外泌体、Fc结合血小板和Fc结合淋巴细胞),其中Fc融合肽包含与Fc结构域的氨基末端连接的跨膜肽结构域。在一个方面中,Fc融合肽的跨膜结构域可以包含裂解或未裂解信号锚定序列,例如神经氨酸酶的跨膜结构域、来自副流感病毒血凝素-神经氨酸酶的信号锚、来自转铁蛋白受体的信号锚、来自II类MHC不变链的信号锚、来自P糖蛋白的信号锚、来自脱唾液酸糖蛋白受体的信号锚或来自中性内肽酶的信号锚。在一个实例中,跨膜结构域包含副流感病毒血凝素-神经氨酸酶(NA)肽序列。如图1中示意性示出,跨膜神经氨酸酶(NA)肽结构域用于使Fc结构域与饲养细胞的外表面偶合或结合。在其它方面中,跨膜神经氨酸酶(NA)肽结构域用于使Fc结构域与PM纳米颗粒、外泌体或固体载体的外表面偶合或结合。NA肽结构域由N末端细胞质尾、充当跨膜结构域的未裂解信号锚和从细胞质膜延伸的茎区组成。应理解,茎区的长度可以变化。
如本文所使用,“NA肽结构域”是指包含以下的肽序列:至少五十(50)个SEQ IDNO:1MNPNQKITTIGSICLVVGLISLILQIGNIISIWISHSIQTGSQNHTGICN氨基酸序列,或与SEQ IDNO:1具有至少约81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的序列。
Fc结构域是与NK表面受体CD16(FcγRIII)结合的配体。CD16是NK细胞上的主要受体之一,并且当CD16与抗体的Fc部分(例如IgG1、IgG2、IgG3和/或IgG4 Fc结构域)结合时,这会激活NK细胞抗体依赖性细胞介导的细胞毒性(ADCC)。在另一个方面中,Fc结构域(IgG1、IgG2、IgG3和/或IgG4)还可以结合其它免疫细胞例如肥大细胞、巨噬细胞、γ-δT细胞上的CD16受体;并由此类似地刺激所述细胞的扩增并增强所述细胞的细胞毒性。在另一个方面中,其它类型的细胞可以被工程化为Fc结合的。因此,本公开还涵盖例如Fc结合的工程化血小板、可以用于肿瘤疫苗的Fc结合的原发性肿瘤样品和表达Fc的工程化iPSC。
在另一个方面中,除IgG之外的其它Fc免疫球蛋白同型(IgA、IgE、IgM)可以用于刺激分别对应的不同Fc受体以刺激其它免疫细胞类型。举例来说,结构域FcαRI(CD89)与巨噬细胞、中性粒细胞、嗜酸性粒细胞上的IgA特异性结合;Fc RI(CD64)与单核细胞和巨噬细胞上的IgG特异性结合;并且FcεRII(CD23)与B细胞上的IgE特异性结合。Fc与单核细胞或巨噬细胞上的CD64结合,并因此对其进行刺激。因此,融合肽、Fc结合饲养细胞(FC)、Fc结合淋巴细胞、Fc结合的工程化细胞质膜(PM)颗粒、Fc结合的工程化外泌体和含有其等的组合物也可以用于根据本文所描述的用于扩增NK细胞的方法来基本上扩增肥大细胞和/或巨噬细胞。
在一个方面中,本文公开了包含如上文所描述与跨膜结构域例如NA肽结构域融合的免疫球蛋白Fc结构域(例如IgGl、IgG2、IgG3、IgG4、IgA和/或IgE Fc结构域)的融合肽。一个或多个Fc结构域可以呈现为单体、二聚体或多聚体构筑体。在一个方面中,一个或多个Fc结构域可以被进一步修饰以优化或增强抗体介导的杀伤、NK细胞辨识以及控制激活Fc受体的扩增。举例来说,一个或多个Fc结构域可以被修饰以增加对CD16的亲和力。因此,举例来说,一个或多个Fc结构域可以包含一种或多种突变,例如T256A、K290A、S298A、E333A、K334A、L235V、F243L、R292P、Y300L和/或P396L。类似地,一个或多个Fc结构域可以被进一步修饰以增加对与激活(IIIa)的结合相对于与抑制性Fc(IIb)受体的结合的选择性。因此,举例来说,一个或多个Fc结构域可以包含一种、两种、三种、四种、五种、六种、七种、八种或更多种突变或替代形式例如S239D、I332E、A330L、F243L、R292P、V305I和/或P396L。举例来说,在一个方面中,Fc结构域可以被修饰以包含R292L、Y300L、V305I和P396L。在另一个实例中,Fc结构域可以被修饰以包含S239D、I332E和A330L。在另一个方面中,具有较低亲和力的Fc结构域的工程化突变体可以用于引发CD16在NK细胞上的较高表达。
跨膜结构域例如NA肽结构域可以通过化学键直接连接到Fc结构域或通过接头间接连接到Fc结构域。直接化学键例如是共价键(例如肽键、酯键等等)或者非共价键(例如离子型、静电、氢、疏水性、凡得瓦相互作用(Van der Waal interaction)或π-效应)。间接连接可以使用接头,即通过至少一个共价键连接一个或多个其它化学基团的化学基团来实现。合适的接头包括氨基酸、肽、核苷酸、核酸、二聚体铰链Fc、有机接头分子(例如马来酰亚胺衍生物、N-乙氧基苄基咪唑、联苯-3,4',5-三甲酸、对氨基苄氧基羰基等等)、二硫键接头和聚合物接头(例如PEG)。接头可以包括一个或多个间隔基团,包括但不限于亚烷基、亚烯基、亚炔基、烷基、烯基、炔基、烷氧基、芳基、杂芳基、芳烷基、芳烯基、芳炔基等等。接头可以是中性的或带有正电荷或负电荷。另外,接头可以是可裂解的以使得使接头连接到另一个化学基团的接头共价键可以在某些条件下断裂或裂解,所述条件包括pH、温度、盐浓度、光、催化剂或酶。在一个方面中,NA肽结构域可以是NA4-Fc Siadel(S239D/I332E/A330L)。
在一个方面中,接头可以是肽接头。合适的肽接头的实例是所属领域中众所周知的,并且用于设计接头的程序是容易获得的(参见例如Crasto等人,《蛋白质工程(ProteinEng.)》,2000年,13(5):309-312)。肽接头可以是限制位点接头例如短序列RS或柔性氨基酸接头(例如包含小型、非极性或极性氨基酸)。柔性接头的非限制性实例包括LEGGGS(SEQ IDNO:2)、TGSG(SEQ ID NO:3)、GGSGGGSG(SEQ ID NO:4)、(GGGGS)1-4(SEQ ID NO:5)、GGGS(SEQID NO:6)1-4、GSGGGG(SEQ ID NO:7)1-4和(Gly)6-8。或者,肽接头可以是刚性氨基酸接头。所述接头包括(EAAAK)1-4(SEQ ID NO:8)、A(EAAAK)2-5A(SEQ ID NO:9)、PAPAP(SEQ ID NO:10)和(AP)6-8。Fc结构域可以与NA肽的N末端、C末端和/或内部位置连接。
在一些方面中,Fc融合肽具有与SEQ ID NO:13具有至少约80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的氨基酸序列。为了靶向Fc结构域于细胞质膜上的放置,可以使用来自充分表征的流感病毒神经氨酸酶蛋白(NA)的膜靶向结构域,所述膜靶向结构域由N末端细胞质尾、充当跨膜结构域的未裂解信号锚和从细胞质膜延伸的茎区组成。图1A和1B是显示了包含未裂解信号锚定序列的膜结合免疫细胞靶向配体的构筑的示意图。图1A显示了I型和II型整合膜蛋白的结构以及每种蛋白的信号锚。图1B显示了来自膜结合免疫细胞靶向配体中使用的II型整合膜蛋白的未裂解信号锚的结构。如图1B中所示,本公开的示例性但非限制性构筑体包含NA-Fc嵌合体,其中Fc结构域(IgG1)通过短接头连接到未裂解NA茎区。
值得注意的是,NA-Fc嵌合体可以被插入重组P/V/F病毒中以生成新颖溶瘤病毒,所述溶瘤病毒相对于正常细胞来说对肿瘤细胞具有特异性(归因于P/V突变),并且可以增强通过NK细胞进行的ADCC。图2显示了具有渐增NA茎长度的NA-Fc嵌合体的替代构筑。
图3显示了NA-Fc嵌合体的一个示例性序列,其中Fc结构域(IgG1)通过短RS连接序列连接到50个氨基酸NA序列,以产生具有阐述于下文并示于图3中的279个氨基酸序列的NA-Fc构筑体的非限制性实例:
MNPNQKITTIGSICLVVGLISLILQIGNIISIWISHSIQTGSQNHTGICNRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:13)。
如图2中所指出,NA-Fc构筑体可以包含NA靶向结构域(SEQ ID NO:1)、接头(例如RS接头)、铰链区DKTHTCPPCPAPELL(SEQ ID NO:11)或TCPPCPAPELL(SEQ ID NO:12)和Fc区
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ IDNO:14),所述Fc区包含CH2结构域
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK(SEQ ID NO:15)和CH3结构域
GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:16)或与SEQ ID NO:14、15或16具有至少约81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的序列。应理解并在本文中考虑,NA-Fc嵌合体可以包括来自充分表征的流感病毒神经氨酸酶蛋白(NA)的任何长度的膜靶向结构域,所述膜靶向结构域包括
MNPNQKITTIGSICLVVGLISLILQIGNIISIWISHSIQTGSQNHTGICNQNIITYKNSTWVKDTTSVILTGNSSLCPIRGWAIYSKDNSIRIGSKGDVFVIREPFISCSHLECRTFFLT(SEQ ID NO:17)或与SEQ IDNO:17具有至少约81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性的序列。在一个方面中,NA-Fc融合体可以包含
MNPNQKITTIGSICLVVGLISLILQIGNIISIWISHSIQTGSQNHTGICNQNIITYKNSTWVKDTTSVILTGNSSLCPIRGWAIYSKDNSIRIGSKGDVFVIREPFISCSHLECRTFFLTDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:18),其由核酸序列
ATGAATCCAAATCAGAAAATAACAACCATTGGATCAATCTGTCTGGTAGTCGGACTAATTAGCCTAATATTGCAAATAGGGAATATAATCTCAATATGGATTAGCCATTCAATTCAAACTGGAAGTCAAAACCATACTGGAATATGCAACCAAAACATCATTACCTATAAAAATAGCACCTGGGTAAAGGACACAACTTCAGTGATATTAACCGGCAATTCATCTCTTTGTCCCATCCGTGGGTGGGCTATATACAGCAAAGACAATAGCATAAGAATTGGTTCCAAAGGAGACGTTTTTGTCATAAGAGAGCCCTTTATTTCATGTTCTCACTTGGAATGCAGGACCTTTTTTCTGACCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATAA(SEQ ID NO:19)编码。
如上文所指出,Fc区可以包含一种或多种突变,例如L234Y、L235V、L235Q、G236W、S239D、S239M、F243L、T256A、K290A、R292P、N297Q、S298A、Y300L、V305I、A330L、I332E、E333A、K334A和/或P396L。因此,本文特定地公开了包含以下的Fc区:在残基234处的亮氨酸(L)或酪氨酸(Y)、在残基235处的亮氨酸(L)、谷氨酰胺酸或缬氨酸(V)、在残基236处的谷氨酰胺酸(G)或色氨酸(W)、在残基239处的丝氨酸(S)、甲硫氨酸(M)或天冬氨酸(D)以及在残基243处的苯丙氨酸(F)或亮氨酸(L)、在残基256处的苏氨酸(T)或丙氨酸(A)、在残基268处的组氨酸(H)或天冬氨酸(D)、在残基270处的天冬氨酸(D)或谷氨酸(E)、在残基290处的赖氨酸(K)或丙氨酸(A)、在残基292处的精氨酸(R)或脯氨酸(P)、在残基298处的丝氨酸(S)或丙氨酸(A)、在残基297处的天冬酰胺酸或谷氨酰胺酸、在残基300处的酪氨酸(Y)或亮氨酸(L)、在残基305处的缬氨酸(V)或异亮氨酸(I)、在残基326处的赖氨酸(K)或天冬氨酸(D)、在残基330处的丙氨酸(A)、甲硫氨酸(M)或亮氨酸(L)以及在残基332处的异亮氨酸(I)或谷氨酸(E)、在残基333处的谷氨酸(E)或丙氨酸(A)、在残基334处的赖氨酸(K)、谷氨酸(E)或丙氨酸(A)和/或在残基396处的脯氨酸(P)或亮氨酸(L)。应特定地理解,Fc区中可以不存在取代或存在本文所提及的取代中的任一种或两种、三种、四种、五种、六种、七种、八种、九种、十种、十一种、十二种、十三种、十四种、十五种、十六种或十七种组合。因此,在本文所公开的一个方面中存在融合蛋白,所述融合蛋白包含在F243L、R292P、Y300L、V305I和P396L处的Fc区的取代,其中Na4-Fc的序列包含
MNPNQKITTIGSICLVVGLISLILQIGNIISIWISHSIQTGSQNHTGICNQNIITYKNSTWVKDTTSVILTGNSSLCPIRGWAIYSKDNSIRIGSKGDVFVIREPFISCSHLECRTFFLTDKTHTCPPCPAPELLGGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSILTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:20);所述取代包含具有序列
GGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSILTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ IDNO:25)的Fc结构域,所述序列包含具有序列
GGPSVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPPEEQYNSTLRVVSILTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK(SEQ ID NO:26)的CH2结构域和具有序列
GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPLVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:27)的CH3结构域。
在一个方面中,Na4-Fc融合体包含S239D、I332E和A330L取代,所述取代具备具有序列
GGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ IDNO:21)的Fc结构域,所述序列包含具有序列
GGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAK(SEQ ID NO:22)的CH2结构域和具有序列
GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:24)的CH2结构域以及
MNPNQKITTIGSICLVVGLISLILQIGNIISIWISHSIQTGSQNHTGICNQNIITYKNSTWVKDTTSVILTGNSSLCPIRGWAIYSKDNSIRIGSKGDVFVIREPFISCSHLECRTFFLTDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:23)的完整序列。
在一个方面中,Na4-Fc融合蛋白可以包含2个通过铰链区连接的Fc结构域。举例来说,Na-Fc融合体可以包含序列
MNPNQKITTIGSICLVVGLISLILQIGNIISIWISHSIQTGSQNHTGICNQNIITYKNSTWVKDTTSVILTGNSSLCPIRGWAIYSKDNSIRIGSKGDVFVIREPFISCSHLECRTFFLTDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:28)。
在另一个方面中,Fc结构域可以是不对称变异体,例如,一个重链Fc结构域可以包含L234Y/L235Q/G236W/S239M/H268D/D270E/S298A,而另一个Fc结构域包含D270E/K326D/A330M/K334E。
一般来说,任何氨基酸取代都是保守的:即限于以下成员内的交换:第1组:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;第2组:丝氨酸、半胱氨酸、苏氨酸和甲硫氨酸;第3组:脯氨酸;第4组:苯丙氨酸、酪氨酸和色氨酸;和第5组:天冬氨酸、谷氨酸、天冬酰胺酸和谷氨酰胺酸。
本公开还考虑了编码本文所公开的任何融合蛋白的核酸,例如,SEQ ID NO:19编码SEQ ID NO:18中所阐述的Na-Fc融合体;SEQ ID NO:29编码SEQ ID NO:20中所阐述的Na-Fc融合体;SEQ ID NO:30编码SEQ ID NO:23中所阐述的Na-Fc融合体;并且SEQ ID NO:31编码SEQ ID NO:28中所阐述的NA-2xFc融合体。本文另外考虑包含根据技术方案的这类核酸的载体以及包含这类载体的细胞。可以使用所属领域中已知的方法制备载体和含有所述载体的细胞。
(II)工程化饲养细胞、工程化细胞质膜颗粒和包含膜结合Fc的工程化外泌体
本公开的组合物包括包含Fc结合饲养细胞(FC)的组合物、包含Fc结合的工程化细胞质膜(PM)颗粒的组合物和包含Fc结合的工程化外泌体的组合物。Fc结合的工程化PM颗粒包括衍生自Fc结合饲养细胞的PM纳米颗粒。Fc结合的工程化外泌体包括衍生自Fc结合饲养细胞的外泌体或其它细胞外囊泡,也如下文进一步详细描述。或者,外泌体可以衍生自其它来源例如血小板和巨核细胞。
