CN115379853A - 对患者新表位有应答的t细胞 - Google Patents
对患者新表位有应答的t细胞 Download PDFInfo
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- CN115379853A CN115379853A CN202180023211.5A CN202180023211A CN115379853A CN 115379853 A CN115379853 A CN 115379853A CN 202180023211 A CN202180023211 A CN 202180023211A CN 115379853 A CN115379853 A CN 115379853A
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Abstract
提供了允许检测和预测经选择接受或已经接受疫苗的受试者中的免疫应答的组合物和方法。在选定的实施例中，使用全血作为起始材料以获得树突细胞和T细胞，并且使用包括疫苗抗原的一种或多种合成或重组多肽。然后将树突细胞暴露于一种或多种合成或重组多肽，并因此暴露的树突细胞与T细胞结合以生成抗原反应性T细胞。为了进行检测或量化，在ELISPOT或FACS分析之前将抗原反应性T细胞在体外进行扩增。有利的是，这样的系统和方法尤其适用于确定在用抗癌疫苗进行疫苗接种后针对癌抗原的免疫应答。
Description
本申请要求2020年03月20日提交的序列号为62/992,794和2020年04月01日提交的序列号为63/003,496的我们共同未决的美国临时专利申请的优先权。将这两个申请通过引用以其全文并入本文，包括附图。
序列表
名称为Seq_listing_ST25、大小为17kb的序列表的ASCII文本文件的内容于2020年02月26日创建，并经由EFS-Web与本申请一起以电子方式提交，且通过引用以其全文并入。
技术领域
本披露涉及确定或预测针对抗原(最典型的是抗肿瘤疫苗中的治疗抗原)的免疫应答的组合物和方法。
背景技术
背景技术描述包括在理解本披露中可能有用的信息。并不承认本文提供的任何信息是现有技术或与当前要求保护的发明相关，也不承认特定地或隐含地引用的任何出版物是现有技术。
本文中的所有出版物和专利申请都通过引用并入，其程度如同每个单独的出版物或专利申请被特定地且单独地指明通过引用并入一样。在并入的参考文献中的术语的定义或用法与本文提供的该术语的定义不一致或相反时，适用本文提供的该术语的定义，而不适用该术语在该参考文献中的定义。
虽然针对许多分子靶标开发了许多癌症疫苗，但临床成功往往是不可预测的，并且在一个抗原与另一个抗原之间或针对常见抗原的不同患者之间可能存在显著差异。事实上，预测治疗效果(无论是否引发针对肿瘤的功能性免疫应答)的可能性一直是难以捉摸的，而治疗效果以及根据其确定是否继续使用疫苗治疗在许多情况下仅基于对延缓或逆转的肿瘤生长进行定量分析。因此，从治疗开始到治疗效果的第一个重要指示之间将会有很长的时间。
最近，已经对来自肿瘤微环境(例如，肿瘤浸润淋巴细胞(TIL))或邻近淋巴器官的T细胞进行了检测，以确定抗原反应性T细胞的反应性和数量。然而，收集这些细胞对患者来说可能具有高度侵入性和不适感，最典型地，这样的细胞获得自肿瘤活检或以其他方式手术切除的肿瘤样品。例如，抗原反应性肿瘤浸润淋巴细胞已被用作与其他免疫调节剂组合的治疗实体，如Nature Medicine[自然医学](URL:doi.org/10.1038/s41591-018-0040-8)中报道的。虽然明显有效，但TIL获得自手术样品。
US 8697371中描述了体外免疫应答的评估，其中提出了一种人工免疫系统，该系统包括T细胞、B细胞和树突细胞，用于体外测试疫苗、佐剂、免疫治疗候选物、生物制剂等。不幸的是，当受试者已经暴露于抗原或抗癌疫苗时，这种系统不会提供体内可能的免疫应答的指示。同样，由于受试者间可变性高，这样的体外测试的结果不一定会同等地转化为大量不同的受试者。
因此，即使本领域已知各种鉴定免疫应答的系统和方法，但所有或几乎所有的这些系统和方法都存在各种缺点。因此，需要提供改善的组合物和方法，这些改善的组合物和方法提供以安全、简单和快速的方式帮助鉴定或甚至预测个体中的免疫应答的改善的系统和方法。
发明内容
本发明人现已发现，典型地使用受试者的全血和重组抗原作为起始材料，可以在受试者中(优选地，在经选择接受或已经接受抗肿瘤疫苗的受试者中)确定或预测免疫应答。因此，所考虑的组合物和方法在概念上是简单的，显著降低了患者的风险和不适，否则需要活检或手术，并且可以在很短的时间(例如，数天)内提供结果，否则需要体内观察(例如，数月)。
在一个方面，披露了一种确定先前暴露于抗原的受试者中针对该抗原的免疫应答的方法，该方法包括从该受试者的外周血生成树突细胞，并将这些树突细胞暴露于含抗原组合物以生成抗原呈递树突细胞的步骤。在另一个步骤中，从该受试者的外周血中分离T细胞，然后使这些分离的T细胞与这些抗原呈递树突细胞接触。为了扩增抗原反应性T细胞，将这些分离的T细胞和这些抗原呈递树突细胞暴露于含细胞因子组合物，并且在又一个步骤中，检测这些扩增的抗原反应性T细胞，由此扩增的抗原反应性T细胞确定针对该抗原的免疫应答。
在一些实施例中，受试者先前暴露于含有抗原或编码该抗原的核酸的疫苗。例如，含有抗原的疫苗可以是重组病毒疫苗、重组酵母疫苗、和/或重组细菌疫苗，并且通常优选(但不是必须)的是，抗原是患者和肿瘤特异性新抗原。最典型地，树突细胞由外周血中的单核细胞生成。
在另外的实施例中，含抗原组合物中的抗原是患者和肿瘤特异性新抗原，并且/或者含抗原组合物中的抗原是含有新抗原的全长蛋白。例如，含抗原组合物可以是重组含抗原组合物。如果需要，含抗原组合物可包含含有多种不同抗原的多表位或源自全长蛋白的抗原库。最典型地，含细胞因子组合物可包含IL7、IL15和IL21，或者含细胞因子组合物可包含IL7/N803/IL21 TxM。
在其他合适的选择中，可以使用ELISPOT测定或FACS测定检测扩增的抗原反应性T细胞。同样容易理解的是，扩增的抗原反应性T细胞可以施用于受试者。
在另一个方面，披露了一种在经选择接受含有抗原的疫苗的受试者中预测可能的针对该抗原的免疫应答的方法。这种方法可包括从受试者的外周血生成树突细胞，并将这些树突细胞暴露于含抗原组合物以生成抗原呈递树突细胞的步骤，以及从受试者的外周血中分离T细胞，并使这些分离的T细胞与这些抗原呈递树突细胞接触的另一个步骤。然后将这些分离的T细胞和这些抗原呈递树突细胞暴露于含细胞因子组合物以扩增抗原反应性T细胞，对扩增的抗原反应性T细胞进行量化，并且在又一个步骤中，当这些量化的扩增的抗原反应性T细胞超过预定阈值时，将受试者鉴定为可能的免疫应答者。
例如，疫苗典型地将是重组病毒疫苗、重组酵母疫苗、和/或重组细菌疫苗，并且抗原将是患者和肿瘤特异性新抗原。如上所述，树突细胞可以由外周血中的单核细胞生成。进一步考虑的是，含抗原组合物中的抗原将是患者和肿瘤特异性新抗原。最典型地，含抗原组合物中的抗原将包含在疫苗中。在更进一步考虑的实施例中，疫苗可包含多种抗原且含抗原组合物包含多种抗原作为抗原库或多表位，并且疫苗中的多种抗原被编码为多表位或作为多表位存在。
