CN114901677A - 治疗脑癌的联合疗法 - Google Patents
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Abstract
本发明提供了用于治疗受试者脑癌的核酸分子、蛋白、合成物和方法。在某些实施例中，所述合成物包含癌抗原hTERT、WT‑1和PSMA。在某些实施例中，所述合成物进一步包含佐剂。所述方法包括向有需要受试者施用癌抗原。根据某些实施例，所述方法进一步包括施用佐剂和抗PD‑1抗体。在某些实施例中，所述方法进一步包括施用放疗和/或化疗剂。在某些实施例中，所述方法临床证明安全、临床证明有效或两种兼有。
Description
相关申请的交叉引用
本专利申请要求2020年8月27日提交的第63/070,987号美国专利申请、2020年4月30日提交的第63/018,060号美国专利申请、2020年3月11日提交的第62/988,102号美国专利申请以及2019年11月4日提交的第62/930,417号美国专利申请的权益。所述申请通过本发明的整体引用，成为本发明的一部分。
序列表
本申请包含一个以ASCII格式用电子方式提交的序列表，所述序列表通过本发明的整体引用成为本发明的一部分。所述ASCII副本创建于2020年11月4日，名为104409_000581_SL.txt，大小为89,861字节。
技术领域
本发明涉及治疗脑癌的联合疗法和方法。
背景技术
尽管胶质母细胞瘤(GBM)治疗取得了进展，但胶质母细胞瘤仍然是最致命的癌症之一。GBM目前的标准治疗方法是对患者进行手术，然后在放疗(RT)期间每天同时进行RT和替莫唑胺(TMZ)化疗，然后在完成RT后进行6-12个维持(辅助)周期[Stupp R，Mason WP，vanden Bent MJ等人，放疗加伴随和辅助替莫唑胺治疗胶质母细胞瘤。《新英格兰医学杂志》，2005，352:987-996]。
检查点抑制剂，例如程序性细胞死亡-1(PD-1)抑制剂，提高了对许多癌症的响应率，但尚未在GBM中显示出临床益处。
因此，需要确定和开发用于治疗GBM的方法来促进疾病临床管理和进展管理。此外，需要更有效的治疗方法来延缓疾病进展和/或降低癌症受试者的死亡率。
发明内容
本发明提供了用于防止或治疗癌症的疫苗和方法。所述癌症为脑癌，例如胶质母细胞瘤。所述疫苗优选包含至少三种癌抗原：hTERT、WT-1和PSMA。在某些实施例中，所述疫苗还包含佐剂(例如IL-12)和抗PD-1抗体。所述方法包括向确诊为癌症的受试者施用癌抗原(hTERT、WT-1和PSMA)、佐剂、程序性死亡受体-1(PD-1)检查点抑制剂(例如抗PD-1抗体)。在某些实施例中，所述方法防止肿瘤生长。在某些实施例中，所述方法可以减少肿瘤生长和/或质量。在某些实施例中，所述方法可以防止肿瘤细胞转移。在某些实施例中，所述方法可以提高受试者体内的细胞免疫反应。在某些实施例中，所述方法可以提高受试者的无肿瘤生存期、无进展生存期、总体生存期或其任何组合。
在某些实施例中，IL-12由DNA质粒编码，例如INO-9012或其生物仿制药或生物等效物。在某些实施例中，hTERT、WT-1和PSMA由一个或多个DNA质粒编码，例如INO-5401或其生物仿制药或生物等效物。在某些实施例中，抗PD-1抗体为西米普利单抗或其生物仿制药或生物等效物。在某些实施例中，所述方法进一步包括施用放疗和/或化疗剂，例如替莫唑胺或其生物等效物。
在某些实施例中，所述方法临床证明安全、临床证明有效或两种兼有。
附图说明
结合附图可更好地理解上述发明内容以及以下具体实施方式。为了说明所公开的方法，在附图中显示了示例性实施例；然而，这些方法不限于所公开的具体实施例。图中：
图1显示了示例的研究设计。
图2显示了示例的研究人群。
图3显示了两名患者的代表性MRI图像，表明在首剂INO-5401+INO-9012和西米普利单抗注射溶液后的时间点上MRI信号增加，有水肿或肿瘤迹象。对几名患者的活检显示了治疗相关的变化，伴有坏死和混合炎症；没有有丝分裂活性；并且没有存活肿瘤的证据。由下图中MRI图像代表的受试者在第9周显示出疾病进展的证据，但在第21周消退。在MRI上具有相似结果并接受切除术的受试者仅显示免疫浸润，没有存活肿瘤。
图4显示了ELISpot结果支持INO-5401和西米普利单抗注射溶液的组合具有免疫原性-在12个月数据截止时，5/11名受试者对所有3种抗原的IFN-g量级高于基线，9名受试者对至少一种抗原的IFN-g量级高于基线。
图5A、5B和5C显示了裂解性颗粒加载测定结果，表明在12个月数据截止时获取的具有裂解潜力(表达颗粒酶A、穿孔素)的活性、抗原特异性、活化(CD38+)CD3+CD8+T细胞的频率。图5A显示了治疗前(前段)以及使用INO-5401和西米普利单抗注射溶液治疗后在最高量级(峰值)处具有裂解潜力(表达颗粒酶A、穿孔素)的活性、抗原特异性、活化(CD38+)CD3+CD8+T细胞的频率。每名受试者用空心圆圈表示，条形表示平均值。图5B显示了各抗原图以及8名被测受试者的前段到峰值的差异(Δ)，图5C显示了在第12周采样的5名受试者从前段到峰值的差异(Δ)。INO-5401是WT1、PSMA和hTERT的总和。箱形图从第25个百分位延伸到第75个百分位数，中位数为水平线，平均值为“+”。
图6显示了队列A(O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)6个月无进展生存期(PFS6)的Kaplan-Meier估计量的可视化表示。此曲线显示了事件在特定时间间隔内的概率。y轴以数字形式表示事件概率，x轴表示时间间隔。显示的事件为无进展生存期。无进展生存期是指给定受试者在给定时间点没有疾病进展。
