CN116133675A - 自体树突细胞疫苗试剂盒及用途 - Google Patents
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Abstract
本文公开了一种用于生产基于自体树突细胞的个性化疫苗的试剂盒。所述试剂盒包含生产针对病原体生物体、病原体生物体的部分、毒素、毒液、通过重组方法或化学合成获得的结构的活树突细胞疫苗剂量所需的所有材料、试剂和信息。
Description
相关申请的交叉引用
本申请要求于2020年6月2日提交的美国临时申请号63/033,678的权益,其全部内容通过引用并入本文。
背景技术
个性化疫苗引起了极大的研究兴趣,但转化为临床实践的情形有限。个性化疫苗的生产通常需要研究机构或专门的制药厂的设备和训练有素的人员,从而限制了它们的可及性,导致高成本,并阻碍了它们的采用。个性化疫苗主要用于癌症治疗,在癌症治疗中,其高成本更容易承担。
发明内容
具有生产基于树突细胞的自体疫苗所需的所有组分的简单的疫苗试剂盒允许快速生产疫苗,包括在紧急情况下。离体制备的基于树突细胞的疫苗避免了抗原毒性的可能性以及可能的免疫耐受诱导。本文公开的个性化自体疫苗试剂盒使得能够在诸如仅具有基本实验室设备的社区医院的设施中生产疫苗。
此处公开的是制备自体疫苗的每个步骤所必需的一套组分的组合或试剂盒。
本文还公开了使用疫苗制造试剂盒生产针对抗原的个性化疫苗的方法。
一个方面是用于为个体制备个性化树突细胞(DC)疫苗的试剂盒。该试剂盒包括试剂盒容器以包含试剂盒的其他组分。试剂盒的组件包括血液收集用品、单核细胞分离培养基或惯性分离装置、DC分化培养基组分、细胞培养容器、唯一身份的标记和抗原。
DC分化培养基组分包含基础细胞培养基,例如RPMI-1640、PRIME-XV树突细胞成熟化学成分确定的培养基或AIM-V培养基。在一些实施方案中,使用不含碳酸氢盐、CO2非依赖性的培养基版本。在一些实施方案中,使用HEPES作为CO2非依赖性缓冲液。在一些实施方案中,培养基包含白细胞介素4(IL-4)。在一些实施方案中,培养基包含IL-4和粒细胞-巨噬细胞集落刺激因子(GM-CSF)。在一些实施方案中,培养基不含GM-CSF。在一些实施方案中,培养基包含干扰素α(IFNα)。在一些实施方案中,培养基包含干扰素γ(IFNγ)。在一些实施方案中,培养基包含白细胞介素2(IL-2)。在一些实施方案中,培养基包含最高达30%的自体血浆。
在一些实施方案中,细胞培养容器是具有至少一个入口的封闭系统。在一些实施方案中,细胞培养容器是袋,而在其他实施方案中,它是具有平坦内表面的刚性器皿。在一些实施方案中,内表面是疏水的。
在各种实施方案中,唯一身份的标记可以是一串字母数字字符、条形码或QR码。
在一些实施方案中,抗原是完整的病原体生物体,或源自病原体生物体例如细菌、真菌、病毒、立克次氏体、支原体或寄生虫的片段。
在一些实施方案中,抗原是毒素或毒液。非限制性示例包括源自细菌、昆虫和植物的毒素和毒液,或合成的化合物。
在一些实施方案中,抗原是纯化的分子,例如蛋白质或肽,或其片段。在一些实施方案中,抗原通过重组技术产生。
在一些实施方案中,抗原通过化学合成产生。
在一些实施方案中,抗原是SARS-CoV-2的全长刺突蛋白。
在一些实施方案中,试剂盒容器能够用作培养箱。在一些实施方案中,试剂盒容器具有绝热壁。在一些实施方案中,试剂盒容器具有可充电电源,例如锂电池。在一些实施方案中,电源是锂聚合物电池,其形状可以适合试剂盒容器。在一些实施方案中,试剂盒容器包含恒温器,但不包括温度控制器。在一些实施方案中,恒温器包含相交换材料和正温度系数材料。
一个方面是一种使用本文公开的试剂盒制备个性化自体DC疫苗的方法。在一些实施方案中,该方法包括从个体收集血液,分离外周血单核细胞(PBMC),通过将DC添加到细胞培养容器中并孵育细胞2-5天来使PBMC分化产生未成熟DC,然后将抗原添加到细胞培养容器中以使未成熟DC负载抗原并再孵育1-2天(其中抗原将用作免疫原以诱导针对作为疫苗靶标的病原体、毒素或毒液的组分的免疫应答),并收获负载有抗原的未成熟DC。
制备个性化自体DC疫苗的方法的一些实施方案还包括保留来自分离步骤的自体血浆。制备个性化自体DC疫苗的方法的一些实施方案还包括将唯一身份的标记贴附到包含来自个体的细胞或血浆的容器上。制备个性化自体DC疫苗的方法的一些实施方案还包括将收获的负载有抗原的未成熟DC重悬浮于自体血浆中。
制备个性化自体DC疫苗的方法的一些实施方案还包括在施用于个体之前储存收获、重悬浮的负载有抗原的未成熟DC。一些实施方案包括将收获、重悬浮的负载有抗原的未成熟DC在室温下储存最长达5小时。一些实施方案包括将收获、重悬浮的负载有抗原的未成熟DC在4℃下储存最长达48小时。一些实施方案包括将收获、重悬浮的负载有抗原的未成熟DC在-80℃下储存最长达21天。
一个方面是一种个性化自体树突细胞(DC)疫苗,其通过本文公开的任何制备这样的疫苗的方法制备。
一个方面是一种对个体进行免疫的方法,其包括向所述个体施用本文公开的个性化自体DC疫苗。在一些实施方案中,通过皮下注射施用个性化自体DC疫苗。在一些实施方案中,通过皮内注射施用个性化自体DC疫苗。在一些实施方案中,通过单次施用实现免疫。
附图说明
图1描绘了自体树突细胞疫苗的主要机制。从对象获得血液样品,从血液样品中分离出单核细胞并使单核细胞在体外分化为树突细胞,所述树突细胞负载有抗原并被重新注射到获得样品的同一人体内。
图2描绘了感染SARS-CoV-2病毒的患者体内内源性产生的针对重组病毒刺突蛋白的IgG抗体的反应性。
图3描绘了11名感染SARS-CoV-2病毒的不同患者体内内源性产生的针对重组病毒核衣壳蛋白的IgG抗体的反应性。
图4描绘了11名感染SARS-CoV-2病毒的不同患者体内内源性产生的针对重组病毒刺突蛋白的IgA抗体的反应性。
图5描绘了11名感染SARS-CoV-2病毒的不同患者体内内源性产生的针对重组病毒核衣壳蛋白的IgA抗体的反应性。
图6描绘了流式细胞术数据,证明单核细胞以高比例分化为CD11c+和CD14阴性树突细胞。
图7描绘了自体混合淋巴细胞与负载有抗原的树突细胞的共培养物中相比于对照中的细胞因子分泌。
图8描绘了在各种抗原负载量下,自体混合淋巴细胞与负载有抗原的树突细胞的共培养物中细胞因子分泌的百分比增加。