优选地但不是必须，含细胞因子组合物包含IL7、IL15和IL21，或者含细胞因子组合物包含IL7/N803/IL21 TxM。同样，优选地，对扩增的抗原反应性T细胞进行量化的步骤使用ELISPOT测定或FACS测定。最典型地，预定阈值是在扩增培养物中以至少1.0％的丰度存在扩增的抗原反应性T细胞。
从以下对优选实施例的详细描述以及附图中，各种目的、特征、方面和优点将变得更加明显，在附图中相同的数字表示相同的组成部分。
附图说明
图1示意性地描绘了CMV病毒颗粒和选定的蛋白质组分。
图2示意性地描绘了CMV病毒pp65蛋白质序列、由此衍生的肽库和选定的pp65495-503肽片段。
图3示意性地描绘了具有右旋糖酐主链的示例性右旋聚体，该右旋聚体用荧光团标记并进一步用与肽抗原结合的MHC蛋白修饰。
图4描绘了可用于在体外生成新抗原(新表位)肽的示例性表达策略和合成核酸。
图5显示了抗原反应性T细胞及其扩增后的富集的示例性FACS结果。
图6A和6B是如下的示例性结果：针对外周血并使用肽库和单个肽片段的肽滴定(6A)以及抗原反应性T细胞响应单个肽片段和对照的干扰素-γ产生(6B)。
图7示出了使用来自人受试者PBMC的单核细胞衍生的树突细胞和T细胞生成扩增的抗原反应性T细胞的示例性工作流程和结果。
图8描绘了检测扩增的抗原反应性T细胞中抗原反应性T细胞分数的示例性结果。
图9描绘了抗原反应性T细胞的干扰素-γ产生的示例性结果。
图10描绘了确定抗原反应性T细胞识别来自多表位的多个表位的示例性结果。
具体实施方式
本发明人现已发现，可以以概念上简单和有效的方式从全血中检测到受试者响应免疫疗法而成功生成的抗原反应性T细胞。更特别地，并且基于疫苗中先前已知的抗原，可以进行体外测定，该测定使用暴露于一种或多种抗原(例如，作为抗原库或多表位)的受试者的单核细胞衍生的树突细胞，然后使如此生成的抗原呈递树突细胞与同一受试者的T细胞接触以生成抗原反应性T细胞，随后使用含特定细胞因子组合物扩增这些抗原反应性T细胞，从而获得扩增的抗原反应性T细胞用于检测和/或量化。正如将容易理解的，抗原反应性T细胞的存在将指示免疫应答，尤其是扩增的抗原反应性T细胞的数量超过预定阈值时的治疗有效免疫应答。有利地，可以使用常规方法和设备进行检测和/或量化。因此，应该认识到，在受试者接受免疫疗法后的几天内，可以验证(或甚至预测)受试者响应免疫疗法而成功生成的抗原反应性T细胞。因此，并且从不同的角度来看，所考虑的组合物和方法将显著减少在癌症疫苗的施用和确定其在特定患者中的功效之间所花费的时间。
正如将容易理解的，免疫疗法的性质可能有很大差异，并且通常包括直接或间接施用一种或多种疾病相关抗原。在优选的实施例中，抗原是癌症相关(例如，MUC-1、CEA等)或癌症特异性(例如，PSA、PSMA、BRCA1等)抗原，并且最优选的是患者和肿瘤特异性新抗原。因此，合适抗原的鉴定可包括文献综述，更典型的是组学测序(例如，全基因组测序、外显子测序、RNA-seq、蛋白质质谱等)。在另外的优选的方面，新抗原将被证实在肿瘤中表达，并且可以将表达的新抗原进一步过滤成对受试者HLA类型具有最小结合亲和力(例如，等于或小于500nM，或等于或小于200nM，或等于或小于100nM)的那些。计算最小结合亲和力的方式有很多种，典型的实例包括NetMHC4.0、NetMHCpan、PSSNetMHCpan、MHCflurry等。
在更进一步考虑的方面，癌症疫苗中的合适抗原将是典型地排列在多表位中的多种抗原，在该多表位中，新抗原按顺序排列，其中散布着(柔性)接头结构域，通常长度为三至十五个氨基酸。例如，所考虑的疫苗组合物尤其包括重组细菌(例如，大肠杆菌，尤其是经工程改造为缺乏LPS表达的大肠杆菌)、病毒(例如，Ad5，尤其是Ad5[E1-Eb2-])和/或酵母(例如，酵母属)，这些重组细菌、病毒和/或酵母包括编码抗原或多表位的重组核酸。当然，应该认识到，受试者可进一步接受额外的治疗剂以刺激免疫应答，这些额外的治疗剂例如免疫刺激细胞因子(例如，IL15、N803等)、检查点抑制剂(例如，靶向CTLA4、PD-1、PD-L1等)、以及基于细胞(如T细胞和/或NK细胞(优选经遗传修饰以表达嵌合抗原受体或其他肿瘤靶向实体))的疗法。
最典型地，关于树突细胞和T细胞，优选这些细胞是从外周血生成/获得的。在大多数情况下，使用本领域众所周知的标准方法(如Ficoll密度梯度离心法以获得血沉棕黄层(buffy coat)或白细胞单采术)从外周获得PBMC。虽然树突细胞可以从PBMC中分离出来，但通常优选树突细胞源自PBMC中的单核细胞(典型地使用本领域众所周知的抗CD14抗体)，从而允许相对大量和相对纯的树突细胞群。这样的单核细胞衍生的树突细胞的制备是本领域众所周知的(参见例如，J Vis Exp[可视化实验杂志]2016)，并且在大多数情况下将包括选定的细胞因子混合物(包括IL4和GM-CSF)。然而，还应当理解，树突细胞和/或T细胞也可以来自异源来源，并且特别考虑的异源来源包括HLA匹配的供体(例如，对于至少两种HLA类型(HLA-A、HLA-B、HLA-C、HLA-DR、HLA-DQ、HLA-DP)，HLA匹配到至少4位或至少6位)。在更进一步考虑的方面，树突细胞和/或T细胞将是新鲜细胞，然而，在一些情况下，这样的细胞可以预先冷冻，特别是在受试者由于化疗而具有低计数的树突细胞和/或T细胞的情况下。
还进一步考虑，在需要预测免疫应答的情况下，可以在患者接受免疫疗法之前进行抽血。另一方面，在患者已经接种抗癌疫苗的情况下，可以在首次接种疫苗后的1至7天、或7至14天、或14-28天之间进行抽血。当然，应该注意的是，预计不止一次抽血和随后的分析，从而允许监测动态免疫应答(例如，其中个别测试用于监测不同的新抗原以鉴定抗原扩散，或用于监测免疫应答随时间变化的强度以确定最佳应答时间，然后切换到新的和不同的疫苗)。
一旦抽取血液并生成树突细胞，树突细胞就能够以多种方式与一种或多种抗原接触。在其他选项中，树突细胞可以暴露于一种或多种单独的纯化的抗原，暴露于至少部分纯化的含有至少两种抗原(典型地由接头肽分开)的多表位，或暴露于来自表达抗原或多表位的细胞的粗提物。在更进一步考虑的方面，抗原也可以从体外转录/翻译反应制备，并且由此制备的抗原可直接用于转录/翻译混合物中或被进一步纯化。在合适的暴露时间后，通常在2-6小时之间，或在6-12小时之间，或在12-24小时之间(并且在一些情况下甚至更长)，T细胞将被添加到经脉冲的树突细胞中。最典型地，T细胞相对于树突细胞以约10:1、或7:1、或5:1、或3:1、或1:1、或1:3、或1:5、或1:7、或1:10的比率存在。在需要时，T细胞暴露于致敏的树突细胞可进一步包括一种或多种免疫刺激细胞因子。
无论具体暴露情况如何，如此激活的T细胞随后在含有细胞因子组合物的扩增培养基中扩增(在使用Ficoll梯度进行可选分离之后)，以优先刺激激活的T细胞的细胞分裂。最典型地，细胞因子组合物将包含IL7、IL15和IL21，或IL7/N803/IL21 TxM。扩增将在约7-20天的时间段内进行，通常持续不到两周，每2-5天(例如，3-4天)更换一次培养基。