如本文所使用,术语“Fc-结合”应理解为指Fc结构域在倒置方向(即细胞内面向的氨基末端)通过跨膜肽偶合到饲养细胞或工程化颗粒的外表面。这可以使用本文所公开的Fc融合肽来实现。因此,本公开的一个方面提供了饲养细胞组合物,所述组合物包含至少一种Fc结合饲养细胞,即包含与饲养细胞的外表面结合的Fc结构域的饲养细胞,如下文进一步详细描述。举例来说,饲养细胞可以被遗传修饰以表达与饲养细胞的外表面结合的Fc结构域,即以表达如下文进一步描述的Fc融合肽。本公开的另一个方面提供了不含饲养细胞的NK细胞扩增组合物,所述组合物包含至少一种Fc结合的工程化颗粒,即包含在倒置方向结合到饲养细胞的外表面的Fc结构域的工程化颗粒。在一些方面中,饲养细胞可以被工程化以表达可以被人类化抗体(例如CD20)标记的配体。
在饲养细胞组合物中,至少一种Fc结合饲养细胞任选地包含至少一种细胞NK细胞效应剂。在一个实例中,Fc结合饲养细胞包含一种细胞NK细胞效应剂,即IL-15或IL-21。Fc结合饲养细胞可以包含至少两种或更多种不同的NK细胞效应剂。
在不含饲养细胞的NK细胞扩增组合物中,Fc结合的工程化PM颗粒任选地包含至少一种细胞NK细胞效应剂。在一个实例中,Fc结合的工程化颗粒包含一种细胞NK细胞效应剂,即IL-15或IL-21。Fc结合的工程化PM颗粒可以包含至少两种或更多种不同的NK细胞效应剂。
在饲养细胞组合物或不含饲养细胞的组合物中,其中存在至少两种NK细胞效应剂,第二NK细胞效应剂可以例如是41BBL。在饲养细胞组合物或不含饲养细胞的NK细胞扩增组合物中,其中饲养细胞或工程化PM颗粒包含一种或多种NK细胞效应剂,NK细胞效应剂可以选自41BBL、IL-15、IL-2、IL-12、IL-18、IL-21、MICA、UBLP、2sB4、LFA-1、Notch配体、NKp46配体或BCM1/SLAMF2、TLR配体以及NKG2D配体或细胞因子。在示例性所述组合物中,至少一种额外NK细胞效应剂是IL-15或IL-21。
(a)Fc结合饲养细胞
本公开提供了包含如上文详述的Fc融合肽的饲养细胞。用于本文所公开的方法中和用于制造本文所公开的PM颗粒和外泌体的NK细胞饲养细胞可以是被照射的自体或同种异体外周血液单核细胞(PBMC)或未被照射的自体或同种异体PBMC、RPMI8866、HFWT、721.221或K562细胞以及EBV-LCL、其它非HLA或低HLA表达性细胞系或可以用作肿瘤疫苗的衍生自患者的原发性肿瘤。Fc结合饲养细胞可以通过使用所属领域中熟知的标准转导或转染技术用本文所描述的任何Fc融合肽转染或转导饲养细胞来制备。举例来说,可以将本文所公开的Fc融合肽的cDNA载体连接到表达质粒中,此举允许在细菌(大肠杆菌)、昆虫或哺乳动物细胞中表达。cDNA载体可以带有FLAG或HIS标签。合适的转染方法包括核转染(或电穿孔)、磷酸钙介导的转染、阳离子聚合物转染(例如DEAE-葡聚糖或聚乙烯亚胺)、病毒转导、病毒体转染、病毒粒子转染、脂质体转染、阳离子脂质体转染、免疫脂质体转染、非脂质体脂质转染、树枝状聚合物转染、热休克转染、磁转染、脂质转染、基因枪递送、穿刺转染、声穿孔、光学转染和专有试剂增强的核酸摄取。转染方法是所属领域中众所周知的(参见例如《分子生物学现行规范(Current Protocols in Molecular Biology)》Ausubel等人,纽约的约翰威立(John Wiley&Sons,New York),2003年;或《分子克隆:实验指南(MolecularCloning:A Laboratory Manual)》Sambrook和Russell,纽约冷泉港的冷泉港出版社(ColdSpring Harbor Press,Cold Spring Harbor,NY),第3版,2001年)。或者,可以通过微注射将分子引入细胞中。举例来说,可以将分子注射到所关注细胞的细胞质或细胞核中。被引入细胞中的每种分子的量可以变化,但所属领域中的技术人员熟悉用于测定适当量的手段。
应理解,可以同时或依序将各种分子引入细胞中。举例来说,可以将Fc融合肽和一种或多种膜结合NK细胞效应剂同时引入饲养细胞中。或者,可以先引入一种分子,之后可以将一种或多种其它分子引入细胞中。举例来说,一旦被Fc融合肽转染或转导的饲养细胞就可以进一步被膜结合NK细胞效应剂例如IL-15和/或IL-21和/或41BBL转染和/或被感染为EBV-LCL和/或一种或多种其它NK细胞效应剂。或者,饲养细胞可以被Fc融合肽和膜结合NK细胞效应剂例如IL-15和/或IL-21和/或41BBL和/或EBV-LCL和/或一种或多种其它NK细胞效应剂同时转染或转导。或者,先前被转染或转导并表达膜结合NK细胞效应剂例如IL-15和/或IL-21和/或41BBL和/或被感染为EBV-LCL和/或一种或多种其它NK细胞效应剂的饲养细胞可以被Fc融合肽转染或转导。还应了解,可以使用其它手段例如所属领域中已知的化学缀合方法来获得膜结合Fc。
一般来说,将细胞维持在适用于细胞生长和/或维持的条件下。合适的细胞培养条件是所属领域中众所周知的并且描述于例如Santiago等人,《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》,2008年,105:5809-5814;Moehle等人《美国国家科学院院刊》,2007年,104:3055-3060;Urnov等人,《自然(Nature)》,2005年,435:646-651;和Lombardo等人,《自然-生物技术(Nat.Biotechnol.)》,2007年,25:1298-1306中。所属领域中的技术人员了解到,用于培养细胞的方法是所属领域中已知的并且可以并且将取决于细胞类型而变化。在所有情况下,都可以使用常规优化来确定用于特定细胞类型的最佳技术。
Fc结合饲养细胞可以用于细胞培养以直接刺激NK细胞,或可以用于制备衍生自饲养细胞的PM颗粒或外泌体。
(b)Fc结合PM颗粒
Fc结合的工程化PM颗粒包括Fc结合PM颗粒,所述Fc结合PM颗粒可以使用众所周知的方法由Fc结合NK细胞饲养细胞制备。PM颗粒是由细胞质膜制成或人工制造的囊泡(即脂质体)。PM颗粒可以含有脂质双层或仅含有单层脂质。PM颗粒可以制备成薄层、多薄层或倒置形式。PM颗粒可以使用已知的细胞质膜制备方案或脂质体制备方案由如本文所描述的Fc结合饲养细胞制备,所述方案例如是美国专利第9,623,082号中描述的方案,所述专利的全部公开内容以引用的方式并入本文中。在某些方面中,如本文所公开的PM颗粒的平均直径范围为约170nm到约300nm。
(c)Fc结合外泌体
如本文所公开的Fc结合外泌体可以由分泌外泌体的细胞制备,所述细胞可以使用众所周知的方法由Fc结合NK细胞饲养细胞制备,其中外泌体是分泌外泌体的细胞的细胞外产物,如美国专利申请公开第20170333479号中所描述,所述公开的全部公开内容以引用的方式并入本文中。外泌体包含脂质和蛋白质,并且在特定外泌体中发现的蛋白质的身份取决于一种或多种产生其的细胞。本文所公开的外泌体包含如本文所公开的Fc融合肽(即是Fc结合的),并且任选地包含存在于外泌体膜中的一种或多种刺激肽(NK细胞效应剂)。外泌体可以例如由被工程化以改进外泌体的形成或释放的细胞系产生。所述细胞系包括但不限于上文在II(a)部分中描述的Fc结合细胞系。非限制性细胞系是Fc结合K562-mb15-41BBL和Fc结合K562。在某些方面中,如本文所公开的外泌体的平均直径范围为约30nm到约100nm或到约160nm。在一个方面中,外泌体的平均直径为约60-80nm。外泌体获得比容易获得的PM颗粒更小的粒径的能力意味着外泌体可以更容易地适应更小尺寸优选情况下的用途。举例来说,在需要通过生理屏障扩散、通过组织隔室增强生物分布或静脉内注射的应用中,外泌体可以是优选的。
(III)组合物
本公开提供了各种NK细胞扩增组合物,所述组合物包含如上文所公开的Fc结合饲养细胞,并且在其它方面中提供了不含饲养细胞的NK细胞扩增组合物,所述组合物包含一种或多种工程化Fc结合颗粒,例如如上文所公开的PM颗粒或外泌体。组合物中使用的任何Fc结合饲养细胞或Fc结合的工程化PM颗粒任选地进一步包含至少一种、两种或更多种不同的NK细胞效应剂。在一个方面中,一种NK细胞效应剂是IL-21,并且在一些方面中,一种NK细胞效应剂是IL-21,而第二种NK细胞效应剂是41BBL。Fc结合饲养细胞或Fc结合的工程化PM颗粒任选地包含一种或多种如上文所公开的额外NK细胞效应剂。
包含有包含细胞质膜的PM颗粒的NK细胞扩增组合物可以进一步包含多个微粒/纳米颗粒,其中细胞质膜包覆多个微粒和/或纳米颗粒。微粒/纳米颗粒可以包含磁性微粒、二氧化硅珠粒、聚苯乙烯珠粒、乳胶珠粒、颗粒状造影剂、颗粒状癌症治疗剂或其任何组合。
本公开还考虑了包含本文所公开的任何NK细胞扩增组合物以及药学上可接受的载体的NK细胞扩增输注制剂。
治疗性药物组合物可以通过使Fc结合饲养细胞或工程化PM颗粒与所属领域中已知的药学上可接受的载体组合来制备,例如《雷明顿:药学的科学与实践(Remington:TheScience and Practice of Pharmacy)》(第19版)编者A.R.Gennaro,宾夕法尼亚州伊斯顿的麦克出版公司(Mack Publishing Company,Easton,Pa.)1995年中所描述。药学上可接受的载体的实例包括但不限于:无菌水、盐水、林格氏溶液(Ringer's solution)、葡萄糖溶液和生理pH下的缓冲溶液。举例来说,溶液的pH优选为约5到约8并且更优选为约7到约7.5。
除了选择的分子之外,药物组合物还可以包括载体、增稠剂、稀释剂、缓冲剂、防腐剂、表面活性剂等等。药物组合物还可以包括一种或多种活性成分,例如抗微生物剂、抗炎剂、麻醉剂等等。
对于所属领域中的技术人员来说显而易见的是,某些载体可能更优选,这取决于例如施用途径和所施用的组合物的浓度。取决于期望局部治疗还是全身治疗以及待治疗的区域,可以适当地制备药物组合物以通过多种已知施用途径中的任一种施用到哺乳动物,尤其是人类。施用可以是局部(包括眼部、阴道、直肠、鼻内)、口服、通过吸入或胃肠外施用,例如通过静脉内滴注或注射,或皮下、腹膜内、肌肉内、腔内或经皮注射。
用于胃肠外施用的制剂包括无菌水溶液或非水溶液、悬浮液和乳液。非水性溶剂的实例是丙二醇、聚乙二醇、植物油(例如橄榄油)和可注射的有机酯(例如油酸乙酯)。水性载体包括水、醇性溶液/水溶液、乳液或悬浮液,包括盐水和缓冲介质。胃肠外载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸林格氏液或固定油。静脉内媒剂包括流体和营养补充剂、电解质补充剂(例如基于林格氏葡萄糖的电解质补充剂)等等。还可以存在防腐剂和其它添加剂,例如抗微生物剂、抗氧化剂、螯合剂和惰性气体等等。
用于局部施用的制剂可以包括软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾剂、液体和散剂。常规的药物载体、水溶液、粉末或油性基质、增稠剂等等可能是必需的或期望的。
用于口服施用的组合物包括散剂或粒剂、悬浮液或在水或非水介质中的溶液、胶囊、小袋或锭剂。可能期望增稠剂、调味剂、稀释剂、乳化剂、分散助剂或粘合剂。
一些组合物可以潜在地作为药学上可接受的酸或碱加成盐施用,通过与无机酸例如盐酸、氢溴酸、高氯酸、硝酸、硫氰酸、硫酸和磷酸以及有机酸例如甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸和富马酸反应而形成,或通过与无机碱例如氢氧化钠、氢氧化铵、氢氧化钾和有机碱例如单、二、三烷基和芳基胺和被取代的乙醇胺反应而形成。
因此,NK细胞扩增输注制剂可以被配制用于胃肠外输注、动脉输注、静脉输注、人工导管介导的输注、静脉内注射、腹膜内注射、皮下注射、口服递送或局部递送。
在一个方面中,本公开涵盖如本文所公开的体外或离体制备的、施用到或注射到需要NK细胞扩增的受试者中的任何NK细胞扩增组合物。应理解并在本文中考虑,输注可以用商业来源的NK细胞体外进行或由供体来源(例如同种异体供体或自体供体来源(即接受扩增的NK细胞的接受受试者))离体进行。
在另一个方面中,本公开考虑了NK细胞组合物,所述组合物包含与如本文所公开的Fc结合饲养细胞组合物或如本文所公开的不含饲养细胞的Fc结合NK细胞扩增组合物接触的体外NK细胞群。
在另一个方面中,本公开考虑了NK细胞的来源,包括但不限于外周血液、iPSC衍生的NK细胞、ESC衍生的NK细胞、在158处具有高亲和力Fc受体Phe或Val的多态性的NK细胞和基因修饰的NK细胞。
在另一个方面中,本公开考虑了体外暴露于NK细胞扩增组合物的扩增的NK细胞群,所述组合物不含饲养细胞并包含至少一种如本文所公开的Fc结合的工程化颗粒,所述Fc结合的工程化颗粒包含至少两种NK细胞效应剂,其中至少两种NK细胞效应剂中的一种是IL-21或IL-15。扩增的NK细胞群可以展现出与未扩增的NK细胞相比增加的细胞毒性。在不同方面中,扩增的NK细胞群可以展现出未扩增的NK细胞的细胞毒性的至少约2倍、5倍或10倍的细胞毒性。
在另一个方面中,本公开提供了包含治疗剂量的NK细胞以及任选的药学上可接受的载体的组合物,所述NK细胞包含如本文所公开的扩增的NK细胞群。扩增的NK细胞群可以展现出更高的CD16和其它有利特性例如更高的细胞毒性和ADCC功能。如所属领域中的技术人员所了解,提供治疗剂量的NK细胞的量将根据许多因素而变化,并且论述于例如美国专利第9.623,082号中。因素包括受试者的年龄、性别和诊断以及施用途径,所述施用途径可以是但不限于口服、口腔、粘膜和静脉内途径。举例来说,治疗剂量可以在每剂1×104/kg到1×108/kg之间,这可以包括在单次剂量中或在多次剂量中被划分。应了解,上文所表述的治疗剂量的同等物或者可以以每总身体表面积的量表示。
在另一个方面中,本公开还提供了包含如本文所公开的任何NK细胞扩增组合物以及包含至少一种可溶性培养基组分例如细胞因子、IL-2、IL-12、IL-15、IL-18、IL-21、NAM、抗坏血酸盐或其任何组合的细胞培养基溶液的NK细胞扩增培养基制剂。
(IV)方法
(a)用于增加NK细胞的细胞毒性的方法
在一个方面中,本公开提供了用于增加NK细胞的细胞毒性的方法,其通过使用如本文所公开的NK细胞扩增组合物或制剂扩增初始NK细胞群来进行。所公开的方法提供了简单的扩增平台,所述平台避免了复杂的替代扩增过程,包括例如用单克隆抗体包被固体载体和在溶液中使用一种或多种可溶性细胞因子。相反地,在本文所公开的方法中,从供体获得初始NK细胞群,并使其暴露于如本文所公开的NK细胞扩增组合物。暴露可以在体外或体内进行。图4是本公开的NK细胞的Fc刺激的示意图。NK细胞与一种或多种Fc结合饲养细胞、Fc结合PM颗粒或Fc结合外泌体或其任何组合接触。暴露的Fc结构域与NK细胞表面上的CD16结合,从而引起对NK细胞的刺激以更快和/或更有效地扩增并产生具有更高抗肿瘤毒性的NK细胞和具有更有利的整体表型的NK细胞。
如图4中所指示,与NK细胞接触的组合物可以包含本文所公开的任何Fc结合饲养细胞或Fc结合的工程化PM颗粒或Fc结合的工程化外泌体。工程化PM颗粒可以是Fc结合PM颗粒。在一个方面中,任选地存在的NK细胞效应剂是IL-21或IL-15。任选地存在的第二种NK细胞效应剂可以选自41BBL、IL-2、IL-12、IL-15、IL-18、IL-21、MICA、UBLP、2B4、LFA-1、Notch配体、NKp46配体或BCM1/SLAMF2、TLR配体以及NKG2D配体。在一个方面中,第二种NK细胞效应剂是41BBL。组合物可以进一步包含选自IL-2、IL-12、IL-15、IL-18、IL-21、MICA、UBLP、2sB4、LFA-1、Notch配体、NKp46配体或BCM1/SLAMF2、TLR配体以及NKG2D配体中的至少一种额外(即第三种、第四种、第五种等)NK细胞效应剂。以这种方式执行的NK细胞扩增可以在10天内实现远不止数倍(约3-4倍)。更确切地说,根据本发明方法的NK细胞扩增可以在16天内实现至少约100倍、约200倍、约300倍、约400倍、约500倍、约600倍、约700倍、约800倍、约900倍、约1100倍、约1200倍、约1300倍、约1400倍、约1500倍、约1600倍、约1700倍、约1800倍、约1900倍到约2000倍细胞数增加或在更长时间内实现更多倍细胞数增加。因此,所公开的方法适用于放大制造NK细胞。NK细胞的来源可以来自外周血液、脾脏NK细胞、淋巴细胞制剂(例如血沉棕黄层、iPSC衍生的NK细胞、ESC衍生的NK细胞和遗传修饰/工程化NK细胞或任何遗传修饰的NK细胞(包括但不限于衍生自Fc受体例如位置158处的Phe或Val的多态性的NK细胞,例如所属领域中已知和描述于例如《血液(Blood)》(1997年)90:1109-14和《临床研究杂志(J Clin Invest.)》(1997年)100:1059–70中的NK细胞))。可以使用所属领域中已知的方法来工程化所述遗传修饰的NK细胞来源。或者,NK细胞可以衍生自携带期望多态性的细胞供体,并且所供给的细胞用作通过本文所描述的方法和使用本文所描述的组合物扩增的初始NK细胞群。因此,在这种情况下,“遗传修饰”涵盖携带多态性的天然存在的NK细胞。所述方法可以应用于来自人类来源或其它动物的NK细胞。
此外,所公开的方法具有提供具有更高细胞毒性和ADCC功能的细胞的额外益处。根据所公开的方法扩增的初始NK细胞群产生扩增的NK细胞群,所述扩增的NK细胞群展现出初始NK细胞群的细胞毒性的至少约2倍的细胞毒性,初始NK细胞群的细胞毒性的至少约4倍的细胞毒性,初始NK细胞群的细胞毒性的至少约5倍的细胞毒性,初始NK细胞群的细胞毒性的至少约8倍的细胞毒性,或初始NK细胞群的细胞毒性的至少约10倍的细胞毒性。此外,根据所公开的方法扩增的NK细胞对具有ADCC能力的标靶展现出更高的细胞毒性。ADCC相关蛋白在非限制性实例中例如CD16或其它NK细胞配体在非限制性实例中例如NKG2D、NKp46、CD62L的更高表达可以用于评估扩增的NK细胞与非扩增的NK细胞或在其它条件下扩增的NK细胞相比的相对细胞毒性。标记物例如NKG2D、NKp46等等是NK细胞处于激活状态的指标。与标记物组合可以提供细胞毒性增加的信号,即使在不能直接评估细胞毒性时。举例来说,与非扩增的NK细胞相比,如本文所公开的扩增的NK细胞群可以展现出增加的对肿瘤标靶的杀伤或分泌更高量的抗肿瘤细胞因子(IFN、TNF)。在另一个方面中,与未扩增的NK细胞相比,如本文所公开的扩增的NK细胞群可以展现出增加的NKG2D、NKp46和CD16的表达。用于检测特异性蛋白质的量以评估NK细胞的激活状态的各种手段是所属领域中已知的并且可以被使用,所述手段包括光谱法例如流式细胞术或免疫检测法例如蛋白质印迹法、酶联免疫吸附分析(ELISA)、蛋白质免疫沉淀;免疫电泳或免疫染色。