图9描绘了流式细胞术数据,证明在暴露于负载有抗原的树突细胞后Tbet转录因子阳性淋巴细胞增加。
图10描绘了本文公开的自体DC疫苗的一个一般制造过程的步骤。
图11A-图11B描绘了在使用对SARS-CoV-2刺突蛋白具有特异性的自体DC疫苗免疫之前(图11A)和之后2周(图11B)PBMC群体中SARS-CoV-2刺突蛋白特异性IFNγ分泌性淋巴细胞的比例,如通过ELISpot测定法确定。
图12表示在使用对SARS-CoV-2刺突蛋白具有特异性的自体DC疫苗免疫之前和之后2周PBMC群体中SARS-CoV-2刺突蛋白特异性IFNγ分泌性淋巴细胞的平均斑点计数,如通过ELISpot测定法确定,其中在所述测定中具有或不具有抗原刺激。
图13A-图13B描绘了记忆应答的评估。图13A显示了在使用对SARS-CoV-2刺突蛋白具有特异性的自体DC疫苗免疫之前和之后2周对SARS-CoV-2刺突蛋白表现出记忆应答的对象的百分比,如通过针对SARS-CoV-2刺突蛋白特异性IFNγ分泌性淋巴细胞的ELISpot测定法确定,其中在所述测定中具有抗原刺激。图13B显示了在免疫后2周时根据转换、增强或无变化的记忆状态的对象数量。
具体实施方式
尽管在研究环境中被证明安全、有效且优于其他疫苗方法,但个性化树突细胞(DC)免疫疗法提出了工业制造规模化的未解决的挑战。本文公开的组合物和方法解决了规模化挑战并为工业提供了可行的解决方案。
病毒抗原的DC处理和呈递是得到确认的,在体外和动物模型中证实了免疫作用。使用树突细胞的疫苗已证明具有针对利什曼病、单纯疱疹病毒、流感病毒、白色念珠菌和人免疫缺陷病毒(HIV)的防护。在APC特异性免疫抑制模型中,基于DC的流感疫苗迅速诱导显著的抗原特异性抗体滴度,这是蛋白质疫苗接种无法达到的。
应用DC免疫疗法预防传染病在科学上是合理的,而且具有成本效益,特别是对于某些有增加的发病风险且对传统疫苗接种反应不佳的小众群体。
DC自然吞噬和消化可溶性抗原以呈递给其他免疫细胞。在此过程中,颗粒在细胞表面受体识别后或通过微胞饮作用或通过溶质的非选择性内吞作用被内吞。抗原的摄取导致激活信号,这导致DC成熟,以促进抗原呈递和细胞的最大刺激以进行适应性免疫应答。人单核细胞衍生的DC和单核细胞衍生的巨噬细胞可以在体外从单核细胞产生。用GM-CSF和IL-4培养单核细胞会产生DC,而用巨噬细胞集落刺激因子(M-CSF)或GM-CSF单独培养会产生巨噬细胞。单核细胞衍生的DC是优秀的抗原呈递者并且诱导抗原特异性CD4+和CD8+T细胞。它们表达多种模式识别受体(PRR),例如Toll样受体(TLR)和C型凝集素受体(CLR),以识别病原体相关分子模式(PAMP)、受损相关分子模式(DAMP)或改变的糖基化自身抗原,如肿瘤抗原。TLR识别诱导细胞内信号传导以及抗原呈递分子(MHC II分子)、共刺激分子(CD80/86、CD40)、炎性和/或抗病毒细胞因子(如TNF-α、IL-12、IL-23、IFNα/β)和趋化因子(即IL-8、RANTES)的表达。
使用非活性或减毒病原体的疫苗需要大量抗原和广泛测试。DNA/RNA疫苗是一种合理的替代方案,因为抗原会立即经历MHC呈递;然而,有效的递送系统仍然是一项重大挑战。基因组递送系统可能具有毒性、免疫原性,并会阻止将来使用相同的载体(例如,腺病毒或腺相关病毒载体)。
模式识别受体表达随着单核吞噬细胞的分化和成熟而变化。我们已经建立了可产生具有高抗原摄取和交叉呈递能力的未成熟DC的培养条件。通过暴露于TLR4配体(LPS,聚I:C)来促进离体成熟。外周注射(皮下或皮内)后,在迁移到区域淋巴结期间在体内完成进一步成熟。
离体负载以促进病毒抗原的摄取、加工和呈递的自体未成熟DC可以克服某些病原体(此类非限制性示例包括冠状病毒、HIV、流感、埃博拉病毒、HSV-1、麻疹、丙型肝炎、登革热病毒等)引起的抑制。由于避免了抑制途径,离体抗原加工增强了对病毒抗原的体液和细胞免疫应答的诱导。
本文介绍的包含离体负载有抗原的未成熟DC的自体疫苗提供了由效应CD8+细胞毒性细胞介导的Th1型免疫偏倚的优势,这是一种在对抗病毒感染方面优于Th2应答的基本机制。
效应CD8+淋巴细胞的细胞介导的应答不必针对特定的抗原表位;对任何表达的抗原中的任何免疫原性表位的应答可能是有益的。相比之下,抗体介导的免疫必须针对病毒表面抗原的特定表位。在许多情况下,中和抗体针对病毒受体的受体结合位点,尽管中和可能涉及阻断脱壳或包膜病毒裂解。当受体区域发生突变并且中和抗体无效时,例如最近的冠状病毒(SARS-CoV-2)大流行中,非中和抗体的积累会导致抗体增强型疾病的风险增加。
无论识别的表位如何,细胞介导的免疫总是具有中和作用,并将靶向受感染的宿主细胞,从而阻碍病毒的进一步复制。
所公开的DC疫苗产品比抗受体结合结构域抗体更能适应突变,这是通过佐剂系统优化以最大化体液应答的经典疫苗的目标。
已知某些病毒,如SARS-CoV-2,会抑制细胞介导的免疫,严重减少循环CD8+细胞并抑制干扰素产生。这些病毒产生的免疫应答大多是体液性的,首先是产生针对未突变表位的抗体,然后在7-14天后产生针对病毒的突变部分的抗体。如果突变发生在受体结合结构域(RBD)中,则存在病毒繁殖和非中和抗体产生的7-14天窗口。这种现象导致先天免疫细胞激活和全身炎症,特别是在针对病毒的受体更丰富的地方,这解释了急性呼吸窘迫综合征(ARDS)病理学,其发生在具有导致Th2偏倚的其他合并症(年龄、糖尿病、肥胖等)的一些患者中。
制造过程
本文公开的制造过程基于分配给单个个体的单个一次性使用试剂盒。试剂盒含有成品的制造和质量控制所需的所有材料和试剂。
试剂盒通常包含:血液收集用品、单核细胞分离培养基、DC分化培养基、塑料器皿、剂量容器、QC取样容器、QC试剂标签和文档。尽管如此,其他布置也是可能的。
每个试剂盒组分都被唯一地识别、记录在制造文档中,并根据现行法规规定可追溯。在各种实施方案中,各个试剂盒的唯一身份的唯一标记可以是一串字母数字字符、条形码、QR码等中的任何一种。在一些实施方案中,标记被印刷在贴纸上,其可以在使用时贴在试剂盒的组分上以及复印文本病历中。
在一些实施方案中,试剂盒容器除了在储存和运输过程中包含各种组分外,还可以用作培养箱。
血液收集是通过使用标准的肝素化真空管和静脉切开术试剂盒完成的。收集管尺寸在5mL和50mL之间变化,并且任选地在每个管中包括Ficoll分离层。一种收集方法是使用预装有分离培养基的真空管。