在抗原反应性T细胞的扩增结束后，可以使用本领域众所周知的各种方法随后确定抗原反应性T细胞群。然而，通常优选该测定将使用ELISPOT测定和/或FACS测定，其中将包含MHC结合的新抗原的经标记构建体用作荧光标记物，如下文更详细描述的。正如将容易理解的，这样的方法不仅提供定性结果，而且还可用于对受试者中的免疫应答进行量化。最典型地，建立反映或预测免疫应答的阈值(例如，在扩增培养物中以至少0.5％、或至少1.0％、或至少1.5％、或至少3％的丰度存在的扩增的抗原反应性T细胞)。
实例
以下实例使用CMV作为人类病毒疫苗的模型系统，CMV是一种常见且表征良好的病毒。特别地，65kDa下基质磷蛋白(pp65)是包膜亚病毒颗粒的主要成分，并且是CD4和CD8 T细胞均识别的免疫显性抗原，如图1示意性所示的。对于下面介绍的研究，使用了全长序列，其中重叠序列的肽库跨越整个序列(例如，长度为15个氨基酸，重叠11个氨基酸)，以及选定的肽(例如，pp65495-503，其在体外进行转录和翻译)，如图2示例性所示的。对于细胞，除非另有说明，否则使用来自CMV血清阳性的、HLA A2 0201阳性的受试者的外周血。使用ELISPOT测定和FACS进行细胞检测和量化，其中使用与pp65495-503肽结合的MHC(HLA A2 0201)修饰的右旋聚体进行激活的T细胞染色，如图3示意性所示的。
虽然合成肽可用于所有单一肽，但以下实例使用了由构建体产生的重组pp65495-503肽，如图4所示的。在这里，制备合成核酸并将其与通用启动子引物杂交以生成有义链RNA，该有义链RNA在体外被翻译成相应的肽(在这里，在N-末端和C-末端有3个额外的氨基酸)。除非另有说明，否则从外周血单核细胞生成树突细胞，外周血单核细胞和T细胞的分离/富集，细胞培养，ELISPOT和FACS分析遵循本领域已知的标准方法。使用IL7/N803/IL21 TxM扩增抗原反应性细胞(如US 2019/0300591中所述，将其通过引用并入本文)。
更特别地，使用静脉穿刺从两名CMV血清阳性的、HLA A2 0201阳性的受试者中抽取外周血。使用EasySepTM人单核细胞分离试剂盒(可商购自干细胞技术公司(Stem cellTechnologies))或按照其他已知的基于CD14的富集方法从PBMC中分离单核细胞。为了使单核细胞进一步成熟和分化为树突细胞，使用了IL-4、GM-CSF和TNF-α。为此，用CellXVivo人单核细胞衍生的DC分化试剂盒(可商购自RD系统公司(RD Systems))处理单核细胞。
然后将如此制备的树突细胞暴露于作为如下的pp65：全长蛋白(参见下面的全长序列)、多表位(参见下面的全长序列)、表达pp65的重组大肠杆菌的粗细胞裂解物、His纯化的pp65、如上所述的pp65肽库、或pp65495-503肽片段(参见图3)。特定地，并且关于图5，通过流式细胞术测量由同一HLA-A2、CMV血清阳性的受试者生成的PBMC(左栏)和T细胞系(右栏)中pp65495-503反应性T细胞的频率。在这里，将细胞用对人HLA-A2呈递的pp65495-503肽特异的右旋聚体(Immudex公司(Immudex.com))与抗CD8抗体一起标记。对照右旋聚体(对照-dex)是不含肽的右旋聚体。图5中的顶部分图示出了细胞的散射(前向散射-FSC；侧向散射-SSC)特性，中间分图示出了用对照右旋聚体进行的标记。下分图示出了用pp65495-503右旋聚体(NLV-dex)进行的标记。
图6A和6B描绘了通过ELISPOT测量的，由同一HLA-A2、CMV血清阳性的受试者生成的PBMC和T细胞系中pp65495-503反应性T细胞的频率。图6A示出了来自HLA-A2、CMV血清阳性的受试者的PBMC的结果，将PBMC用跨越CMV pp65(肽库)或pp65495-503肽(495-503)序列的重叠肽库(长度为11个氨基酸)进行脉冲。使用ELISPOT检测分泌IFN-γ的细胞。图6B描绘了使用跨越CMV pp65序列的重叠肽库(长度为11个氨基酸)生成的T细胞系的结果，评估了T细胞系的pp65495-503肽反应性T细胞的频率。用抗原(体外转录和翻译的肽495-503，又名NLV)或对照抗原(体外转录和翻译的对照肽)对抗原呈递细胞(自体单核细胞衍生的树突细胞)进行脉冲。然后将经脉冲的APC与T细胞系一起培养，并使用ELISPOT通过IFN-γ分泌检测抗原反应性T细胞的频率。
从图5可以容易地看出，抗原反应性T细胞在外周血中以相对较低的频率存在，但可以通过在体外生成短期T细胞系来富集。更特别地，如图7所示，单核细胞衍生的树突细胞在与抗原(在这里是作为如下的pp65：全长蛋白(参见下面的全长序列)、多表位(参见下面的全长序列)、表达pp65的重组大肠杆菌的粗细胞裂解物、His纯化的pp65、如上所述的pp65肽库、或pp65495-503肽片段)接触后将激活T细胞。更特定地，用培养基(含有10％胎牛血清的RPMI)中的抗原以先前确定的刺激T细胞的浓度对树突细胞进行脉冲(16小时)。洗涤经脉冲的树突细胞，计数，然后以1:5的树突细胞与T细胞的比率添加。请注意，图中使用的术语“组合因子(combokine)”是指单独的细胞因子IL-7、N-803、IL-21的混合物。有趣的是，当使用TxM(具有IL-7/15/21部分，如US 2019/0300591中所述，将其通过引用并入本文)时，与IL-7、N-803、IL-21的组合相比，获得了基本相同的结果。
然后使用标准ELISPOT测定以及FACS分析，使用荧光标记的右旋聚体检测和/或量化抗原反应性T细胞，该右旋聚体用与肽抗原(例如，pp65495-503肽片段)结合的MHC修饰。从图7所示的FACS结果可以看出，在激活的T细胞扩增后可以检测和量化抗原反应性T细胞。图8描绘了扩增的抗原反应性T细胞(短期T细胞系)的另外的示例性结果，其中图3的右旋聚体用于检测和量化一定比例的抗原反应性细胞。在这里，这些实例说明了与肽库(参见图2)、全长pp65蛋白(作为粗提物或作为分离的蛋白)和重组多表位(参见下面的多表位序列)(作为粗提物或作为分离的多表位)一起孵育的树突细胞的结果。很明显，肽库和分离的多表位在引发显著的免疫应答方面是有效的，这反映了重组多表位疫苗。
特别地，如上文针对图7所述生成T细胞系。pp65495-503反应性T细胞的频率是如图5和图7中使用NLV-右旋聚体和流式细胞术测定的。选择以椭圆形圈出的细胞系是因为它们的pp65495-503反应性T细胞的频率相对更高，因此，当通过体外转录和翻译提供肽时，它们可以用于评估肽反应性，如图9所示。在这里，图9描绘了干扰素-γ的示例性结果，再次证明肽库和分离的多表位在引发显著的免疫应答方面是有效的。更特别地，使用ELISPOT测定pp65495-503反应性T细胞的频率。用抗原对自体单核细胞衍生的树突细胞进行脉冲(如下面的条形图所示)，然后添加T细胞(树突细胞与T细胞的比率为1:5)并测量IFN-γ分泌。虚线表示不添加抗原时，即仅添加培养基时，IFN-γ斑点形成细胞(SFC)的频率。
此外，从图10所示的关键数据可以看出，用大肠杆菌表达的多表位生成的T细胞(与图9的中间分图中生成的那些T细胞相同)使得这些T细胞可以识别来自该多表位的多个表位。进一步参考图10，应当理解，表位E1、E6和E9被T细胞系中的T细胞识别。图11示出了为图10中测试的ELISPOT翻译的肽的氨基酸序列。这样的结果有力地表明，用大肠杆菌(LPS缺陷型)中表达的T细胞表位的多表位生成的T细胞实际上是由具有多种特异性的T细胞组成的。预计这种类型的结果将在患者新表位和患者血液中重复。