另外,如本文所公开的扩增的NK细胞群可以展现出改进的耐受低温保存、保持活力和细胞毒性以及冷冻和解冻后的能力。
用表达Fc的饲养细胞扩增的NK细胞组合物对SKOV3卵巢癌靶细胞展现出更高的细胞毒性,如图2和图3中所示。用表达Fc结构域的饲养细胞扩增的NK细胞组合物具备具有增加的CD16、NKp46和CD62L的增强的表型。这些具备增强的表型的NK细胞可以具有增强的治疗功效。增加的CD16可以允许增强的接合包覆抗体的靶细胞的能力。增加的NKp46可以具有更强的结合激活配体的能力。作为L-选择素配体的增加的CD62L可以增强NK细胞向淋巴或骨髓区室的运输。
(b)治疗性方法
本文所公开的组合物和方法可以用于多种治疗、诊断、工业和研究应用。在一些方面中,本公开可以用于治疗癌症。因此,在一个方面中,本文公开了治疗、抑制、减轻和/或预防受试者的癌症、癌症复发或癌转移或传染病例如病毒感染或细菌感染的方法,所述方法包含向有需要的受试者施用有效量的如本文所描述的组合物或扩增的NK细胞群。
癌症可以选自但不限于血液学癌症、淋巴瘤、结肠直肠癌、结肠癌、肺癌、头颈癌、卵巢癌、前列腺癌、睾丸癌、肾癌、皮肤癌、宫颈癌、胰腺癌和乳腺癌。在一个方面中,癌症包含实体肿瘤。在另一个方面中,癌症选自急性骨髓性白血病、骨髓增生异常综合征、慢性骨髓性白血病、急性淋巴细胞性白血病、骨髓纤维化、多发性骨髓瘤。在另一个方面中,癌症选自白血病、淋巴瘤、肉瘤、癌瘤,并且可以起源于骨髓、脑、肺、乳腺、胰腺、肝、头颈部、皮肤、生殖道、前列腺、结肠、肝、肾、腹膜内、骨、关节、眼。
在另一个方面中,治疗方法包括:在干细胞移植之后预防、抑制、减轻或减少癌症复发或癌转移的方法;在干细胞移植之后调节T细胞库的方法;用于调节免疫组库的一般方法、预防、抑制、减轻或减少急性或慢性移植物抗宿主疾病的方法;以及预防、抑制、减轻或减少病毒再激活的方法,所述病毒再激活例如是单纯疱疹病毒-1(HSV-1)、单纯疱疹病毒-2(HSV-2)、巨细胞病毒(CMV)、水痘带状疱疹病毒(VZV)、EB病毒(Epstein-Barr virus,EBV)、腺病毒、腺相关病毒、细小病毒、JC病毒和/或BK病毒的再激活;其中每种方法都包含向有需要的受试者施用有效量的如本文所描述的组合物或扩增的NK细胞群。
任何公开的治疗方法可以进一步包含向受试者施用(同时或作为单一制剂)额外治疗剂或治疗方案以及有效量的如本文所描述的组合物或扩增的NK细胞群。额外治疗剂可以是基于药物的制备方案例如Cy-Flu、Bu-Flu、Flu-Mel或与剂量或给药调整类似。或者,额外治疗剂可以是移植物抗宿主(GvHD)防治剂,例如但不限于环磷酰胺。或者,额外治疗剂或治疗方案可以选自化疗剂和化疗方案,在非限制性实例中例如通过首字母缩略词CHOP、FLAG(包括FLAG-Ida或FLAG-IDA或IDA-FLAG或Ida-FLAG;和FLAG-Mito或FLAG-MITO或Mito-FLAG或MITO-FLAG或FLANG)、IA或IAC或7+3著称的化疗剂和化疗方案。举例来说,本文预期,所公开的抑制、减轻和/或预防癌转移和/或复发的方法可以包含施用所属领域中已知的任何抗癌剂,包括但不限于阿贝西利(Abemaciclib)、乙酸阿比特龙酯(AbirateroneAcetate)、阿比特曲沙(Abitrexate)(甲氨蝶呤)、亚伯杉(Abraxane)(紫杉醇白蛋白稳定的纳米颗粒制剂)、ABVD、ABVE、ABVE-PC、AC、AC-T、阿德塞特里斯(Adcetris)(贝伦妥单抗-维多汀(Brentuximab Vedotin))、ADE、阿多-曲妥珠单抗-美坦新(Ado-TrastuzumabEmtansine)、阿霉素(Adriamycin)(盐酸多柔比星(Doxorubicin Hydrochloride))、二马来酸阿法替尼(Afatinib Dimaleate)、癌伏妥(Afinitor)(依维莫司(Everolimus))、阿金泽奥(Akynzeo)(盐酸奈托匹坦(Netupitant Hydrochloride)和盐酸帕洛诺司琼(Palonosetron Hydrochloride))、阿尔达拉(Aldara)(咪喹莫特(Imiquimod))、阿地白介素(Aldesleukin)、阿莱森萨(Alecensa)(艾乐替尼(Alectinib))、艾乐替尼、阿仑单抗(Alemtuzumab)、爱宁达(Alimta)(培美曲塞二钠(Pemetrexed Disodium))、阿里科帕(Aliqopa)(盐酸考班昔布(Copanlisib Hydrochloride))、注射用阿尔克兰(Alkeran)(盐酸美法仑(Melphalan Hydrochloride))、阿尔克兰锭剂(美法仑)、阿洛西(Aloxi)(盐酸帕洛诺司琼)、阿伦布里奇(Alunbrig)(布加替尼(Brigatinib))、安伯氯林(Ambochlorin)(苯丁酸氮芥)、安伯氯林(苯丁酸氮芥)、氨磷汀、氨基酮戊酸、阿那曲唑(Anastrozole)、阿瑞匹坦(Aprepitant)、阿雷迪亚(Aredia)(帕米膦酸二钠(Pamidronate Disodium))、安美达(Arimidex)(阿那曲唑)、诺曼癌素(Aromasin)(依西美坦(Exemestane)),阿仑恩(Arranon)(奈拉滨(Nelarabine))、三氧化二砷、阿泽拉(Arzerra)(奥法木单抗(Ofatumumab))、天冬酰胺酶菊欧文氏菌(Asparaginase Erwinia chrysanthemi)、阿特珠单抗(Atezolizumab)、阿瓦斯汀(Avastin)(贝伐单抗(Bevacizumab))、阿维鲁单抗(Avelumab)、阿西替尼(Axitinib)、阿扎胞苷(Azacitidine)、百稳益(Bavencio)(阿维鲁单抗)、BEACOPP、贝塞纳姆(Becenum)(卡莫司汀(Carmustine))、贝莱奥达克(Beleodaq)(贝利诺司他(Belinostat))、贝利诺司他、盐酸苯达莫司汀(Bendamustine Hydrochloride)、BEP、贝斯邦萨(Besponsa)(伊珠单抗奥唑米星(Inotuzumab Ozogamicin))、贝伐单抗(Bevacizumab)、贝沙罗汀(Bexarotene)、贝克萨(Bexxar)(托西妥单抗(Tositumomab)和碘I 131托西妥单抗)、比卡鲁胺(Bicalutamide)、BiCNU(卡莫司汀)、博莱霉素(Bleomycin)、博纳吐单抗(Blinatumomab)、布林赛特(Blincyto)(博纳吐单抗)、硼替佐米(Bortezomib)、博苏利夫(Bosulif)(博舒替尼(Bosutinib))、博舒替尼、贝伦妥单抗-维多汀、布加替尼、BuMel、白消安、布舒克斯(Busulfex)(白消安)、卡巴他赛(Cabazitaxel)、卡贝泰克斯(Cabometyx)(卡博替尼-S-苹果酸盐(Cabozantinib-S-Malate))、卡博替尼-S-苹果酸盐、CAF、康帕斯(Campath)(阿仑单抗)、坎普托萨(Camptosar)、(盐酸伊立替康(IrinotecanHydrochloride))、卡培他滨(Capecitabine)、CAPOX、卡拉克(Carac)(局部氟尿嘧啶)、卡铂、卡铂-紫杉醇、卡非佐米(Carfilzomib)、卡穆布里斯(Carmubris)(卡莫司汀)、卡莫司汀、卡莫司汀植入体、康士得(Casodex)(比卡鲁胺)、CEM、色瑞替尼(Ceritinib)、色鲁比丁(Cerubidine)(盐酸柔红霉素(Daunorubicin Hydrochloride))、赛瓦里克斯(Cervarix)(重组HPV二价疫苗)、西妥昔单抗(Cetuximab)、CEV、苯丁酸氮芥、苯丁酸氮芥-泼尼松、CHOP、顺铂、克拉屈滨(Cladribine)、克拉芬(Clafen)(环磷酰胺)、氯法拉滨(Clofarabine)、氯法雷(Clofarex)(氯法拉滨)、克洛拉(Clolar)(氯法拉滨)、CMF、考比替尼(Cobimetinib)、科特里克(Cometriq)(卡博替尼-S-苹果酸盐(Cabozantinib-S-Malate))、盐酸考班昔布、COPDAC、COPP、COPP-ABV、考斯梅根(Cosmegen)(放线菌素D)、可泰利(Cotellic)(考比替尼)、克唑替尼(Crizotinib)、CVP、环磷酰胺、Cyfos(异环磷酰胺)、欣锐择(Cyramza)(雷莫芦单抗(Ramucirumab))、阿糖胞苷、阿糖胞苷脂质体、赛德萨-U(Cytosar-U)(阿糖胞苷)、环磷酰胺(Cytoxan/Cyclophosphamide)、达拉非尼(Dabrafenib)、达卡巴嗪(Dacarbazine)、达珂(Dacogen)(地西他滨)、放线菌素D、达雷妥尤单抗(Daratumumab)、兆珂(Darzalex)(达雷妥尤单抗)、达沙替尼(Dasatinib)、盐酸柔红霉素、盐酸柔红霉素和阿糖胞苷脂质体、地西他滨、去纤苷钠、去纤钠(去纤苷钠)、地加瑞克(Degarelix)、地尼白介素(Denileukin Diftitox)、地诺单抗(Denosumab)、DepoCyt(阿糖胞苷脂质体)、地塞米松(Dexamethasone)、盐酸右雷佐生(Dexrazoxane Hydrochloride)、地妥昔单抗(Dinutuximab)、多西他赛(Docetaxel)、多西尔(Doxil)(盐酸阿霉素脂质体)、盐酸阿霉素、盐酸阿霉素脂质体、Dox-SL(盐酸阿霉素脂质体)、DTIC-Dome(达卡巴嗪)、度伐利尤单抗(Durvalumab)、艾弗迪(Efudex)(局部氟尿嘧啶)、艾利泰克(Elitek)(拉布立酶(Rasburicase))、埃伦斯(Ellence)(盐酸表阿霉素(Epirubicin Hydrochloride))、埃罗妥珠单抗(Elotuzumab)、埃洛沙丁(Eloxatin)(奥沙利铂)、艾曲波帕奥拉敏(EltrombopagOlamine)、埃蒙德(Emend)(阿瑞匹坦(Aprepitant))、恩必喜(Empliciti)(埃罗妥珠单抗(Elotuzumab))、甲磺酸依那西尼(Enasidenib Mesylate)、恩杂鲁胺(Enzalutamide)、盐酸表阿霉素、EPOCH、爱必妥(Erbitux)(西妥昔单抗(Cetuximab))、甲磺酸艾日布林(EribulinMesylate)、爱維德(Erivedge)(维莫德吉(Vismodegib))、盐酸厄洛替尼(ErlotinibHydrochloride)、欧文纳泽(Erwinaze)(天冬酰胺酶菊欧文氏菌)、阿密磷定(Ethyol)(氨磷汀(Amifostine))、凡毕复(Etopophos)(磷酸依托泊苷(Etoposide Phosphate))、依托泊苷、磷酸依托泊苷、艾瓦西特(Evacet)(盐酸阿霉素脂质体)、依维莫司(Everolimus)、易维特(Evista)(盐酸雷洛昔芬(Raloxifene Hydrochloride))、优维宁(Evomela)(盐酸美法仑)、依西美坦(Exemestane)、5-FU(氟尿嘧啶注射剂)、5-FU(局部氟尿嘧啶)、法乐通(Fareston)(托瑞米芬(Toremifene))、法里达克(Farydak)(帕比司他(Panobinostat))、法洛德(Faslodex)(氟维司群(Fulvestrant))、FEC、费马拉(Femara)(来曲唑(Letrozole))、非格司亭(Filgrastim)、氟达拉(Fludara)(磷酸氟达拉滨(Fludarabine Phosphate))、磷酸氟达拉滨、氟尿嘧啶乳膏(Fluoroplex)(局部氟尿嘧啶)、氟尿嘧啶注射剂、局部氟尿嘧啶、氟他胺、脱叶亚磷(甲氨蝶呤)、脱叶亚磷PFS(甲氨蝶呤)、FOLFIRI、FOLFIRI-贝伐珠单抗、FOLFIRI-西妥昔单抗、FOLFIRINOX、FOLFOX、服瘤停(Folotyn)(普拉曲沙(Pralatrexate))、FU-LV、氟维司群、加卫苗(Gardasil)(重组HPV四价疫苗)、加卫苗9(重组HPV九价疫苗)、癌即瓦(Gazyva)(奥比妥珠单抗(Obinutuzumab))、吉非替尼(Gefitinib)、盐酸吉西他滨、吉西他滨-顺铂、吉西他滨-奥沙利铂、吉妥珠单抗奥佐米星、健择(Gemzar)(盐酸吉西他滨)、吉洛特里夫(Gilotrif)(二马来酸阿法替尼)、格列卫(Gleevec)(甲磺酸伊马替尼(Imatinib Mesylate))、格利亚德尔(Gliadel)(卡莫司汀植入物)、格利亚德尔晶片(卡莫司汀植入物)、谷卡匹酶(Glucarpidase)、乙酸戈舍瑞林(Goserelin Acetate)、海乐卫(Halaven)(甲磺酸艾日布林)、心得安(Hemangeol)(盐酸普萘洛尔(PropranololHydrochloride))、赫赛汀(Herceptin)(曲妥珠单抗)、重组HPV二价疫苗、重组HPV九价疫苗、重组HPV四价疫苗、海康丁(Hycamtin)(盐酸拓扑替康(Topotecan Hydrochloride))、爱治(Hydrea)(羟基脲)、羟基脲、Hyper-CVAD、伊布兰斯(Ibrance)(帕博西尼(Palbociclib))、替伊莫单抗(Ibritumomab Tiuxetan)、依鲁替尼(Ibrutinib)、ICE、伊卢西格(Iclusig)(盐酸普纳替尼(Ponatinib Hydrochloride))、伊达霉素(Idamycin)(盐酸伊达比星(Idarubicin Hydrochloride))、盐酸伊达比星、艾代拉里斯(Idelalisib)、伊迪法(Idhifa)(甲磺酸依那地尼(Enasidenib Mesylate))、伊法克斯(Ifex)(异环磷酰胺)、异环磷酰胺、匹服平(Ifosfamidum)(异环磷酰胺)、IL-2(阿尔德白介素(Aldesleukin))、甲磺酸伊马替尼(Imatinib Mesylate)、亿珂(Imbruvica)(依鲁替尼(Ibrutinib))、英飞凡(Imfinzi)(度伐利尤单抗)、咪喹莫特、伊利吉克(Imlygic)(拉他莫基(TalimogeneLaherparepvec))、英利达(Inlyta)(阿西替尼(Axitinib))、奥英妥珠单抗奥佐米星(Inotuzumab Ozogamicin)、重组干扰素α-2b、白介素-2(阿尔德白介素)、内含子A(重组干扰素α-2b)、碘I 131托西妥单抗和托西妥单抗、伊匹单抗(Ipilimumab)、易瑞沙(Iressa)(吉非替尼(Gefitinib))、盐酸伊立替康(Irinotecan Hydrochloride)、盐酸伊立替康脂质体、伊斯托达克斯(Istodax)(罗米地辛(Romidepsin))、伊沙匹隆(Ixabepilone)、柠檬酸伊沙佐米(Ixazomib Citrate)、伊克森普拉(Ixempra)(伊沙匹隆)、贾卡菲(Jakafi)(磷酸鲁索替尼(Ruxolitinib Phosphate))、JEB、耶夫塔娜(Jevtana)(卡巴他赛(Cabazitaxel))、卡德西拉(Kadcyla)(阿多-曲妥珠单抗-美坦新)、克昔芬(Keoxifene)(盐酸雷洛昔芬(Raloxifene Hydrochloride))、凯皮万斯(Kepivance)(帕利弗明(Palifermin))、可瑞达(Keytruda)(派姆单抗(Pembrolizumab))、基斯卡利(Kisqali)(利博西尼(Ribociclib))、凯姆利亚(Kymriah)(替沙来塞(Tisagenlecleucel))、凯普罗利斯(Kyprolis)(卡非佐米(Carfilzomib))、乙酸兰瑞肽(Lanreotide Acetate)、二甲苯磺酸拉帕替尼(LapatinibDitosylate)、拉特鲁沃(Lartruvo)(奥拉单抗(Olaratumab))、来那度胺(Lenalidomide)、甲磺酸乐伐替尼(Lenvatinib Mesylate)、莱维玛(Lenvima)(甲磺酸乐伐替尼)、来曲唑(Letrozole)、尔可服钙(Leucovorin Calcium)、瘤克宁(Leukeran)(苯丁酸氮芥)、乙酸亮丙瑞林(Leuprolide Acetate)、禄斯得停(Leustatin)(克拉屈滨)、勒乌兰(Levulan)(氨基乙酰丙酸(Aminolevulinic Acid))、林福利嗪(Linfolizin)(苯丁酸氮芥)、力得(LipoDox)(盐酸阿霉素脂质体)、洛莫司汀(Lomustine)、朗斯弗(Lonsurf)(三氟胸苷和盐酸替吡嘧啶(Tipiracil Hydrochloride))、卢普龙(Lupron)(乙酸亮丙瑞林)、卢普龙杜泊特(LupronDepot)(乙酸亮丙瑞林)、卢普龙杜泊特-派德(Lupron Depot-Ped)(乙酸亮丙瑞林)、林帕萨(Lynparza)(奥拉帕尼(Olaparib))、马奇博(Marqibo)(硫酸长春新碱脂质体)、马图兰(Matulane)(盐酸丙卡巴肼)、盐酸甲氯乙胺、乙酸甲地孕酮、麦欣霓(Mekinist)(曲美替尼)、美法仑、盐酸美法仑、巯嘌呤、梅斯纳(Mesna)、梅斯内克斯(Mesnex)(梅斯纳)、麦塞唑拉斯通(Methazolastone)(替莫唑胺)、甲氨蝶呤、甲氨蝶呤LPF(甲氨蝶呤)、甲基纳曲酮溴化物、甲氨蝶呤钠(Mexate)(甲氨蝶呤)、甲氨蝶呤钠-AQ(甲氨蝶呤)、米哚妥林(Midostaurin)、丝裂霉素C、盐酸米托蒽醌(Mitoxantrone Hydrochloride)、米托曲士(Mitozytrex)(丝裂霉素C)、MOPP、释倍灵(Mozobil)(普乐沙福(Plerixafor))、氮芥(盐酸甲氯乙胺)、自力霉素(Mutamycin)(丝裂霉素C)、马利芒(Myleran)(白消安)、米洛萨(Mylosar)(阿扎胞苷)、麦洛塔格(Mylotarg)(吉妥珠单抗奥佐米星)、纳米颗粒紫杉醇(紫杉醇白蛋白稳定的纳米颗粒制剂)、诺维本(Navelbine)(酒石酸长春瑞滨(VinorelbineTartrate))、奈西妥珠单抗(Necitumumab)、奈拉滨(Nelarabine)、尼欧萨(Neosar)(环磷酰胺)、马来酸来那替尼(Neratinib