另一种收集方法使用惯性微流体装置进行血液分离。此类装置使用非平衡惯性分离阵列。
通过离心或同一闭环系统中的切向流过滤浓缩外周血单核细胞(PBMC)。收集少量血浆并单独储存(保留)用于最终产品组合物。在一些实施方案中,肝素用作抗凝血剂。
然后将分离的PBMC暴露于树突细胞分化培养基2-5天。
用于DC分化的示例性培养基是包含非碳酸氢盐缓冲液的CO2非依赖性制剂。CO2非依赖性培养基制剂的示例是不含碳酸氢盐的RPMI-1640和AIM V培养基(ThermoFisher)。适用于组织培养的非碳酸氢盐缓冲液的一个示例是HEPES。
在一些实施方案中,DC分化培养基包含抗氧化剂和自由基清除剂。自由基清除剂的示例包括N-乙酰基-半胱氨酸、羧基-PTIO、类黄酮和L-NG-甲基精氨酸。
在一些实施方案中,DC分化培养基包含GM-CSF和IL-4。
在一些实施方案中,DC分化培养基不包含GM-CSF。
在一些实施方案中,DC分化培养基包含IFNγ。
在一些实施方案中,DC分化培养基包含IFNα。
在一些实施方案中,DC分化培养基包含IL-2。
在一些实施方案中,DC分化培养基可包含最高达30%的自体血浆,其在血液收集和PBMC分离过程中保留。在一些实施方案中,培养基包含5%至30%自体血浆,或该范围内的任何整数值,包括端值。
然后将PBMC细胞悬浮液转移到封闭系统细胞培养容器中,用于DC分化和抗原暴露。
示例性封闭系统细胞培养容器是具有大约50cm2的内部细胞培养表面和至少一个入口的柔性袋。
另一种封闭系统细胞培养容器是具有大约50cm2的平坦内部细胞培养表面和入口的刚性容器。
封闭系统细胞培养容器内部表面是疏水性的以防止细胞附着。
用于封闭系统细胞培养容器的示例性材料是透气材料,例如氟化聚乙烯及其共聚物。
封闭系统细胞培养容器材料的替代品是经过疏水性化学修饰的纤维素。在各种实施方案中,化学修饰的纤维素是用脂肪酸(例如,棕榈酸根、硬脂酸根等)酰化或酯化的醋酸纤维素。
可替代地,可以通过用疏水材料涂覆内表面来实现疏水特性。这样的材料可以是例如疏水硅烷。
包含PBMC和培养基的容器在37℃孵育2-5天。
示例性培养箱是包含可充电电源和恒温器的试剂盒容器。试剂盒容器壁提供隔热功能,其允许最小的能量耗散,以将内容物在约37℃保持5-7天。在一些实施方案中,电源由锂聚合物电池组成,其形状可以适合盒子。
示例性恒温器包括消除对温度控制器的需要的相交换材料和/或正温度系数(PTC)材料。如本文所用,恒温器是保持恒定温度(在公差内)的任何系统,而温度控制器是具有传感器和反馈回路以启用或禁用能量(热)注入的机械或电子系统。如本文所用,相交换材料是在相变过程中释放或吸收足够能量以提供加热或冷却的物质。例如,随着加热将固相交换材料的温度升高到熔化温度,热量被吸收而温度几乎没有变化,直到所有材料熔化。类似地,随着热量消散并且液相的温度朝熔点下降,材料凝固并释放热量,温度几乎没有变化,直到所有材料都凝固。在一些实施方案中,相交换材料是石蜡20-碳(熔点36.7℃)。在一些实施方案中,相交换材料是莰尼酮(熔点39℃)。在一些实施方案中,相交换材料被称为用于释放或吸收能量的手段或用于潜热储存的手段。
PTC材料表现出随着温度升高电阻增加。PTC材料可以设计为达到给定输入电压的最高温度,因为在某个点时温度的任何进一步升高都会遇到更大的电阻。与线性电阻加热或负温度材料不同,PTC材料具有固有的自限性。在一些实施方案中,PTC材料是硅橡胶,硅橡胶导电时对于所有温度而言电阻率随着温度的升高而指数性增加,直到电阻率增长到无穷大的温度。高于此温度,PTC橡胶是电绝缘体。特别是,PTC橡胶可以由载有碳纳米颗粒的聚二甲基硅氧烷(PDMS)制成。在一些实施方案中,PTC材料是基于碳的PTC墨水。PTC墨水沉积在细胞培养容器的外表面上。在一些实施方案中,PTC材料被称为用于PTC限制性加热的手段。
在各种实施方案中,恒温器包含相交换材料或PTC材料或两者。在一些实施方案中,恒温器被称为用于维持恒定温度的手段。在一些实施方案中,恒定温度为约37℃。
然后将未成熟树突细胞暴露于抗原1或2天。可以通过兼容端口(例如,自密封抽吸阀(self-sealing swabbable valve))将抗原添加到封闭系统细胞培养容器中。在一些实施方案中,在整个3-7天的培养期内,培养基从不改变。
适用于DC负载的抗原包括源自病原体、毒素和毒液的可溶性或不溶性抗原,或包括完整的、减毒活的、不能存活的病原体片段或蛋白质复合物的不溶性抗原。从病原体的DNA/RNA序列设计的多种合成结构或重组结构可用作抗原来源。此外,抗原可以与增强抗原性或刺激树突细胞的末端肽序列融合。融合的肽序列可以包括例如人免疫球蛋白的片段和激活树突细胞的toll样受体(TLR)的化学结构。
正如别处发表的那样,重组方法可用于生产抗原。重组方法使用源自病原体的DNA/RNA分析和化学结构的序列。抗原性的预测也可以基于主要和次要亚类上的人HLA匹配。
抗原靶标的验证可以通过来自病原体感染幸存者或被确认对靶标病原体呈阳性的恢复期患者的抗体结合试验来进行。
抗原的组合可用于生产具有更广泛保护的疫苗。
对于剂量制备,将容器中的细胞内容物收集在离心管中,并且通过离心去除上清液并用自体血浆代替。
如果预期在施用前冷冻剂量,则可以在此步骤添加冷冻保护剂溶液。在一些实施方案中,冷冻保护剂与等体积的自体血浆混合以重悬浮细胞。示例性冷冻保护剂包含海藻糖和甘油。使用海藻糖和甘油作为冷冻保护剂允许直接注射解冻产品,因为它们在USP中列为疫苗佐剂。一些其他的冷冻保护剂,如DMSO,在注射解冻产品之前必须去除。
任选地对少量细胞进行质量控制。在一些实施方案中,细胞群包含5-30%树突细胞和70-95%淋巴细胞,并且未分化单核细胞的含量小于1%。巨噬细胞的缺失表明DC分化的有效性,并且在DC分化之前去除贴壁细胞是不必要的。
在一些实施方案中,剂量不含残留抗原或细胞培养基。
然后将剂量转移到最终容器中,其在室温储存以供立即使用,在4-8℃储存以供接下来的2天使用,在-65至-85℃储存最多达21天,以及在液氮(<-165℃)中用于长期储存。
质量控制可包括身份测试,例如CD14-CD11+细胞测试;微生物污染(支原体、内毒素和无菌性)的安全测试和效力测定,例如上清液中IL12的存在。
示例性效力测定包括快速评估方法,例如侧流免疫测定。