序列
pp65全长蛋白的氨基酸序列如SEQ ID NO:1所示。
pp65多表位(具有柔性接头的31聚体)的氨基酸序列如SEQ ID NO:2所示。计算出的多表位内序列的结合亲和力如下所示：
表1
表2
下面描绘了用于在体外产生新表位肽的示例性合成DNA模板，并且相应的序列分别如SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20和SEQ ID NO:21所示。表3列出了在图10的实验中使用的多种其他序列构建体。
表3
如图4所示，只要启动子在+1上是双链的，使用单链寡核苷酸模板进行体外转录就是有效的。使用每个表位一个模板链寡核苷酸加上有义链通用启动子寡核苷酸。DNA模板无需酶操作、纯化、克隆。相反，该反应只需要将退火的寡核苷酸添加到表达混合物中，并允许混合物反应2小时。在如图3所示的用于在体外产生新表位肽的示例性方法中，使用pp65NLV表位+/-3个氨基酸，3XFlag用作对照，SPR测得的浓度为约10mg/mL，并且使用20mL反应体积重构大肠杆菌偶联的转录/翻译系统(NEB PURExpress)。
如本文所使用的，术语“施用”药物组合物或药物是指直接和间接施用药物组合物或药物，其中直接施用药物组合物或药物通常通过健康护理专业人员(例如，医师、护士等)进行，并且其中间接施用包括向健康护理专业人员提供药物组合物或药物或使健康护理专业人员可用药物组合物或药物的步骤，以用于直接施用(例如，经由注射、输注、口服递送、局部递送等)。还应注意，术语“预后”或“预测”病状、疾病发展的易感性或对预期治疗的应答旨在涵盖进行预测或预测病状、易感性和/或应答(包括受试者中病状的进展速度、改善和/或持续时间)的行为(但不包括治疗行为或诊断行为)。
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，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。除非在本文中另外指示或另外明显地与上下文矛盾，否则本文所述的所有方法能以任何合适顺序进行。关于本文某些实施例而提供的任何和所有实例或示例性语言(如“例如”)的应用仅旨在更好地说明本披露的全部范围，而不对另外要求保护的本发明范围做出限制。本说明书中的任何语言都不应当被解释为指示任何未要求保护的要素是实践要求保护的发明所必需的。
本领域技术人员应当清楚的是，在不背离本文所披露的概念的全部范围的情况下，除了已经描述的那些以外，还可以进行许多其他修改。因此，本披露主题仅受限于所附权利要求的范围。此外，在解释本说明书和权利要求时，所有术语都应当以与上下文一致的尽可能广泛的方式来解释。特别地，术语“包含/包括”(“comprises”和“comprising”)应当被解释为以非排他性方式提及要素、组分或步骤，从而指示所提及的要素、组分或步骤可以与未明确提及的其他要素、组分或步骤一起存在、或使用、或组合。在本说明书的权利要求提及选自由A、B、C……和N组成的组的某物中的至少一种的情况下，该文本应当被解释为仅需要该组中的一种要素，而不是A加N或B加N等。
<110> 南特细胞公司（NantBio Inc）
<120> 对患者新表位有应答的T细胞
<130> 102719.0027PCT
<150> 62/992,794
<151> 2020-03-20
<150> 63/003,496
<151> 2020-04-01
<160> 32
<170> PatentIn 3.5版
<210> 1
<211> 624
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<220>
<223> pp65全长蛋白
<400> 1
Met Ala Ser Val Leu Gly Pro Ile Ser Gly His Val Leu Lys Ala Val
1 5 10 15
Phe Ser Arg Gly Asp Thr Pro Val Leu Pro His Glu Thr Arg Leu Leu
20 25 30
Gln Thr Gly Ile His Val Arg Val Ser Gln Pro Ser Leu Ile Leu Val
35 40 45
Ser Gln Tyr Thr Pro Asp Ser Thr Pro Cys His Arg Gly Asp Asn Gln
50 55 60
Leu Gln Val Gln His Thr Tyr Phe Thr Gly Ser Glu Val Glu Asn Val
65 70 75 80
Ser Val Asn Val His Asn Pro Thr Gly Arg Ser Ile Cys Pro Ser Gln
85 90 95
Glu Pro Met Ser Ile Tyr Val Tyr Ala Leu Pro Leu Lys Met Leu Asn
100 105 110
Ile Pro Ser Ile Asn Val His His Tyr Pro Ser Ala Ala Glu Arg Lys
115 120 125
His Arg His Leu Pro Val Ala Asp Ala Val Ile His Ala Ser Gly Lys
130 135 140
Gln Met Trp Gln Ala Arg Leu Thr Val Ser Gly Leu Ala Trp Thr Arg
145 150 155 160
Gln Gln Asn Gln Trp Lys Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe
165 170 175
Val Phe Pro Thr Lys Asp Val Ala Leu Arg His Val Val Cys Ala His
180 185 190
Glu Leu Val Cys Ser Met Glu Asn Thr Arg Ala Thr Lys Met Gln Val
195 200 205
Ile Gly Asp Gln Tyr Val Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp
210 215 220
Val Pro Ser Gly Lys Leu Phe Met His Val Thr Leu Gly Ser Asp Val
225 230 235 240
Glu Glu Asp Leu Thr Met Thr Arg Asn Pro Gln Pro Phe Met Arg Pro
245 250 255
His Glu Arg Asn Gly Phe Thr Val Leu Cys Pro Lys Asn Met Ile Ile
260 265 270
Lys Pro Gly Lys Ile Ser His Ile Met Leu Asp Val Ala Phe Thr Ser
275 280 285
His Glu His Phe Gly Leu Leu Cys Pro Lys Ser Ile Pro Gly Leu Ser
290 295 300
Ile Ser Gly Asn Leu Leu Met Asn Gly Gln Gln Ile Phe Leu Glu Val