Maleate)、纳林克斯(Nerlynx)(马来酸来那替尼)、奈托匹坦(Netupitant)和盐酸帕洛诺司琼、纽拉斯塔(Neulasta)(聚乙二醇非格司亭)、优保津(Neupogen)(非格司亭)、蕾莎瓦(Nexavar)(甲苯磺酸索拉非尼(Sorafenib Tosylate))、尼兰德龙(Nilandron)(尼鲁米特(Nilutamide))、尼罗替尼(Nilotinib)、尼鲁米特、宁拉罗(Ninlaro)(柠檬酸伊沙佐米(Ixazomib Citrate))、单水合甲苯磺酸尼拉帕利(NiraparibTosylate Monohydrate)、纳武单抗(Nivolumab)、诺瓦得士(Nolvadex)(柠檬酸他莫昔芬)、尼普雷特(Nplate)(罗米司亭(Romiplostim))、奥比妥珠单抗、奥多姆佐(Odomzo)(索尼德吉布(Sonidegib))、OEPA、奥法木单抗、OFF、奥拉帕尼、奥拉单抗、高三尖杉酯碱(Omacetaxine Mepesuccinate)、昂卡斯帕(Oncaspar)(培门冬酶)、盐酸昂丹司琼(Ondansetron Hydrochloride)、奥尼维德(Onivyde)(盐酸伊立替康脂质体)、昂泰克(Ontak)(地尼白介素(Denileukin Diftitox))、欧迪沃(Opdivo)(纳武单抗)、OPPA、奥希替尼(Osimertinib)、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定的纳米颗粒制剂、PAD、帕博西尼、帕利弗明(Palifermin)、盐酸帕洛诺司琼(Palonosetron Hydrochloride)、盐酸帕洛诺司琼和奈妥匹坦(Netupitant)、帕米膦酸二钠、帕尼单抗(Panitumumab)、帕比司他(Panobinostat)、帕拉普拉特(Paraplat)(卡铂)、对铂(卡铂)、盐酸帕唑帕尼(PazopanibHydrochloride)、PCV、PEB、培门冬酶、聚乙二醇非格司亭、聚乙二醇干扰素α-2b、PEG-内含子(聚乙二醇干扰素α-2b)、派姆单抗、培美曲塞二钠、佩杰塔(Perjeta)(帕妥珠单抗)、帕妥珠单抗、顺铂(Platinol/Cisplatin)、顺铂-AQ(顺铂)、普乐沙福、泊马度胺(Pomalidomide)、泊马利斯特(Pomalyst)(泊马度胺)、盐酸普纳替尼、波尔拉扎(Portrazza)(奈西妥珠单抗)、普拉曲沙(Pralatrexate)、泼尼松、盐酸丙卡巴肼、白介素(阿尔德白介素)、普罗利亚(Prolia)(地诺单抗(Denosumab))、普罗马塔(Promacta)(艾曲波帕奥拉敏(Eltrombopag Olamine))、盐酸普萘洛尔(Propranolol Hydrochloride)、普列威(Provenge)(西普乐赛尔-T(Sipuleucel-T))、嘌呤醇(巯嘌呤)、普立克山(Purixan)(巯嘌呤)、二氯化镭223、盐酸雷洛昔芬、雷莫芦单抗(Ramucirumab)、拉布立酶(Rasburicase)、R-CHOP、R-CVP、重组人乳头瘤病毒(HPV)二价疫苗、重组人乳头瘤病毒(HPV)九价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素α-2b、瑞戈非尼(Regorafenib)、雷斯特(Relistor)(甲基纳曲酮溴化物)、R-EPOCH、雷米德(Revlimid)(来那度胺)、氨克生(Rheumatrex)(甲氨蝶呤)、利博西尼、R-ICE、利妥昔单抗(Rituxan/Rituximab)、利妥昔单抗透明质酸酶(Rituxan Hycela)(人类利妥昔单抗和透明质酸酶(Rituximab andHyaluronidase Human))、利妥昔单抗、人类利妥昔单抗和透明质酸酶、,RolapitantHydrochloride、罗米地辛(Romidepsin)、罗米司汀(Romiplostim)、红比霉素(Rubidomycin)(盐酸柔红霉素)、鲁布拉卡(Rubraca)(樟脑磺酸鲁卡帕里布(RucaparibCamsylate))、樟脑磺酸鲁卡帕里布、磷酸鲁索替尼、瑞达普(Rydapt)(米哚妥林)、斯凯洛罗瑟尔(Sclerosol)胸膜内气雾剂(滑石)、司妥昔单抗(Siltuximab)、西普卢塞尔-T、索马杜林杜泊特(Somatuline Depot)(乙酸兰瑞肽)、索尼德吉布(Sonidegib)、甲苯磺酸索拉非尼(Sorafenib Tosylate)、斯派塞尔(Sprycel)(达沙替尼(Dasatinib))、史丹佛V(STANFORDV)、无菌滑石粉(滑石)、无菌滑石(滑石)、斯蒂瓦尔加(Stivarga)(瑞戈非尼(Regorafenib))、苹果酸舒尼替尼、萨顿(Sutent)(苹果酸舒尼替尼)、赛拉创(Sylatron)(聚乙二醇干扰素α-2b)、西尔万特(Sylvant)(司妥昔单抗)、西里博(Synribo)(高三尖杉酯碱)、泰泊洛德(Tabloid)(硫鸟嘌呤)、TAC、塔芬拉尔(Tafinlar)(达拉非尼(Dabrafenib))、塔格里索(Tagrisso)(奥希替尼(Osimertinib))、滑石、拉他莫基、柠檬酸他莫昔芬、塔拉宾PFS(Tarabine PFS)(阿糖胞苷)、特罗凯(Tarceva)(盐酸厄洛替尼(ErlotinibHydrochloride))、塔格瑞丁(Targretin)(贝沙罗汀(Bexarotene))、塔西尼亚(Tasigna)(尼罗替尼(Nilotinib))、紫杉醇(Taxol/Paclitaxel)、泰索帝(Taxotere)(多西他赛)、泰森特瑞克(Tecentriq)(阿特珠单抗)、泰莫达(Temodar)(替莫唑胺)、替莫唑胺、替西罗莫司(Temsirolimus)、沙利度胺(Thalidomide)、沙利度胺(Thalomid/Thalidomide)、硫鸟嘌呤、噻替巴(Thiotepa)、替沙来塞、托拉克(Tolak)(局部氟尿嘧啶)、盐酸拓扑替康、托瑞米芬(Toremifene)、托里塞尔(Torisel)(替西罗莫司)、托西妥单抗和碘I 131托西妥单抗、托泰克(Totect)(盐酸右雷佐生)、TPF、曲贝替丁(Trabectedin)、曲美替尼(Trametinib)、曲妥珠单抗、特雷安达(Treanda)(盐酸苯达莫司汀)、三氟胸苷和盐酸替匹嘧啶、特里赛诺克斯(Trisenox)(三氧化二砷)、泰克布(Tykerb)(二甲苯磺酸拉帕替尼(LapatinibDitosylate))、尤尼吐星(Unituxin)(地妥昔单抗(Dinutuximab))、三乙酸尿苷、VAC、凡德他尼(Vandetanib)、VAMP、瓦鲁比(Varubi)(盐酸罗拉匹坦(Rolapitant Hydrochloride))、维克替比(Vectibix)(帕尼单抗)、VeIP、维尔本(Velban)(硫酸长春碱)、万珂(Velcade)(硼替佐米(Bortezomib))、韦尔瑟(Velsar)(硫酸长春碱)、威罗非尼(Vemurafenib)、文克莱斯特(Venclexta)(威尼托克(Venetoclax))、威尼托克、韦尔泽尼奥(Verzenio)(阿贝西利(Abemaciclib))、维亚杜瓦(Viadur)(乙酸亮丙瑞林)、维达萨(Vidaza)(阿扎胞苷)、硫酸长春碱、文卡萨PFS(Vincasar PFS)(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨、VIP、维莫德吉(Vismodegib)、维斯托加德(Vistogard)(三乙酸尿苷)、葡糖苷酶(Voraxaze)(谷卡匹酶)、伏立诺他(Vorinostat)、褔退癌(Votrient)(盐酸帕唑帕尼(Pazopanib Hydrochloride))、伟艾克斯(Vyxeos)(盐酸柔红霉素和阿糖胞苷脂质体)、康福林(Wellcovorin)(留可佛林钙(Leucovorin Calcium))、截剋瘤(Xalkori)(克唑替尼(Crizotinib))、希罗达(Xeloda)(卡培他滨(Capecitabine))、XELIRI、XELOX、杰瓦(Xgeva)(地诺单抗)、菲戈(Xofigo)(二氯化镭223)、坦迪(Xtandi)(恩杂鲁胺)、埃尔沃伊(Yervoy)(伊匹单抗)、永德利斯(Yondelis)(曲贝替丁(Trabectedin))、扎尔特拉普(Zaltrap)(齐夫-阿柏西普(Ziv-Aflibercept))、扎尔修(Zarxio)(非格司亭)、泽茹拉(Zejula)(单水合甲苯磺酸尼拉帕利(Niraparib Tosylate Monohydrate))、泽尔博拉夫(Zelboraf)(威罗非尼)、泽娃灵(Zevalin)(替伊莫单抗)、新卡德(Zinecard)(盐酸右雷佐生)、齐夫-阿柏西普、佐夫兰(Zofran)(盐酸昂丹司琼)、佐拉德(Zoladex)(乙酸戈舍瑞林)、唑来膦酸、佐林扎(Zolinza)(伏立诺他)、佐美达(Zometa)(唑来膦酸)、齐德利格(Zydelig)(艾代拉里斯)、齐卡迪亚(Zykadia)(色瑞替尼)和/或齐蒂加(Zytiga)(乙酸阿比特龙)。本文还考虑了作为PD1/PDL1阻断抑制剂的化学治疗剂(例如兰博利珠单抗、纳武单抗、派姆单抗、匹迪利珠单抗(pidilizumab)、BMS-936559、阿特珠单抗、度伐利尤单抗或阿维鲁单抗)。
或者,额外治疗剂可以是选自但不限于5-取代的2-脱氧尿苷类似物、核苷类似物、(非核苷)焦磷酸类似物、核苷逆转录酶(RT)抑制剂(NRTI)、非核苷逆转录酶抑制剂(NNRTI)、蛋白酶抑制剂(PI)和整合酶抑制剂、进入抑制剂和无环鸟苷类似物、无环核苷膦酸酯(ANP)类似物、丙型肝炎病毒(HCV)NS5A和NS5B抑制剂以及流感病毒抑制剂、免疫刺激剂、干扰素、寡核苷酸和抗有丝分裂抑制剂的抗病毒剂。抗病毒剂的非限制性实例是阿昔洛韦(acyclovir)、泛昔洛韦(famciclovir)、伐昔洛韦(valacyclovir)、喷昔洛韦(penciclovir)、更昔洛韦(ganciclovir)、利托那韦(ritonavir)、洛匹那韦(lopinavir)、沙奎那韦(saquinavir)等等;西咪替丁(cimetidine);雷尼替丁(ranitidine);卡托普利(captopril);二甲双胍;安非他酮(bupropion);非索非那定(fexofenadine);奥卡西平(oxcarbazepine);左乙拉西坦(leveteracetam);曲马多(tramadol);或其任何异构体、互变异构体、类似物、多晶型物、溶剂化物、衍生物或药学上可接受的盐。
或者,额外治疗剂可以是选自但不限于青霉素、四环素、头孢菌素、林可霉素、大环内酯、磺酰胺、糖肽、氨基糖苷和碳青霉烯的抗生素剂。抗病毒剂的非限制性实例是阿莫西林(amoxicillin)、强力霉素(doxycycline)、头孢氨苄(cephalexin)、环丙沙星(ciprofloxacin)、克林霉素(clindamycin)、甲硝唑(metronidazole)、阿奇霉素(azithromycin)、磺胺甲恶唑(sulfamethoxazole)和甲氧苄啶(trimethoprim)、克拉维酸(clavulanate)和左氧氟沙星(levofloxacin)。
(V)试剂盒
本公开的另一个方面提供了试剂盒,所述试剂盒包含上文所详述的融合肽中的至少一种、和/或上文所详述的Fc结合饲养细胞中的至少一种、和/或上文所详述的Fc结合的工程化颗粒(PM颗粒和/外泌体)中的至少一种。融合肽可以与其它试剂盒组分一起提供在合适容器中,所述其它试剂盒组分例如是细胞试剂、细胞生长培养基、选择培养基、蛋白质纯化试剂、缓冲剂等等。本文所提供的试剂盒一般包括用于实施下文所详述的方法的说明书。试剂盒中所包括的说明书可以贴在包装材料上,或可以作为包装说明书包括在内。虽然说明书通常是书面或印刷材料,但其不限于此。本公开考虑了能够储存所述说明书并将其传达给最终用户的任何介质。所述介质包括但不限于电子储存介质(例如磁盘、磁带、盒式磁带、芯片)、光学介质(例如CD ROM)等等。如本文所使用,术语“说明书”可以包括提供指令的互联网站点的地址。
实例
实例1-通过Fc区进行的CD16接合在第14天后增强了增殖率
获得了K562细胞系,即表达41BBL和膜结合IL-21(“CSTX-002”)的细胞系。
用NA-Fc转染K562细胞的独立样品以产生Fc结合K562细胞(“CSTX002-Fc”)。
从来自两个不同供体(L43和L44)的白细胞来源获得外周血液单核细胞(PBMC),并将其分成多个等分试样。在存在CSTX002的情况下测试来自每个供体的PBMC样品的NK细胞扩增,并且在存在CSTX002-Fc的情况下测试另一个样品的NK细胞扩增。
在补充有10%FBS和100U/mL IL-2以及被丝裂霉素C处理或被照射的饲养细胞(CSTX002细胞或CSTX002-Fc细胞)的SCGM CellGro培养基中生长通过菲科帕克(Ficoll-Paque)密度梯度从血沉棕黄层分离的PBMC,以每个NK细胞1个饲养细胞的比率共培养。将细胞维持在37℃下具有5%CO2的加湿氛围中。从第5天开始,每隔一天通过用补充有100U IL2的新鲜培养基替换一半培养基来更换培养基。每隔一天对细胞进行计数,并从第7天开始定期检查培养物含量。
图5展现了NK细胞扩增相对于培养天数的图式,所述图式显示了CD16通过Fc区进行的接合在第14天后增强了增殖率。使用CSTX002(开符号)或CSTX002-Fc细胞系(闭符号)作为饲养细胞从源自两个供体L54(圆圈)或L44(正方形)的PBMC扩增NK细胞。CD16接合允许增加NK细胞增殖。来自两个供体的NK细胞在用单独的IL21或IL21和Fc刺激后以相同的速率扩增直到第14天,此时Fc刺激的培养物与仅IL21相比以增加的速率分裂。
实例2–在存在Fc结合饲养细胞的情况下扩增的自然杀伤细胞的细胞毒性
如实例1中所描述制备CSTX002细胞和CSTX002-Fc细胞。如下执行细胞毒性分析。使用转染绿色荧光蛋白(GFP)的卵巢癌衍生靶细胞系SKOV3作为标靶来测量效应NK细胞的抗肿瘤细胞毒性。将靶细胞在37℃、5%CO2氛围中单独培养(对照孔)或以0.5×106个细胞/mL与NK细胞以指定的效应物与标靶(E:T)比率共培养45分钟。然后,将细胞离心并重悬于含有Annexin V-PacBlue抗体的Annexin V标记缓冲液中,并在4℃下培育15分钟,之后进行流式细胞术分析。基于具有效应物的每个孔中剩余的活靶细胞(GFP+/Annexin V-)的绝对量(VTCE:T)并参考“单独标靶”对照孔中的平均VTC(VTCT对照)测定细胞毒性。
细胞毒性E:T(%)=(VTCE:T/平均VTCT对照)×100
图6展现了两张图,每张图都显示了从获自两个不同供体(L43和L44)的PBMC扩增的NK细胞的细胞毒性。对于每个供体,使用CSTX002(·)或CSTX002-Fc(■)细胞系作为饲养细胞从PBMC扩增NK细胞。对于两个不同供体中的每一个,发现用CSTX002-Fc扩增的NK细胞对SKOV3细胞具有增加的细胞毒性。
实例3–增加来自反应不佳的供体PBMC的自然杀伤细胞的细胞毒性
从先前观察到当通过用CSTX002细胞(未添加Fc)刺激进行扩增时对SKOV3细胞不具有细胞毒性的供体获得PBMC。使用CSTX002(·)或CSTX002-Fc(■)细胞系作为饲养细胞从先前观察为反应不佳的PBMC扩增NK细胞,如实例1中所描述。然后,也如实例1中所描述但使用被转型以表达Fc的SKOV3,分别测试两种不同的所得NK细胞群的细胞毒性。图7是使用CSTX002(·)或CSTX002-Fc(■)从PBMC扩增的NK细胞的细胞毒性图。图7中显示的结果表明,相对于那些来自获自同一反应不佳的供体的PBMC并用未与Fc结合的饲养细胞(CSTX002)扩增的NK细胞来说,来自获自对SKOV3细胞的细胞毒性反应不佳的供体的PBMC的NK细胞在用对肿瘤标靶显示细胞毒性、具有结合Fc结构域的Fc结合饲养细胞(CSTX002-Fc)扩增时反应良好。用CSTX002-Fc扩增的NK细胞将更好地发挥抗体依赖性细胞毒性,并对与抗体结合的肿瘤标靶产生更高的杀伤活性。
实例4–有利的受体表达
使用CSTX002或CSTX002-Fc细胞系作为饲养细胞从源自两个供体L43(·)或L44(■)的PBMC扩增NK细胞,如实例1中所描述。然后,分析所得NK细胞。图8是一系列六(6)个图,每个图都显示了通过NK细胞进行的比较受体表达,所述NK细胞用具有或不具有膜结合Fc的CSTX002饲养细胞扩增。使用CSTX002或CSTX002-Fc细胞系作为饲养细胞从源自两个供体L43(·)或L44(■)的PBMC扩增NK细胞。分析扩增的NK细胞的受体表达,所述受体被认为对细胞毒性功能和归巢至关重要。用CSTX002-Fc扩增的NK细胞比用CSTX002扩增的NK细胞具有更高的CD16、NKp46和CD62L表达。
实例5–Fc结合细胞质膜颗粒
工程化K562细胞,即表达41BBL和膜结合IL-21的细胞系如美国专利第9,623,082号中所描述进行处理以获得PM-mb21-41BBL细胞质膜囊泡或“CSTX002”颗粒或PM21颗粒。简单地说,在补充有10%FBS的RPMI培养基中培养K562,并且将培养物按比例增大至1L。通过在1000×g下离心收取细胞,将其用具有10mM EDTA的冷PBS洗涤并再悬于裂解缓冲液(50mMHEPES,pH 7.4,蛋白酶抑制剂混合液)。使细胞分裂,并且将裂解溶液在300×g下离心15分钟以去除任何剩余的完整细胞。通过在4℃下离心30分钟将粗细胞质膜与细胞质组分分离。使粗质膜再悬浮并使用蔗糖密度梯度对其进一步纯化以产生纯细胞质膜囊泡,所述囊泡称为PM-mb21-41BBL。
将K562细胞的独立样品转染以表达Fc来产生Fc结合K562,然后如上文所描述对其进行处理以获得Fc结合PM-mb21-41BBL细胞质膜囊泡或“CSTX002-Fc”颗粒。