在一些实施方案中,剂量通过患者身份验证并通过s.c.注射施用。
加工和产品分配
可以从中心地点协调疫苗产品的生产和分配。在一些实施方案中,个性化DC疫苗是在使用普通生物技术或临床实验室设置和技能的低技术实验室中生产的。在一些实施方案中,疫苗产品的生产和分配在同一地点进行。
第一步,对实验室的空间、设备和人员资格进行评估。典型的实验室将包括生物安全2级空间,其中包括培养箱、离心机、冰箱、冰柜、显微镜和普通实验室仪器。
在一些实施方案中,专门的软件模块在设施现有的质量管理系统(QMS)中实施。该软件提供符合美国食品和药物管理局或其他国家的同等监管机构的说明、制造记录、控制和释放程序。该模块与协调中心的集中QMS通信,以确保制造试剂盒、培训和疑难排解的可用性。
评估每个地点的生产能力,并相应地计划或保留制造试剂盒。每个组分的供应链都有合同保障。
试剂盒可由专门的第三方组装和仓储组织根据材料清单制造,并根据当地生产进行分配。
示例性试剂盒形式包括细胞培养容器中已包含的所有干物质形式的试剂,液体形式的重构通过在PBMC分离后添加悬浮在氯化钠0.8%溶液中的细胞来进行。对于其中DC分化培养基包含自体血浆的实施方案,自体血浆也在此时加入到细胞培养物中。
一旦负载有抗原的未成熟DC被重悬浮,它们就可以使用了,但预计需要一段时间的储存;例如,质量控制测定通常可以在约3小时内完成。此外,患者不一定会出现在制备疫苗的设施中。疫苗可在室温储存至少最长达5小时,在4℃储存至少最长达48小时,或在-80℃储存至少最长达21天,以允许患者的行程时间和/或疫苗的运输时间。
实施例
实施例1.从个体血液样品中产生树突细胞并负载源自SARS-CoV-2病毒基因组的重组抗原
第一步,验证靶向抗原与已知COVID-19患者体内自然产生的抗体的反应性。为此,收集了先前通过PCR检测诊断为SARS-CoV-2感染的知情同意供体的血清,并将其暴露于ELISA板,这些板涂有从SARS-CoV-2病毒的刺突蛋白和核衣壳蛋白的DNA序列获得的重组肽。
图2-图5中描绘的ELISA板的分析证实了与重组抗原的反应性。
抗原验证后,对四名志愿供体在肝素化的真空采血管中收集50mL全血,以生产自体DC疫苗。
进行全血细胞计数(CBC)以评估起始单核细胞群。所有志愿者的CBC值都在正常范围内。
在收集的6小时内,对全血进行Ficoll分离。部分单核细胞转移至75cm2细胞培养皿中,部分细胞分布于12孔板中。
主要由淋巴细胞组成的非贴壁细胞被移除并保存以备后用。
贴壁群体与包含GM-CSF和IL-4的AIM-V培养基一起孵育5天。单核细胞以90%CD11c阳性/CD14细胞群的比例分化为树突细胞(图6)。
然后去除培养基并用包含SARS CoV-2抗原的新鲜相同培养基替换,这些抗原通过重组方法源自刺突蛋白(S1、S2)和核衣壳的DNA序列(3μg/每个患者培养物)。
2天后,对负载的树突细胞进行表型取样,并以1:3的比例与相应的自体淋巴细胞重新混合。
将DC和自体淋巴细胞共培养72小时,并分析表明淋巴细胞激活的标志物。
结果显示单核细胞成功分化为树突细胞、抗原的毒性缺乏以及与负载的树突细胞共培养的淋巴细胞的细胞毒性激活(表1、图7和图8)。
表1.自体混合淋巴细胞与不同抗原浓度的负载有抗原的树突细胞的共培养物中
的细胞因子分泌,取自4名患者的平均值
与其中分化的DC未暴露于抗原的对照相比,在暴露于抗原后CD8+群体增加至41%。
CD4辅助群体显示出显著的激活,观察到Tbet转录因子阳性平均比无抗原对照增加17%(图9),以及由于FoxP3阳性细胞的缺乏(平均0.06%)而缺少免疫耐受。Tbet阳性细胞负责适应性免疫系统的Th1和Th2激活。
这些实验证明重组抗原是天然产生的抗体的有效靶标,因此针对这些抗原的免疫可以产生与天然病毒抗原反应的抗体。
实验还表明抗原对树突细胞没有直接毒性,并且以细胞毒性方式激活淋巴细胞。
从另外六个患者样品中验证了临床制造(图10)。所述制造使用预先包装在个体患者专用试剂盒中的所有材料和试剂。维持血液收集和最终剂量的监管链的物流被纳入组分的标记系统。
出于实用性考虑,单个试剂盒分为四个部分,A部分和B部分根据储存条件在制造站点使用,而C部分和D部分在临床站点用于血液收集和施用。
每个试剂盒都包含符合GMP标准的文档,并且预计收集的数据将集中在公司的数据库中以实现可追溯性。本公开还考虑现场培训材料
电子GMP文档和数据收集软件安装在每个站点,并具有中心报告功能。该软件具有远程更新的能力,从而避免了本地文件变更控制系统的实施。
组装好的试剂盒可以在疫苗接种季节之前由一个或多个制造站点以商业模式进行预留,以确保材料的覆盖范围并避免供应链在需求高峰期耗竭。
实施例2.负载有重组全长SARS-CoV-2刺突蛋白的自体DC疫苗的安全性和有效性
使用自体疫苗产品进行的临床试验是从40mL外周血淋巴细胞进行的,这些淋巴细胞经受了从所含的单核细胞的DC分化,并负载了0.1、0.33或1μg SARS-CoV-2全长重组刺突蛋白。该试验采用了广泛的纳入标准,仅排除医学状况不稳定的患者和某些受保护类别的个体(即儿童、孕妇、身体上、社会上和精神上无行为能力的个体)。评估的主要结果是临床和实验室评估的安全性和替代标志物的功效。
编码SARS-CoV-2刺突蛋白的载体可以包含信号序列,并可以包含His标签或其他有助于纯化的序列,但这些部分通常不存在于成熟的重组蛋白中。在一些实施方案中,SARS-CoV-2的成熟全长重组刺突蛋白具有以下氨基酸序列:
QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFF
SNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWI
FGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKS
WMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKN
IDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLAL
HRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAV
DCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCP
FGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGV
SPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDD
FTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQ
AGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLH
APATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQ
FGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVL
YQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHV
NNSYECDIPIGAGICASYQTQTNSPGSASSVASQSIIAYTMSLGAEN
SVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSN
LLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDF
GGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDI
AARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGA
GAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQ
DSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDIL
SRLDPPEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATK
MSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQE
KNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTD
NTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDV
DLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPGYIPEAPRDGQAYVRKDGEWVLLSTFLLEVLFQGP(SEQ ID NO:1)
制造遵循本文所述的方法。为每个对象分配唯一标识的试剂盒,向对象提供相同的标识收据。使用1.073密度梯度Ficoll试剂分离PBMC。
在250μg/L GM-CSF和100μg/L IL4存在的情况下,PBMC以25mL在VueLife生物工艺袋(Saint Gobain)中在PRIME-XV树突细胞成熟化学成分确定的培养基(FujiFilm IrvineScientific)或AIM-V培养基(Thermo Fisher)中分化5天。第5天,将总量为0.1、0.33或1μg的抗原引入袋中。2天后,收获细胞并通过将细胞重悬浮在自体血浆中来制备剂量。为了收获,通过离心使细胞沉淀,吸出上清液,并且将细胞通过在盐水中重悬浮然后离心并吸出上清液来洗涤。洗涤除去培养基组分和任何游离抗原。将剂量储存在4℃,第二天通过皮下注射施用。
注射后观察对象3小时,然后接下来的3天每天观察一次,接下来的4周每周观察一次。针对安全实验室和替代功效收集血液。
在非刺激条件相比于抗原刺激条件下,通过ELISPOT测试干扰素γ的替代功效。该测定检测抗原特异性激活的IFN-γ分泌性细胞,并通过以下进行测定:在CPT真空抽血管(Becton Dickinson)中收集8mL血液,通过离心分离PBMC并在存在或不存在刺突蛋白抗原和IL-2的情况下以标准化浓度在24孔板中铺板。在没有进一步抗原刺激的情况下10天后,将细胞以预定浓度转移到96孔ELISPOT板中,每个条件一式三份孔。根据制造商的标准程序(Becton Dickinson)对斑点进行染色和计数。
共有138名对象接受了剂量;筛选了216名。有61名对象具有至少一次不良事件(AE)。总共有100次不良事件。所有事件都被认为是轻度(94%)到中度(6%)。
没有记录到重度或严重的不良事件。没有对象因不良事件而中止。
疫苗接种后,所有对象均未感染有症状的COVID-19疾病。
最常见的AE是如其他疫苗常见的局部注射部位反应(表2)。
表2.不良事件
基线ELISPOT数据表明,30%的对象有SARS-CoV-2暴露史(自然感染或未公开的疫苗),但没有对象在筛选时出现抗体(图11A)。由于重组SARS-CoV-2刺突蛋白被用作刺激剂,因此预计阳性反应反映了对SARS-CoV-2的实际暴露,而不是与对象可能暴露过的另一种冠状病毒的交叉反应。
到疫苗接种后两周,ELISPOT反应性增加到受试对象的92.9%(图11B)。在刺激和无刺激两种条件下,平均斑点计数都显著增加(p<<0.001)(图12、表3),43%的对象表现出SARS-CoV-2刺突蛋白特异性细胞毒性记忆细胞(IFNγ分泌性淋巴细胞;图13A)。大多数在疫苗接种后两周具有细胞毒性记忆细胞的对象是转化的结果。一些预先存在反应性的对象在疫苗接种后表现出增强作用,而一些则保持不变(图13B)。
表3.平均斑点计数
ELISPOT数据表明了疫苗接种后两周时的高反应性,这表明大多数对象存在初级免疫应答。
来自28名患者试点安全研究的数据表明,细胞毒性记忆应答在疫苗接种后持续至少四个月,但预计会持续更长时间。
总之,这些数据表明诱导了细胞介导的免疫。
除非另有说明,否则在说明书和权利要求书中使用的所有表示成分的量、性质如分子量、反应条件等的数字应理解为在所有情况下均由术语“约”修饰。如本文所用,术语“约”和“大约”是指在10%至15%内,优选地在5%至10%内。因此,除非有相反的说明,否则说明书和所附权利要求中阐述的数值参数是近似值,其可以根据本发明寻求获得的期望特性而变化。至少,而不是试图将等同原则的应用限制在权利要求的范围内,每个数值参数至少应根据报告的有效数字的数量并通过应用普通的舍入技术来解释。虽然阐述本发明的广泛范围的数值范围和参数是近似值,但是在具体示例中阐述的数值被尽可能地精确地报告。然而,任何数值都固有地包含必然由其各自测试测量中所发现的标准偏差引起的某些误差。