305 310 315 320
Gln Ala Ile Arg Glu Thr Val Glu Leu Arg Gln Tyr Asp Pro Val Ala
325 330 335
Ala Leu Phe Phe Phe Asp Ile Asp Leu Leu Leu Gln Arg Gly Pro Gln
340 345 350
Tyr Ser Glu His Pro Thr Phe Thr Ser Gln Tyr Arg Ile Gln Gly Lys
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Leu Glu Tyr Arg His Thr Trp Asp Arg His Asp Glu Gly Ala Ala Gln
370 375 380
Gly Asp Asp Asp Val Trp Thr Ser Gly Ser Asp Ser Asp Glu Glu Leu
385 390 395 400
Val Thr Thr Glu Arg Lys Thr Pro Arg Val Thr Gly Gly Gly Ala Met
405 410 415
Ala Gly Ala Ser Thr Ser Ala Gly Arg Lys Arg Lys Ser Ala Ser Ser
420 425 430
Ala Thr Ala Cys Thr Ala Gly Val Met Thr Arg Gly Arg Leu Lys Ala
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Glu Ser Thr Val Ala Pro Glu Glu Asp Thr Asp Glu Asp Ser Asp Asn
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Glu Ile His Asn Pro Ala Val Phe Thr Trp Pro Pro Trp Gln Ala Gly
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Ile Leu Ala Arg Asn Leu Val Pro Met Val Ala Thr Val Gln Gly Gln
485 490 495
Asn Leu Lys Tyr Gln Glu Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg
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Ile Phe Ala Glu Leu Glu Gly Val Trp Gln Pro Ala Ala Gln Pro Lys
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Arg Arg Arg His Arg Gln Asp Ala Leu Pro Gly Pro Cys Ile Ala Ser
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Thr Pro Lys Lys His Arg Gly Ala Ala Ala Ala Glu Val Ser Gly Leu
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Glu Gln Leu Glu Ser Ile Ile Asn Phe Glu Lys Leu Thr Glu Trp Thr
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Ser Ser Asn Val Ala Ala Ala Ala Met Thr Glu Gln Gln Trp Asn Phe
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Ala Gly Ile Glu Ala Ala Ala Ser Ala Ile Gln Gly Asn Val Thr Ser
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Ile His Ser Leu Leu Asp Ala Ala Ala Ala His His His His His His
610 615 620
<210> 2
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<212> PRT
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<220>
<223> pp65多表位（具有柔性接头的31聚体）
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Met Leu Pro His Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val Arg
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Val Ser Gln Pro Ser Leu Ile Leu Val Ser Gln Tyr Thr Pro Asp Ser
20 25 30
Gly Pro Gly Pro Gly Cys Pro Ser Gln Glu Pro Met Ser Ile Tyr Val
35 40 45
Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser Ile Asn Val His
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His Tyr Pro Ser Gly Pro Gly Pro Gly Val Ala Asp Ala Val Ile His
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Ala Ser Gly Lys Gln Met Trp Gln Ala Arg Leu Thr Val Ser Gly Leu
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Ala Trp Thr Arg Gln Gln Asn Gln Gly Pro Gly Pro Gly Gln Gln Asn
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Gln Trp Lys Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro
115 120 125
Thr Lys Asp Val Ala Leu Arg His Val Val Cys Ala Gly Pro Gly Pro
130 135 140
Gly Gln Val Ile Gly Asp Gln Tyr Val Lys Val Tyr Leu Glu Ser Phe
145 150 155 160