从单个供体获得外周血液单核细胞(PBMC)并将其分成样品。在存在CSTX002膜颗粒或CSTX002-Fc膜颗粒的情况下测试由PBMC进行的NK细胞扩增。每个膜颗粒的用量是200μg膜蛋白/1mL培养物。在补充有10%FBS和100U/mL IL-2的SCGM CellGro培养基中生长通过菲科帕克密度梯度从血液分离的PBMC。将细胞维持在37℃下具有5%CO2的加湿氛围中。从第5天开始,每隔一天通过用新鲜培养基替换一半培养基以及替换所述量的通过培养基替换去除的膜来更换培养基。每隔一天对细胞进行计数,并在第7、10和14天检查培养物含量。
如实例1中所描述执行细胞毒性分析。用CSTX002-Fc扩增的NK细胞将显示增加的针对SKOV3细胞的细胞毒性。
序列
SEQ ID NO:29
ATGAATCCAAATCAGAAAATAACAACCATTGGATCAATCTGTCTGGTAGTCGGACTAATTAGCCTAATATTGCAAATAGGGAATATAATCTCAATATGGATTAGCCATTCAATTCAAACTGGAAGTCAAAACCATACTGGAATATGCAACCAAAACATCATTACCTATAAAAATAGCACCTGGGTAAAGGACACAACTTCAGTGATATTAACCGGCAATTCATCTCTTTGTCCCATCCGTGGGTGGGCTATATACAGCAAAGACAATAGCATAAGAATTGGTTCCAAAGGAGACGTTTTTGTCATAAGAGAGCCCTTTATTTCATGTTCTCACTTGGAATGCAGGACCTTTTTTCTGACCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCCTGCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCCGGAGGAGCAGTACAACAGCACGCTGCGTGTGGTCAGCATTCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCTGGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
SEQ ID NO:30
ATGAATCCAAATCAGAAAATAACAACCATTGGATCAATCTGTCTGGTAGTCGGACTAATTAGCCTAATATTGCAAATAGGGAATATAATCTCAATATGGATTAGCCATTCAATTCAAACTGGAAGTCAAAACCATACTGGAATATGCAACCAAAACATCATTACCTATAAAAATAGCACCTGGGTAAAGGACACAACTTCAGTGATATTAACCGGCAATTCATCTCTTTGTCCCATCCGTGGGTGGGCTATATACAGCAAAGACAATAGCATAAGAATTGGTTCCAAAGGAGACGTTTTTGTCATAAGAGAGCCCTTTATTTCATGTTCTCACTTGGAATGCAGGACCTTTTTTCTGACCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGGATGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCACTGCCCGAAGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATAATAA
SEQ ID NO:31
ATGAATCCAAATCAGAAAATAACAACCATTGGATCAATCTGTCTGGTAGTCGGACTAATTAGCCTAATATTGCAAATAGGGAATATAATCTCAATATGGATTAGCCATTCAATTCAAACTGGAAGTCAAAACCATACTGGAATATGCAACCAAAACATCATTACCTATAAAAATAGCACCTGGGTAAAGGACACAACTTCAGTGATATTAACCGGCAATTCATCTCTTTGTCCCATCCGTGGGTGGGCTATATACAGCAAAGACAATAGCATAAGAATTGGTTCCAAAGGAGACGTTTTTGTCATAAGAGAGCCCTTTATTTCATGTTCTCACTTGGAATGCAGGACCTTTTTTCTGACCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGGATGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCACTGCCCGAAGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCACGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
序列表
<110> 弗罗里达中央大学研究基金会
<120> 用于刺激自然杀伤细胞的组合物和方法
<130> 10613-070WO1
<160> 31
<170> PatentIn 3.5版
<210> 1
<211> 50
<212> PRT
<213> 智人
<400> 1
Met Asn Pro Asn Gln Lys Ile Thr Thr Ile Gly Ser Ile Cys Leu Val
1 5 10 15
Val Gly Leu Ile Ser Leu Ile Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ile Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Ile
35 40 45
Cys Asn
50
<210> 2
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 2
Leu Glu Gly Gly Gly Ser
1 5
<210> 3
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 3
Thr Gly Ser Gly
1
<210> 4
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 4
Gly Gly Ser Gly Gly Gly Ser Gly
1 5
<210> 5
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 5
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 6
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 6
Gly Gly Gly Ser
1
<210> 7
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 7
Gly Ser Gly Gly Gly Gly
1 5
<210> 8
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 8
Glu Ala Ala Ala Lys
1 5
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 9
Ala Glu Ala Ala Ala Lys Ala
1 5
<210> 10
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 10
Pro Ala Pro Ala Pro
1 5
<210> 11
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 11
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
1 5 10 15
<210> 12
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 12
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
1 5 10
<210> 13
<211> 279
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 13
Met Asn Pro Asn Gln Lys Ile Thr Thr Ile Gly Ser Ile Cys Leu Val
1 5 10 15
Val Gly Leu Ile Ser Leu Ile Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ile Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Ile
35 40 45
Cys Asn Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
50 55 60
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
65 70 75 80
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
85 90 95
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
100 105 110
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
115 120 125
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
130 135 140
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
145 150 155 160
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
165 170 175
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
180 185 190
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
195 200 205
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
210 215 220
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
225 230 235 240
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
245 250 255
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
260 265 270
Leu Ser Leu Ser Pro Gly Lys
275
<210> 14
<211> 212
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 14
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
1 5 10 15
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
20 25 30
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
35 40 45
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
50 55 60
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
65 70 75 80
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
85 90 95
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
100 105 110
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
115 120 125
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
130 135 140
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
145 150 155 160
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
165 170 175
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
180 185 190
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
195 200 205
Ser Pro Gly Lys
210
<210> 15
<211> 105
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 15
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
1 5 10 15
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
20 25 30
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
35 40 45
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
50 55 60
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
65 70 75 80
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
85 90 95
Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105
<210> 16
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 16
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 17
<211> 120
<212> PRT
<213> 智人
<400> 17
Met Asn Pro Asn Gln Lys Ile Thr Thr Ile Gly Ser Ile Cys Leu Val
1 5 10 15
Val Gly Leu Ile Ser Leu Ile Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ile Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Ile
35 40 45
Cys Asn Gln Asn Ile Ile Thr Tyr Lys Asn Ser Thr Trp Val Lys Asp
50 55 60
Thr Thr Ser Val Ile Leu Thr Gly Asn Ser Ser Leu Cys Pro Ile Arg
65 70 75 80
Gly Trp Ala Ile Tyr Ser Lys Asp Asn Ser Ile Arg Ile Gly Ser Lys
85 90 95
Gly Asp Val Phe Val Ile Arg Glu Pro Phe Ile Ser Cys Ser His Leu
100 105 110
Glu Cys Arg Thr Phe Phe Leu Thr
115 120
<210> 18
<211> 347
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 18
Met Asn Pro Asn Gln Lys Ile Thr Thr Ile Gly Ser Ile Cys Leu Val
1 5 10 15
Val Gly Leu Ile Ser Leu Ile Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ile Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Ile
35 40 45
Cys Asn Gln Asn Ile Ile Thr Tyr Lys Asn Ser Thr Trp Val Lys Asp
50 55 60
Thr Thr Ser Val Ile Leu Thr Gly Asn Ser Ser Leu Cys Pro Ile Arg
65 70 75 80
Gly Trp Ala Ile Tyr Ser Lys Asp Asn Ser Ile Arg Ile Gly Ser Lys
85 90 95
Gly Asp Val Phe Val Ile Arg Glu Pro Phe Ile Ser Cys Ser His Leu
100 105 110
Glu Cys Arg Thr Phe Phe Leu Thr Asp Lys Thr His Thr Cys Pro Pro
115 120 125
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
130 135 140
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
145 150 155 160
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
165 170 175