除非本文中另外指示或上下文明显相矛盾,否则在描述本发明的上下文中(特别是在所附权利要求的上下文中)使用的术语“一个/一种(a/an)”和“该(the)”以及类似指示物将视为涵盖单数与复数两者。本文中对值的范围的描述仅旨在用作单独提及落入该范围内的每个单独值的简写方法。除非在本文中另有说明,否则将每个单独的值并入说明书中,如同其在本文中单独引用一样。在本文描述的所有方法能够以任何合适顺序进行,除非本文另外指明或另外与上下文明显相矛盾。本文提供的任何和所有示例或示例性语言(例如“例如”)的使用仅旨在更好地说明本发明并且除非另有声明,否则不构成对本发明范围的限制。说明书中的任何语言都不应当解释为指示任何未要求保护的要素为实践本发明所必需的。
本文公开的本发明的替代要素或实施方案的分组不应该被解释为限制。每个组成员都可以单独或以与组的其他成员或本文中的其他要素的任何组合进行引用和要求保护。预计出于方便和/或可专利性的原因,组的一个或多个成员可以被包括在组中或从组中删除。当出现任何此类包括或删除时,说明书被视为包含修改后的组,从而满足所附权利要求中使用的所有马库什(Markush)组的书面描述。
本文描述了本发明的某些实施方案,包括发明人已知的用于实施本发明的最佳方式。当然,在阅读前述描述后,这些描述的实施方案的变型对于本领域的普通技术人员将变得显而易见。发明人期望熟练的技术人员适当地采用这样的变型,并且发明人打算以不同于本文具体描述的方式来实践本发明。因此,在适用法律允许的情况下,本发明包括对所附权利要求书所引用的主题的所有修改和等效物。此外,本发明涵盖以上描述的要素以其所有可能的变型的任意组合,除非另外在本文中指出或另外明确地与上下文相矛盾。
本文公开的具体实施方案可以进一步在权利要求中使用语言由……组成或基本上由……组成进行限定。当在权利要求中使用时,无论是提交的还是根据修订添加的,过渡术语“由……组成”不包括权利要求中未指定的任何要素、步骤或成分。过渡术语“基本上由……组成”将权利要求的范围限制于指定的材料或步骤和“那些不会对要求保护的一种或多种基本和新颖特征产生实质影响的材料或步骤”。如此要求保护的本发明的实施方案在本文中被固有地或明确地描述和启用。
此外,在整个说明书中已经对专利和印刷出版物进行了大量参考。上面引用的每篇参考文献和印刷出版物均单独地通过引用以其整体并入本文。
最后,应当理解,本文公开的本发明的实施方案是对本发明原理的说明。可以采用的其他修改在本发明的范围内。因此,作为示例而非限制,可以根据本文的教导使用本发明的替代配置。因此,本发明不限于如所示出和描述的那样。
序列表
<110> 艾维塔生物医学公司
<120> 自体树突细胞疫苗试剂盒及用途
<130> 1959090-00104
<150> US 63/033,678
<151> 2020-06-02
<160> 1
<170> PatentIn版本3.5
<210> 1
<211> 1235
<212> PRT
<213> 严重急性呼吸综合征病毒2型
<400> 1
Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr
1 5 10 15
Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser
20 25 30
Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn
35 40 45
Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys
50 55 60
Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala
65 70 75 80
Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr
85 90 95
Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn
100 105 110
Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu
115 120 125
Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe
130 135 140
Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln
145 150 155 160
Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu
165 170 175
Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser
180 185 190
Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser
195 200 205
Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg
210 215 220
Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp
225 230 235 240
Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr
245 250 255
Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile
260 265 270
Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys
275 280 285
Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn
290 295 300
Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr
305 310 315 320
Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser
325 330 335
Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr
340 345 350
Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly
355 360 365
Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala
370 375 380
Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly
385 390 395 400
Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe
405 410 415
Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val
420 425 430
Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu
435 440 445
Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser
450 455 460
Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln
465 470 475 480
Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg
485 490 495
Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys
500 505 510
Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe
515 520 525
Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys
530 535 540
Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr
545 550 555 560
Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro
565 570 575
Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser
580 585 590
Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro
595 600 605
Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser
610 615 620
Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala
625 630 635 640
Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly
645 650 655
Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Gly Ser Ala Ser
660 665 670
Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala
675 680 685
Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn
690 695 700
Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys
705 710 715 720
Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys
725 730 735
Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg
740 745 750
Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val
755 760 765
Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe
770 775 780
Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser
785 790 795 800
Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala
805 810 815
Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala
820 825 830
Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu
835 840 845
Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu
850 855 860
Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala
865 870 875 880
Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile
885 890 895
Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn
900 905 910
Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr
915 920 925
Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln
930 935 940
Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile
945 950 955 960
Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala
965 970 975
Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln
980 985 990
Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser
995 1000 1005
Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln
1010 1015 1020
Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser
1025 1030 1035
Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr
1040 1045 1050
Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile
1055 1060 1065
Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val
1070 1075 1080
Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu
1085 1090 1095
Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
1100 1105 1110
Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu
1115 1120 1125
Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe
1130 1135 1140
Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly
1145 1150 1155
Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu
1160 1165 1170
Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln
1175 1180 1185
Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Gly Tyr Ile
1190 1195 1200
Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly
1205 1210 1215
Glu Trp Val Leu Leu Ser Thr Phe Leu Leu Glu Val Leu Phe Gln
1220 1225 1230
Gly Pro
1235
Claims (19)
1.一种个性化疫苗试剂盒,其包含,
a.试剂盒容器,
b.血液收集用品,
c.单核细胞分离培养基或惯性微流体装置,
d.树突细胞(DC)分化培养基组分,
e.具有至少一个入口的细胞培养容器,
f.唯一身份的标记,以及
g.抗原。
2.如权利要求1所述的个性化疫苗试剂盒,其中所述试剂盒容器包含绝热壁并且能够用作培养箱。
3.如权利要求2所述的个性化疫苗试剂盒,其中所述培养箱包含电源和恒温系统。
4.如权利要求3所述的个性化疫苗试剂盒,其中所述恒温系统包含相交换材料和正温度系数(PTC)材料,但不包含温度控制器。
5.如权利要求1-4中任一项所述的个性化疫苗试剂盒,其中在所述细胞培养容器中提供干燥的所述DC分化培养基组分。
6.如权利要求1-5中任一项所述的个性化疫苗试剂盒,其中所述DC分化培养基组分包含IL-4。
7.如权利要求6所述的个性化疫苗试剂盒,其中所述DC分化培养基组分包含GM-CSF。
8.如权利要求1-7中任一项所述的个性化疫苗试剂盒,其中所述DC分化培养基组分包含IFNγ、IFNα、IL-2或其任何组合。
9.如权利要求1-8中任一项所述的个性化疫苗试剂盒,其中所述抗原是SARS-CoV-2全长重组刺突蛋白。
10.一种使用如权利要求1-9中任一项所述的试剂盒制备个性化自体树突细胞(DC)疫苗的方法,其包括:
a)从个体收集5至50mL的血液,
b)从所述血液中分离外周血单核细胞(PBMC),
c)通过将所述DC添加到所述细胞培养容器中并孵育所述细胞2-5天来使所述PBMC分化以产生未成熟DC,然后
d)将抗原添加到所述细胞培养容器中,以使所述未成熟DC负载抗原并再孵育1-2天,以及
e)收获负载有抗原的未成熟DC。
11.如权利要求10所述的方法,其进一步包括保留来自所述分离步骤的自体血浆。
12.如权利要求10或11所述的方法,其进一步包括将收获的所述负载有抗原的未成熟DC重悬浮于自体血浆中。
13.如权利要求10-12中任一项所述的方法,其进一步包括将所述唯一身份的标记贴附到包含来自所述个体的细胞或血浆的容器上。
14.如权利要求10-13中任一项所述的方法,其进一步包括在施用于所述个体之前储存收获、重悬浮的所述负载有抗原的未成熟DC。
15.如权利要求14所述的方法,其包括将收获、重悬浮的所述负载有抗原的未成熟DC在室温下储存最长达6小时。
16.如权利要求14所述的方法,其包括将收获、重悬浮的所述负载有抗原的未成熟DC在4℃下储存最长达48小时。
17.如权利要求10或11所述的方法,其进一步包括将收获的所述负载有抗原的未成熟DC重悬浮于自体血浆和冷冻保护剂的混合物中,并将收获、重悬浮的所述负载有抗原的未成熟DC在-80℃下储存最长达21天。
18.一种个性化自体树突细胞(DC)疫苗,其通过如权利要求10-17中任一项所述的方法制备。
19.一种对个体进行免疫的方法,其包括通过皮下或皮内注射向所述个体施用个性化自体树突细胞(DC)疫苗。
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