Cys Glu Asp Val Pro Ser Gly Lys Leu Phe Met His Val Thr Leu Gly
165 170 175
Pro Gly Pro Gly Thr Arg Asn Pro Gln Pro Phe Met Arg Pro His Glu
180 185 190
Arg Asn Gly Phe Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys Pro
195 200 205
Gly Lys Ser Gly Pro Gly Pro Gly Ile Ser His Ile Met Leu Asp Val
210 215 220
Ala Phe Thr Ser His Glu His Phe Gly Leu Leu Cys Pro Lys Ser Ile
225 230 235 240
Pro Gly Leu Ser Ile Ser Gly Gly Pro Gly Pro Gly Thr Val Glu Leu
245 250 255
Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe Phe Phe Asp Ile Asp Leu
260 265 270
Leu Leu Gln Arg Gly Pro Gln Tyr Ser Glu His Gly Pro Gly Pro Gly
275 280 285
Trp Pro Pro Trp Gln Ala Gly Ile Leu Ala Arg Asn Leu Val Pro Met
290 295 300
Val Ala Thr Val Gln Gly Gln Asn Leu Lys Tyr Gln Glu Phe Phe Gly
305 310 315 320
Pro Gly Pro Gly Gln Glu Phe Phe Trp Asp Ala Asn Asp Ile Tyr Arg
325 330 335
Ile Phe Ala Glu Leu Glu Gly Val Trp Gln Pro Ala Ala Gln Pro Lys
340 345 350
Arg Arg Arg Gly Pro Gly Pro Gly Ser Ile Pro Gly Leu Ser Ile Ser
355 360 365
Gly Asn Leu Leu Met Asn Gly Gln Gln Ile Phe Leu Glu Val Gln Ala
370 375 380
Ile Arg Glu Thr Val Glu Leu His His His His His His
385 390 395
<210> 3
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<212> PRT
<213> 人工序列
<220>
<223> PP65肽
<400> 3
Asn Leu Val Pro Met Val Ala Thr Val
1 5
<210> 4
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽2
<400> 4
Tyr Thr Ser Ala Phe Val Phe Pro Thr
1 5
<210> 5
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽3
<400> 5
Arg Ile Phe Ala Glu Leu Glu Gly Val
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽4
<400> 6
Leu Met Asn Gly Gln Gln Ile Phe Leu
1 5
<210> 7
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽5
<400> 7
Met Leu Asn Ile Pro Ser Ile Asn Val
1 5
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽6
<400> 8
Gln Met Trp Gln Ala Arg Leu Thr Val
1 5
<210> 9
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽7
<400> 9
Arg Leu Leu Gln Thr Gly Ile His Val
1 5
<210> 10
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽8
<400> 10
Ser Ile Tyr Val Tyr Ala Leu Pro Leu
1 5
<210> 11
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽9
<400> 11
Ala Leu Phe Phe Phe Asp Ile Asp Leu
1 5
<210> 12
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽10
<400> 12
Ile Met Leu Asp Val Ala Phe Thr Ser
1 5
<210> 13
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PP65肽11
<400> 13
Tyr Leu Glu Ser Phe Cys Glu Asp Val
1 5
<210> 14
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> PP65肽12
<400> 14
Thr Gly Ile His Val Arg Val Ser Gln Pro Ser Leu Ile Leu Val Ser
1 5 10 15
Gln
<210> 15
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> PP65肽13
<400> 15
Ser His Glu His Phe Gly Leu Leu Cys Pro Lys Ser Ile Pro Gly Leu
1 5 10 15
<210> 16
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> PP65肽14
<400> 16
Glu Arg Asn Gly Phe Thr Val Leu Cys Pro Lys Asn Met Ile Ile Lys
1 5 10 15
<210> 17
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> PP65肽15
<400> 17
Tyr Ala Leu Pro Leu Lys Met Leu Asn Ile Pro Ser Ile Asn Val His
1 5 10 15
His
<210> 18
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 转录序列1
<400> 18