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
180 185 190
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
195 200 205
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
210 215 220
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
225 230 235 240
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
245 250 255
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
260 265 270
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
275 280 285
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
290 295 300
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
305 310 315 320
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
325 330 335
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345
<210> 19
<211> 1044
<212> DNA
<213> 人工序列
<220>
<223> 合成构筑体
<400> 19
atgaatccaa atcagaaaat aacaaccatt ggatcaatct gtctggtagt cggactaatt 60
agcctaatat tgcaaatagg gaatataatc tcaatatgga ttagccattc aattcaaact 120
ggaagtcaaa accatactgg aatatgcaac caaaacatca ttacctataa aaatagcacc 180
tgggtaaagg acacaacttc agtgatatta accggcaatt catctctttg tcccatccgt 240
gggtgggcta tatacagcaa agacaatagc ataagaattg gttccaaagg agacgttttt 300
gtcataagag agccctttat ttcatgttct cacttggaat gcaggacctt ttttctgacc 360
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 420
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 480
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 540
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 600
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 660
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 720
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 780
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 840
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 900
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 960
aacgtcttct catgctccgt gatgcacgag gctctgcaca accactacac gcagaagagc 1020
ctctccctgt ctccgggtaa ataa 1044
<210> 20
<211> 347
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 20
Met Asn Pro Asn Gln Lys Ile Thr Thr Ile Gly Ser Ile Cys Leu Val
1 5 10 15
Val Gly Leu Ile Ser Leu Ile Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ile Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Ile
35 40 45
Cys Asn Gln Asn Ile Ile Thr Tyr Lys Asn Ser Thr Trp Val Lys Asp
50 55 60
Thr Thr Ser Val Ile Leu Thr Gly Asn Ser Ser Leu Cys Pro Ile Arg
65 70 75 80
Gly Trp Ala Ile Tyr Ser Lys Asp Asn Ser Ile Arg Ile Gly Ser Lys
85 90 95
Gly Asp Val Phe Val Ile Arg Glu Pro Phe Ile Ser Cys Ser His Leu
100 105 110
Glu Cys Arg Thr Phe Phe Leu Thr Asp Lys Thr His Thr Cys Pro Pro
115 120 125
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Leu Pro
130 135 140
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
145 150 155 160
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
165 170 175
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Pro
180 185 190
Glu Glu Gln Tyr Asn Ser Thr Leu Arg Val Val Ser Ile Leu Thr Val
195 200 205
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
210 215 220
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
225 230 235 240
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
245 250 255
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
260 265 270
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
275 280 285
Asn Asn Tyr Lys Thr Thr Pro Leu Val Leu Asp Ser Asp Gly Ser Phe
290 295 300
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
305 310 315 320
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
325 330 335
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345
<210> 21
<211> 211
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 21
Gly Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
1 5 10 15
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
20 25 30
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
35 40 45
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
50 55 60
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
65 70 75 80
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro
85 90 95
Glu Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
100 105 110
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
115 120 125
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
130 135 140
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
145 150 155 160
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
165 170 175
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
180 185 190
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
195 200 205
Ser Pro Gly
210
<210> 22
<211> 105
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 22
Gly Gly Pro Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
1 5 10 15
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
20 25 30
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
35 40 45
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
50 55 60
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
65 70 75 80
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Leu Pro
85 90 95
Glu Glu Lys Thr Ile Ser Lys Ala Lys
100 105
<210> 23
<211> 347
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 23
Met Asn Pro Asn Gln Lys Ile Thr Thr Ile Gly Ser Ile Cys Leu Val
1 5 10 15
Val Gly Leu Ile Ser Leu Ile Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ile Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Ile
35 40 45
Cys Asn Gln Asn Ile Ile Thr Tyr Lys Asn Ser Thr Trp Val Lys Asp
50 55 60
Thr Thr Ser Val Ile Leu Thr Gly Asn Ser Ser Leu Cys Pro Ile Arg
65 70 75 80
Gly Trp Ala Ile Tyr Ser Lys Asp Asn Ser Ile Arg Ile Gly Ser Lys
85 90 95
Gly Asp Val Phe Val Ile Arg Glu Pro Phe Ile Ser Cys Ser His Leu
100 105 110
Glu Cys Arg Thr Phe Phe Leu Thr Asp Lys Thr His Thr Cys Pro Pro
115 120 125
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Asp Val Phe Leu Phe Pro
130 135 140
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
145 150 155 160
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
165 170 175
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
180 185 190
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
195 200 205
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
210 215 220
Asn Lys Ala Leu Pro Leu Pro Glu Glu Lys Thr Ile Ser Lys Ala Lys
225 230 235 240
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
245 250 255
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
260 265 270
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
275 280 285
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
290 295 300
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
305 310 315 320
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
325 330 335
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345
<210> 24
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 24
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
100 105
<210> 25
<211> 212
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 25
Gly Gly Pro Ser Val Phe Leu Leu Pro Pro Lys Pro Lys Asp Thr Leu
1 5 10 15
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
20 25 30
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
35 40 45
Val His Asn Ala Lys Thr Lys Pro Pro Glu Glu Gln Tyr Asn Ser Thr
50 55 60
Leu Arg Val Val Ser Ile Leu Thr Val Leu His Gln Asp Trp Leu Asn
65 70 75 80
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
85 90 95
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
100 105 110
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
115 120 125
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
130 135 140
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
145 150 155 160
Leu Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
165 170 175
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
180 185 190
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
195 200 205
Ser Pro Gly Lys
210
<210> 26
<211> 105
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 26
Gly Gly Pro Ser Val Phe Leu Leu Pro Pro Lys Pro Lys Asp Thr Leu
1 5 10 15
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
20 25 30
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
35 40 45
Val His Asn Ala Lys Thr Lys Pro Pro Glu Glu Gln Tyr Asn Ser Thr
50 55 60
Leu Arg Val Val Ser Ile Leu Thr Val Leu His Gln Asp Trp Leu Asn
65 70 75 80
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
85 90 95
Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105
<210> 27
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 27
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Leu Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 28
<211> 559
<212> PRT
<213> 人工序列
<220>
<223> 合成构筑体
<400> 28
Met Asn Pro Asn Gln Lys Ile Thr Thr Ile Gly Ser Ile Cys Leu Val
1 5 10 15
Val Gly Leu Ile Ser Leu Ile Leu Gln Ile Gly Asn Ile Ile Ser Ile
20 25 30
Trp Ile Ser His Ser Ile Gln Thr Gly Ser Gln Asn His Thr Gly Ile
35 40 45
Cys Asn Gln Asn Ile Ile Thr Tyr Lys Asn Ser Thr Trp Val Lys Asp
50 55 60
Thr Thr Ser Val Ile Leu Thr Gly Asn Ser Ser Leu Cys Pro Ile Arg
65 70 75 80
Gly Trp Ala Ile Tyr Ser Lys Asp Asn Ser Ile Arg Ile Gly Ser Lys
85 90 95
Gly Asp Val Phe Val Ile Arg Glu Pro Phe Ile Ser Cys Ser His Leu
100 105 110
Glu Cys Arg Thr Phe Phe Leu Thr Asp Lys Thr His Thr Cys Pro Pro
115 120 125
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
130 135 140
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
145 150 155 160
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
165 170 175
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
180 185 190
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
195 200 205
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
210 215 220
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
225 230 235 240
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
245 250 255
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
260 265 270
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
275 280 285
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
290 295 300
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
305 310 315 320
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
325 330 335
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Pro Ser Val
340 345 350
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
355 360 365
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
370 375 380
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
385 390 395 400
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
405 410 415
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
420 425 430
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
435 440 445
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
450 455 460
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
465 470 475 480
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
485 490 495
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
500 505 510
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
515 520 525
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
530 535 540
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
545 550 555
<210> 29
<211> 1041
<212> DNA
<213> 人工序列
<220>
<223> 合成构筑体
<400> 29
atgaatccaa atcagaaaat aacaaccatt ggatcaatct gtctggtagt cggactaatt 60
agcctaatat tgcaaatagg gaatataatc tcaatatgga ttagccattc aattcaaact 120
ggaagtcaaa accatactgg aatatgcaac caaaacatca ttacctataa aaatagcacc 180
tgggtaaagg acacaacttc agtgatatta accggcaatt catctctttg tcccatccgt 240
gggtgggcta tatacagcaa agacaatagc ataagaattg gttccaaagg agacgttttt 300
gtcataagag agccctttat ttcatgttct cacttggaat gcaggacctt ttttctgacc 360
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 420
ttcctcctgc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 480
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 540
ggcgtggagg tgcataatgc caagacaaag ccgccggagg agcagtacaa cagcacgctg 600
cgtgtggtca gcattctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 660
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 720
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 780
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 840
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctctggt gctggactcc 900
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 960
aacgtcttct catgctccgt gatgcacgag gctctgcaca accactacac gcagaagagc 1020
ctctccctgt ctccgggtaa a 1041
<210> 30
<211> 1047
<212> DNA
<213> 人工序列
<220>
<223> 合成构筑体
<400> 30
atgaatccaa atcagaaaat aacaaccatt ggatcaatct gtctggtagt cggactaatt 60
agcctaatat tgcaaatagg gaatataatc tcaatatgga ttagccattc aattcaaact 120
ggaagtcaaa accatactgg aatatgcaac caaaacatca ttacctataa aaatagcacc 180
tgggtaaagg acacaacttc agtgatatta accggcaatt catctctttg tcccatccgt 240
gggtgggcta tatacagcaa agacaatagc ataagaattg gttccaaagg agacgttttt 300
gtcataagag agccctttat ttcatgttct cacttggaat gcaggacctt ttttctgacc 360
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accggatgtc 420
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 480
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 540
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 600
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 660
tgcaaggtct ccaacaaagc cctcccactg cccgaagaga aaaccatctc caaagccaaa 720
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 780
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 840
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 900
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 960
aacgtcttct catgctccgt gatgcacgag gctctgcaca accactacac gcagaagagc 1020
ctctccctgt ctccgggtaa ataataa 1047
<210> 31
<211> 1722
<212> DNA
<213> 人工序列
<220>
<223> 合成构筑体
<400> 31
atgaatccaa atcagaaaat aacaaccatt ggatcaatct gtctggtagt cggactaatt 60
agcctaatat tgcaaatagg gaatataatc tcaatatgga ttagccattc aattcaaact 120
ggaagtcaaa accatactgg aatatgcaac caaaacatca ttacctataa aaatagcacc 180
tgggtaaagg acacaacttc agtgatatta accggcaatt catctctttg tcccatccgt 240
gggtgggcta tatacagcaa agacaatagc ataagaattg gttccaaagg agacgttttt 300
gtcataagag agccctttat ttcatgttct cacttggaat gcaggacctt ttttctgacc 360
gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 420
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 480
tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 540
ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 600
cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 660
tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 720
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 780
aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 840
tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 900
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 960
aacgtcttct catgctccgt gatgcacgag gctctgcaca accactacac gcagaagagc 1020
ctctccctgt ctccgggtaa agacaaaact cacacatgcc caccgtgccc agcacctgaa 1080
ctcctggggg gaccggatgt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 1140
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 1200
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1260
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1320
ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccact gcccgaagag 1380
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1440
tcccgggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1500
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1560
acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1620
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcacga ggctctgcac 1680
aaccactaca cgcagaagag cctctccctg tctccgggta aa 1722
Claims (64)
1.一种融合蛋白,其包含与Fc结构域的氨基末端连接的跨膜结构域。
2.根据权利要求1所述的融合蛋白,其中所述跨膜结构域包含选自以下的信号锚定序列:神经氨酸酶的跨膜结构域、来自副流感病毒血凝素-神经氨酸酶的信号锚、来自转铁蛋白受体的信号锚、来自II类MHC不变链的信号锚、来自P糖蛋白的信号锚、来自脱唾液酸糖蛋白受体的信号锚和来自中性内肽酶的信号锚。
3.根据权利要求1所述的融合蛋白,其中所述跨膜结构域包含副流感病毒血凝素-神经氨酸酶(NA)肽序列。
4.根据权利要求3所述的融合蛋白,其中所述副流感病毒血凝素-神经氨酸酶(NA)肽序列包含与SEQ ID NO:1或SEQ ID NO:17具有至少约81%序列一致性的序列。
5.根据权利要求4所述的融合蛋白,其中所述副流感病毒血凝素-神经氨酸酶(NA)肽序列包含与SEQ ID NO:1或SEQ ID NO:17具有至少约95%序列一致性的序列。
6.根据权利要求1所述的融合蛋白,其中所述Fc结构域包含选自IgGl、IgG2、IgG3、IgG4、IgA和IgE的免疫球蛋白Fc结构域。
7.根据权利要求1所述的融合蛋白,其进一步包含在所述跨膜结构域与所述Fc结构域之间的肽接头。