cttctaatac gactcactat ag 22
<210> 19
<211> 104
<212> DNA
<213> 人工序列
<220>
<223> 转录序列2
<400> 19
gaagattatg ctgagtgata tcccgaattc atattcctcc ttatttatac gaacgtgcat 60
tagaacatgg ataccaacgt tgacaagttc cagttatcat tact 104
<210> 20
<211> 83
<212> RNA
<213> 人工序列
<220>
<223> 转录序列3
<400> 20
gggcuuaagu auaaggagga auaaauaugc uugcacguaa ucuuguaccu augguugcaa 60
cuguucaagg ucaauaguaa uga 83
<210> 21
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 转录序列4
<400> 21
Met Leu Ala Arg Asn Leu Val Pro Met Val Ala Thr Val Gln Gly Gln
1 5 10 15
<210> 22
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽1
<400> 22
Glu Thr Arg Leu Leu Gln Thr Gly Ile His Val Arg Val Ser Gln Pro
1 5 10 15
Ser Leu Ile Leu Val Ser Gln Tyr Thr
20 25
<210> 23
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽2
<400> 23
Gln Glu Pro Met Ser Ile Tyr Val Tyr Ala Leu Pro Leu Lys Met Leu
1 5 10 15
Asn Ile Pro Ser Ile Asn Val His His
20 25
<210> 24
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽3
<400> 24
Ala Val Ile His Ala Ser Gly Lys Gln Met Trp Gln Ala Arg Leu Thr
1 5 10 15
Val Ser Gly Leu Ala Trp Thr Arg Gln
20 25
<210> 25
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽4
<400> 25
Gln Trp Lys Glu Pro Asp Val Tyr Tyr Thr Ser Ala Phe Val Phe Pro
1 5 10 15
Thr Lys Asp Val Ala Leu Arg His Val
20 25
<210> 26
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽5
<400> 26
Ile Gly Asp Gln Tyr Val Lys Val Tyr Leu Glu Ser Phe Cys Glu Asp
1 5 10 15
Val Pro Ser Gly Lys Leu Phe Met His
20 25
<210> 27
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽6
<400> 27
Phe Met Arg Pro His Glu Arg Asn Gly Phe Thr Val Leu Cys Pro Lys
1 5 10 15
Asn Met Ile Ile Lys Pro Gly Lys Ile
20 25
<210> 28
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽7
<400> 28
Ile Met Leu Asp Val Ala Phe Thr Ser His Glu His Phe Gly Leu Leu
1 5 10 15
Cys Pro Lys Ser Ile Pro Gly Leu Ser
20 25
<210> 29
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽8
<400> 29
Leu Arg Gln Tyr Asp Pro Val Ala Ala Leu Phe Phe Phe Asp Ile Asp
1 5 10 15
Leu Leu Leu Gln Arg Gly Pro Gln Tyr
20 25
<210> 30
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽9
<400> 30
Trp Gln Ala Gly Ile Leu Ala Arg Asn Leu Val Pro Met Val Ala Thr
1 5 10 15
Val Gln Gly Gln Asn Leu Lys Tyr Gln
20 25
<210> 31
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽10
<400> 31
Phe Trp Asp Ala Asn Asp Ile Tyr Arg Ile Phe Ala Glu Leu Glu Gly
1 5 10 15
Val Trp Gln Pro Ala Ala Gln Pro Lys
20 25
<210> 32
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> IVT&T肽11
<400> 32
Gly Leu Ser Ile Ser Gly Asn Leu Leu Met Asn Gly Gln Gln Ile Phe
1 5 10 15
Leu Glu Val Gln Ala Ile Arg Glu Thr
20 25
Claims (20)
1.一种确定先前暴露于抗原的受试者中针对该抗原的免疫应答的方法，该方法包括：
从该受试者的外周血生成树突细胞，并将这些树突细胞暴露于含抗原组合物以生成抗原呈递树突细胞；
从该受试者的外周血中分离T细胞，并使这些分离的T细胞与这些抗原呈递树突细胞接触；
将这些分离的T细胞和这些抗原呈递树突细胞暴露于含细胞因子组合物以扩增抗原反应性T细胞；以及
检测这些扩增的抗原反应性T细胞。
2.如权利要求1所述的方法，其中先前暴露于该抗原的该受试者是先前暴露于含有该抗原的疫苗的受试者。
3.如权利要求2所述的方法，其中含有该抗原的该疫苗是重组病毒疫苗、重组酵母疫苗、和/或重组细菌疫苗，并且其中该抗原是患者和肿瘤特异性新抗原。
4.如前述权利要求中任一项所述的方法，其中这些树突细胞由外周血中的单核细胞生成。
5.如前述权利要求中任一项所述的方法，其中该含抗原组合物中的该抗原是患者和肿瘤特异性新抗原。
6.如前述权利要求中任一项所述的方法，其中该含抗原组合物中的该抗原是含有新抗原的全长蛋白。
7.如前述权利要求中任一项所述的方法，其中该含抗原组合物是重组含抗原组合物。