8.一种核酸,其编码根据权利要求1至7中任一项所述的融合蛋白。
9.一种载体,其包含根据权利要求8所述的核酸。
10.一种细胞,其包含根据权利要求9所述的载体。
11.一种工程化细胞质膜(PM)颗粒或外泌体,其包含根据权利要求1至7中任一项所述的融合蛋白。
12.一种NK细胞扩增组合物,其包含与饲养细胞、工程化PM颗粒或外泌体的外表面结合的膜结合反向Fc结构域。
13.根据权利要求12所述的NK细胞扩增组合物,其包含基本上不含饲养细胞的工程化PM颗粒或工程化外泌体。
14.根据权利要求13所述的NK细胞扩增组合物,其中所述工程化颗粒进一步包含至少一种NK细胞效应剂。
15.根据权利要求12所述的NK细胞扩增组合物,其进一步包含至少一种NK细胞效应剂。
16.根据权利要求14或15所述的NK细胞扩增组合物,其中所述至少一种NK细胞效应剂是IL-21或IL-15。
17.根据权利要求16所述的NK细胞扩增组合物,其进一步包含第二NK细胞效应剂,其中所述第二NK细胞效应剂是41BBL。
18.根据权利要求12所述的NK细胞扩增组合物,其中所述工程化PM颗粒包含从被融合蛋白转染或转导的NK细胞饲养细胞纯化的细胞质膜囊泡以及所述至少一种NK细胞效应剂,所述融合蛋白包含与Fc结构域连接的跨膜结构域。
19.根据权利要求12所述的NK细胞扩增组合物,其中所述工程化PM颗粒包含从被融合蛋白转染的NK细胞饲养细胞衍生的外泌体以及所述至少一种NK细胞效应剂,所述融合蛋白包含与Fc结构域连接的跨膜结构域。
20.根据权利要求17所述的NK细胞扩增组合物,其进一步包含至少一种额外NK细胞效应剂,其中所述至少一种额外NK细胞效应剂是细胞因子、粘附分子或NK细胞活化剂;其中所述至少一种额外NK细胞效应剂选自IL-15、IL-2、IL-12、IL-18、IL-21、MICA、UBLP、2sB4、LFA-1、Notch配体、NKp46配体或BCM1/SLAMF2、TLR配体以及NKG2D配体。
21.根据权利要求12所述的NK细胞扩增组合物,其中所述工程化颗粒是包含细胞质膜的细胞质膜颗粒,并且所述组合物进一步包含固体表面,其中所述细胞质膜包覆所述固体表面的至少一部分。
22.根据权利要求21所述的NK细胞扩增组合物,其中固体表面包含磁性微粒、二氧化硅珠粒、聚苯乙烯珠粒、乳胶珠粒、微结构、造影剂和/或癌症治疗剂中的至少一种。
23.一种NK细胞扩增输注制剂,其包含根据权利要求12至22中任一项所述的NK细胞扩增组合物和药学上可接受的载体。
24.根据权利要求23所述的NK细胞扩增输注制剂,其中所述制剂选自胃肠外输注剂、动脉输注剂、静脉输注剂、人工导管介导的输注剂、静脉内注射剂、腹膜内注射剂、皮下注射剂、口服制剂和局部制剂。
25.根据权利要求24所述的NK细胞扩增输注制剂,其被输注到需要体内NK细胞扩增的受试者中。
26.一种NK细胞组合物,其包含与根据权利要求12所述的NK细胞扩增组合物接触的体外NK细胞群。
27.根据权利要求26所述的NK细胞组合物,其进一步包含至少一种NK细胞效应剂。
28.根据权利要求27所述的NK细胞组合物,其中所述至少一种NK细胞效应剂是IL-21或IL-15。
29.根据权利要求27所述的NK细胞组合物,其中所述至少一种NK细胞效应剂是可溶的。
30.一种扩增的NK细胞群,其体外暴露于根据权利要求26所述的NK细胞扩增组合物,所述组合物包含饲养细胞或包含至少一种工程化颗粒并且不含饲养细胞,其中所述饲养细胞或工程化颗粒包含与其外表面结合的Fc结构域。
31.根据权利要求32所述的扩增的NK细胞群,其中所述NK细胞与非扩增的NK细胞相比具有增加的细胞毒性。
32.根据权利要求30所述的扩增的NK细胞群,其中所述扩增的NK细胞的细胞毒性是非扩增的NK细胞的细胞毒性的至少约2倍。
33.根据权利要求30所述的扩增的NK细胞群,其中所述扩增的NK细胞的细胞毒性是非扩增的NK细胞的细胞毒性的至少约5倍。
34.根据权利要求30所述的扩增的NK细胞群,其中所述扩增的NK细胞的细胞毒性是非扩增的NK细胞的细胞毒性的至少约10倍。
35.一种组合物,其包含治疗剂量的NK细胞和药学上可接受的载体,所述NK细胞包含根据权利要求30至34中任一项所述的扩增的NK细胞群。
36.根据权利要求30所述的扩增的NK细胞群或根据权利要求35所述的组合物,其进一步包含至少一种NK细胞效应剂。
37.根据权利要求36所述的组合物,其中所述至少一种NK细胞效应剂选自IL-15、IL-2、IL-12、IL-18、IL-21、MICA、UBLP、2sB4、LFA-1、Notch配体、NKp46配体或BCM1/SLAMF2、TLR配体以及NKG2D配体。
38.根据权利要求37所述的组合物,其中所述至少一种NK细胞效应剂是可溶的。
39.根据权利要求37所述的组合物,其进一步包含第二NK细胞效应剂,其中所述第二NK细胞效应剂是41BBL。
40.一种治疗、改善、减轻和/或抑制受试者的癌症或癌转移或传染病的方法,其包含向有需要的所述受试者施用任选地与NK细胞群接触的有效量的根据权利要求12至39中任一项所述的组合物或扩增的NK细胞群。
41.根据权利要求40所述的方法,其中所述癌症选自由以下组成的群组:肿瘤、血液学癌症、淋巴瘤、白血病、急性骨髓性白血病、骨髓增生异常综合征、慢性骨髓性白血病、急性淋巴细胞性白血病、骨髓纤维化、多发性骨髓瘤、结直肠癌、结肠癌、肺癌、头颈癌、卵巢癌、胰腺癌、肝癌、皮肤癌、前列腺癌、肾癌、腹膜内癌和乳腺癌。
42.一种在干细胞移植之前或之后抑制、减轻和/或预防癌症或癌转移复发的方法,其包含向有需要的受试者施用有效量的根据权利要求12至39中任一项所述的组合物或扩增的NK细胞群。
43.根据权利要求40至42中任一项所述的方法,其进一步包含向所述受试者施用至少一种癌症治疗剂以及所述有效量的所述组合物或扩增的NK细胞群。
44.根据权利要求43所述的方法,其中所述至少一种癌症治疗剂选自化学治疗剂、基于药物的制备方案或其组合。
45.根据权利要求44所述的方法,其中化学治疗剂选自CHOP、FLAG、7+3),并且基于药物的制备方案选自Cy-Flu、Bu-Flu和Flu-Mel。
46.一种在干细胞移植期间或之后调节T细胞库的方法,其包含向有需要的受试者施用有效量的根据权利要求12至39中任一项所述的组合物或扩增的NK细胞群。
47.一种预防、抑制、减轻或缓解急性或慢性移植物抗宿主疾病的方法,其包含向有需要的受试者施用有效量的根据权利要求12至39中任一项所述的组合物或扩增的NK细胞群。
48.根据权利要求47所述的预防、抑制、减轻或缓解急性或慢性移植物抗宿主疾病的方法,其进一步包含向所述受试者施用GvHD预防剂以及所述有效量的所述组合物或扩增的NK细胞群。
49.一种预防、抑制、减轻或缓解病毒再激活的方法,其包含向有需要的受试者施用有效量的根据权利要求12至39中任一项所述的组合物或扩增的NK细胞群。
50.根据权利要求49所述的预防、抑制、减轻或缓解病毒再激活的方法,其中病毒感染包含单纯疱疹病毒-1(HSV-1)、单纯疱疹病毒-2(HSV-2)、巨细胞病毒(CMV)、水痘带状疱疹病毒(VZV)、EB病毒(Epstein-Barr virus,EBV)、腺病毒、腺相关病毒、细小病毒、JC病毒和BK病毒。
51.一种预防、抑制、减轻或缓解机会性感染的方法,其包含向有需要的受试者施用有效量的根据权利要求12至39中任一项所述的组合物或扩增的NK细胞群。
52.一种NK细胞扩增培养基制剂,其包含根据权利要求12所述的NK细胞扩增组合物和至少一种培养基组分。
53.根据权利要求52所述的NK细胞扩增培养基制剂,其进一步包含选自细胞因子、IL-2、IL-12、IL-18、NAM、还原剂、人类血小板、人类血小板溶解物、胰岛素和抗坏血酸盐中的至少一种额外组分。
54.根据权利要求30至34所述的扩增的NK细胞群,其中所述扩增的NK细胞与非扩增的NK细胞相比展现出增加的抗肿瘤细胞因子分泌。
55.根据权利要求30至34所述的扩增的NK细胞群,其中所述扩增的NK细胞与非扩增的NK细胞相比展现出增加的NKG2D、NKp46和CD16表达。
56.一种低温保存的治疗剂量的根据权利要求30至34中任一项所述的扩增的NK细胞群,其中所述扩增的NK细胞在解冻之后仍然存活。
57.一种增加NK细胞的细胞毒性的方法,其包含使初始NK细胞群体外暴露于NK细胞扩增组合物,所述组合物包含至少一种饲养细胞或工程化颗粒和与所述饲养细胞或工程化颗粒的外表面结合的Fc结构域,所述至少一种饲养细胞或工程化颗粒包含至少两种NK细胞效应剂,其中所述至少两种NK细胞效应剂中的一种是IL-21。
58.根据权利要求57所述的方法,其中所述NK细胞扩增组合物包含至少一种具有膜结合Fc结构域的饲养细胞。
59.根据权利要求57所述的方法,其中所述NK细胞扩增组合物包含选自具有膜结合Fc结构域的PM颗粒和具有膜结合Fc结构域的外泌体的工程化颗粒。
60.根据权利要求57所述的方法,其进一步包含获得与所述初始NK细胞群相比具有增加的细胞毒性的扩增的NK细胞群。
61.根据权利要求57所述的方法,其中所述扩增的NK细胞的所述细胞毒性是所述初始NK细胞群的细胞毒性的至少约2倍。
62.根据权利要求57所述的方法,其中所述扩增的NK细胞的所述细胞毒性是所述初始NK细胞群的细胞毒性的至少约5倍。
63.根据权利要求57所述的方法,其中所述扩增的NK细胞的所述细胞毒性是所述初始NK细胞群的细胞毒性的至少约10倍。
64.根据权利要求40至51或57至63中任一项所述的方法,其中待扩增或刺激的NK细胞的来源可以包括外周血液(PBMC、血液单采物(apheresis)、白细胞单采物(leukopaks)、血沉棕黄层)、iPSC衍生的NK细胞、ESC衍生的NK细胞、具备在158处具有Phe或Val的高亲和力Fc受体的多态性的NK细胞和基因修饰的NK细胞。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115216442A (zh) * | 2022-09-05 | 2022-10-21 | 杭州易文赛生物技术有限公司 | 外泌体的制备方法和培养基及其应用 |
CN115521914A (zh) * | 2022-10-12 | 2022-12-27 | 西北工业大学 | 一种人原代自然杀伤细胞体外扩增体系及方法 |
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US20240010976A1 (en) * | 2020-08-12 | 2024-01-11 | University Of Central Florida Research Foundation, Inc. | Methods and compositions for stimulating gamma delta t cells |
CN111944754B (zh) * | 2020-08-26 | 2024-04-19 | 沈阳细胞治疗工程技术研发中心有限公司 | 一种自然杀伤细胞的培养方法 |
AU2022355091A1 (en) * | 2021-09-29 | 2024-05-09 | University Of Central Florida Research Foundation, Inc. | Engineered nk cells and uses thereof |
CN115181727A (zh) * | 2022-08-04 | 2022-10-14 | 广州蒽恺赛生物科技有限公司 | Nk细胞的扩增载体及其在在扩增培养nk细胞中的应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100285030A1 (en) * | 2006-01-12 | 2010-11-11 | Alexion Pharmaceuticals, Inc. | Antibodies to Ox-2/Cd200 and Uses Thereof |
WO2014005072A1 (en) * | 2012-06-28 | 2014-01-03 | University Of Central Florida Research Foundation, Inc. | Methods and compositions for natural killer cells |
US20180245044A1 (en) * | 2015-09-04 | 2018-08-30 | Miltenyi Biotec Gmbh | Method for natural killer cell expansion |
WO2018218151A1 (en) * | 2017-05-25 | 2018-11-29 | University Of Central Florida Research Foundation, Inc. | Novel oncolytic viruses for sensitizing tumor cells to killing by natural killer cells |
CN109195634A (zh) * | 2016-04-15 | 2019-01-11 | 延龄草疗法有限公司 | Cd47阻断治疗中的巨噬细胞刺激 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102559600A (zh) * | 2011-12-29 | 2012-07-11 | 上海交通大学医学院 | 一种人工抗原递呈细胞及其在nk细胞扩增中的应用 |
JP6164650B2 (ja) * | 2014-01-20 | 2017-07-19 | 国立大学法人九州大学 | Nk細胞の調製方法 |
EP3442999A2 (en) * | 2016-04-15 | 2019-02-20 | Alpine Immune Sciences, Inc. | Icos ligand variant immunomodulatory proteins and uses thereof |
CA3042238C (en) * | 2016-10-28 | 2021-08-10 | Nant Holdings Ip, Llc | Avatar dendritic cells: the neoantigen natural killer t-cell chemo immuno radiation composition inducing immunogenic cell death |
US10300089B2 (en) * | 2016-11-08 | 2019-05-28 | University Of Central Florida Research Foundation, Inc. | Methods for high scale therapeutic production of memory NK cells |
CA3057211A1 (en) * | 2017-02-28 | 2018-09-07 | University Of Central Florida Research Foundation, Inc. | Pm21 particles to improve bone marrow homing of nk cells |
-
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100285030A1 (en) * | 2006-01-12 | 2010-11-11 | Alexion Pharmaceuticals, Inc. | Antibodies to Ox-2/Cd200 and Uses Thereof |
WO2014005072A1 (en) * | 2012-06-28 | 2014-01-03 | University Of Central Florida Research Foundation, Inc. | Methods and compositions for natural killer cells |
US20150190471A1 (en) * | 2012-06-28 | 2015-07-09 | University Of Central Florida Research Foundation, Inc. | Methods and Compositions for Natural Killer Cells |
US20180245044A1 (en) * | 2015-09-04 | 2018-08-30 | Miltenyi Biotec Gmbh | Method for natural killer cell expansion |
CN109195634A (zh) * | 2016-04-15 | 2019-01-11 | 延龄草疗法有限公司 | Cd47阻断治疗中的巨噬细胞刺激 |
WO2018218151A1 (en) * | 2017-05-25 | 2018-11-29 | University Of Central Florida Research Foundation, Inc. | Novel oncolytic viruses for sensitizing tumor cells to killing by natural killer cells |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115216442A (zh) * | 2022-09-05 | 2022-10-21 | 杭州易文赛生物技术有限公司 | 外泌体的制备方法和培养基及其应用 |
CN115216442B (zh) * | 2022-09-05 | 2024-04-16 | 杭州易文赛生物技术有限公司 | 外泌体的制备方法和培养基及其应用 |
CN115521914A (zh) * | 2022-10-12 | 2022-12-27 | 西北工业大学 | 一种人原代自然杀伤细胞体外扩增体系及方法 |
CN115521914B (zh) * | 2022-10-12 | 2024-04-19 | 西北工业大学 | 一种人原代自然杀伤细胞体外扩增体系及方法 |
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