8.如前述权利要求中任一项所述的方法，其中该含抗原组合物包含含有多种不同抗原的多表位或源自全长蛋白的抗原库。
9.如前述权利要求中任一项所述的方法，其中该含细胞因子组合物包含IL7、IL15和IL21，或者其中该含细胞因子组合物包含IL7/N803/IL21 TxM。
10.如前述权利要求中任一项所述的方法，其中检测这些扩增的抗原反应性T细胞包括ELISPOT测定或FACS测定。
11.如前述权利要求中任一项所述的方法，该方法进一步包括向该受试者施用这些扩增的抗原反应性T细胞的步骤。
12.一种在经选择接受含有抗原的疫苗的受试者中预测可能的针对该抗原的免疫应答的方法，该方法包括：
从该受试者的外周血生成树突细胞，并将这些树突细胞暴露于含抗原组合物以生成抗原呈递树突细胞；
从该受试者的外周血中分离T细胞，并使这些分离的T细胞与这些抗原呈递树突细胞接触；
将这些分离的T细胞和这些抗原呈递树突细胞暴露于含细胞因子组合物以扩增抗原反应性T细胞；
对这些扩增的抗原反应性T细胞进行量化；以及
当这些量化的扩增的抗原反应性T细胞超过预定阈值时，将该受试者鉴定为可能的免疫应答者。
13.如权利要求12所述的方法，其中含有该抗原的该疫苗是重组病毒疫苗、重组酵母疫苗、和/或重组细菌疫苗，并且其中该抗原是患者和肿瘤特异性新抗原。
14.如权利要求12-13中任一项所述的方法，其中这些树突细胞由外周血中的单核细胞生成。
15.如权利要求12-14中任一项所述的方法，其中该含抗原组合物中的该抗原是患者和肿瘤特异性新抗原。
16.如权利要求12-15中任一项所述的方法，其中该含抗原组合物中的该抗原包含在该疫苗中。
17.如权利要求12-16中任一项所述的方法，其中该疫苗包含多种抗原，并且其中该含抗原组合物包含多种抗原作为抗原库或作为多表位，并且其中该疫苗中的该多种抗原被编码为多表位或作为多表位存在。
18.如前述权利要求中任一项所述的方法，其中该含细胞因子组合物包含IL7、IL15和IL21，或者其中该含细胞因子组合物包含IL7/N803/IL21 TxM。
19.如前述权利要求中任一项所述的方法，其中对这些扩增的抗原反应性T细胞进行量化包括ELISPOT测定或FACS测定。
20.如前述权利要求中任一项所述的方法，其中该预定阈值是在扩增培养物中以至少1.0％的丰度存在这些扩增的抗原反应性T细胞。
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| US202062992794P | 2020-03-20 | 2020-03-20 | |
| US62/992794 | 2020-03-20 | ||
| US202063003496P | 2020-04-01 | 2020-04-01 | |
| US63/003496 | 2020-04-01 | ||
| PCT/IB2021/051786 WO2021186278A1 (en) | 2020-03-20 | 2021-03-04 | T cells that respond to patient neoepitopes |
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| CN115379853A true CN115379853A (zh) | 2022-11-22 |
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| US (1) | US20230236172A1 (zh) |
| EP (1) | EP4121102A4 (zh) |
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| EP1332371A2 (en) * | 2000-09-18 | 2003-08-06 | Genzyme Corporation | Method to identify antibody targets based on mass spectrometry (maldi-tof) |
| US8071373B2 (en) * | 2004-04-28 | 2011-12-06 | Sanofi Pasteur Vaxdesign Corp. | Co-culture lymphoid tissue equivalent (LTE) for an artificial immune system (AIS) |
| AU2008323853B8 (en) * | 2007-11-08 | 2014-07-24 | Beth Israel Deaconess Medical Center | Stimulation of anti-tumor immunity using dendritic cell/tumor cell fusions and anti-CD3/CD28 |
| EP3193892A4 (en) * | 2014-09-14 | 2018-09-12 | Washington University | Personalized cancer vaccines and methods therefor |
| SG11201810332TA (en) * | 2016-05-27 | 2018-12-28 | Etubics Corp | Neoepitope vaccine compositions and methods of use thereof |
| US20200282037A1 (en) * | 2017-06-16 | 2020-09-10 | Nantbio, Inc. | Bacterial vaccine |
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- 2021-03-04 CN CN202180023211.5A patent/CN115379853A/zh active Pending
- 2021-03-04 WO PCT/IB2021/051786 patent/WO2021186278A1/en active Application Filing
- 2021-03-04 EP EP21771387.4A patent/EP4121102A4/en active Pending
- 2021-03-04 US US17/906,782 patent/US20230236172A1/en active Pending
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| Publication number | Publication date |
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| EP4121102A1 (en) | 2023-01-25 |
| EP4121102A4 (en) | 2024-04-10 |
| US20230236172A1 (en) | 2023-07-27 |
| WO2021186278A1 (en) | 2021-09-23 |
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