图7显示了队列B(具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)6个月无进展生存期(PFS6)的Kaplan-Meier估计量的可视化表示。此曲线显示事件在特定时间间隔内的概率。y轴以数字形式表示事件概率，x轴表示时间间隔。显示的事件为无进展生存期。无进展生存期是指给定受试者在给定时间点没有疾病进展。
图8显示了队列A(具有O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)和队列B(具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)6个月无进展生存期(PFS6)的Kaplan-Meier估计量的可视化表示。此曲线显示事件在特定时间间隔内的概率。y轴以数字形式表示事件概率，x轴表示时间间隔。显示的事件为无进展生存期。无进展生存期是指给定受试者在给定时间点没有疾病进展。
图9显示了队列A、队列B和两个队列组合在6个月内无进展生存期(PFS6)的Kaplan-Meier估计量的表格表示。此图提供了每个队列的受试者总数、事件数量、事件(PFS6)估计以及事件(PFS6)数值估计存在的95％置信区间(CI)。
图10A显示了队列A(具有O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)12个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。图10B显示了队列A(具有O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)18个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。队列A的中位随访时间为17.8个月。mITT包括接受≥1剂研究治疗的任何受试者。阴影表示在该时间点上基于生存点估计值的置信带。
图11A显示了队列B(具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)12个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。图11B显示了队列B(对于具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)18个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。队列B的中位随访时间为15.6个月。删失；队列B中的两名受试者在第3周撤回随访同意书。mITT包括接受≥1剂研究治疗的任何受试者。阴影表示在该时间点上基于生存点估计值的置信带。
图12显示了队列A+B 12个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。
图13显示了队列A、队列B和两个队列组合12个月和18个月总体生存期的疗效数据。此图显示了在12个月和18个月时报告存活的受试者总数。此图提供了受试者总数、事件(OS12或OS18)估计以及事件(OS12或OS18)数值估计存在的95％置信区间(CI)。使用Clopper-Pearson精确方法计算95％CI。
图14显示了示例中≥NCI CTCAE 3级的临床研究方案定义的所有不良事件。
图15显示了示例中临床研究方案定义的免疫相关不良事件。
图16A和16B显示了在18个月数据截止时，按队列总结的ELISpot结果。在队列A中，迄今为止测试的19/22(86％)名受试者对一种或多种抗原INO-5401的IFN-g量级高于基线(图16A)。在队列B中，迄今为止测试的16/17(94％)名受试者对一种或多种抗原INO-5401的IFN-g量级高于基线(图16B)。对治疗后峰值时间点的基线值进行绘制。在Q3周采样4次，然后在Q12周采样。
图17A和17B显示了在18个月数据截止时，通过流式细胞术(具有裂解潜力的抗原特异性CD8+T细胞的扩增)按队列总结的INO-5401后外周免疫反应的评估结果。在队列A中，迄今为止测试的13/19(68％)名受试者对INO-5401中一种或多种抗原的CD38+GrzA+Prf+CD8+T细胞频率高于基线(图17A)。在队列B中，迄今为止测试的8/10(80％)名受试者对INO-5401中一种或多种抗原的CD38+GrzA+Prf+CD8+T细胞频率高于基线(图17B)。对治疗后峰值时间点的基线值进行绘制。在Q3周采样4次，然后在Q12周采样。
具体实施方式
本发明所公开的核酸分子、蛋白、疫苗和方法可以通过参考以下具体实施方式并结合附图而更容易理解，这些附图构成本发明的一部分。应当理解的是，所公开的核酸分子、蛋白、疫苗和方法不限于本发明所述和/或所示的特定核酸分子、蛋白、疫苗和方法，并且本发明所用术语仅用于通过示例描述特定实施例，并不旨在限制所要求的核酸分子、蛋白、疫苗和方法。
除非另有明确规定，否则任何关于可能的作用机制或方式或改进原因的描述仅用于说明，所公开的核酸分子、蛋白、疫苗和方法不受任何此类建议的作用机制或方式的正确性或不正确性或改进原因的限制。
在本发明中，所描述的对象是指合成物以及使用所述合成物的方法。如果本发明描述或要求与合成物相关的特征或实施例，此类特征或实施例同样适用于使用所述合成物的方法。同样，如果本发明描述或要求与使用合成物相关的特征或实施例，此类特征或实施例同样适用于所述合成物。
应理解的是，为了清楚起见，还可在单个实施例中组合提供在单独实施例背景中描述的所述核酸分子、蛋白、疫苗和方法的某些特征。
相反，为了简洁起见，还可单独提供或以任何子组合提供在单个实施例背景中描述的所述核酸分子、蛋白、疫苗和方法的各种特征。
本发明提供了用于防止或治疗癌症的疫苗和方法。所述癌症为脑癌，例如胶质母细胞瘤。所述疫苗优选包含至少三种癌抗原：hTERT、WT-1和PSMA。在某些实施例中，所述疫苗还包含佐剂(例如IL-12)和抗PD-1抗体。所述方法包括向有需要受试者施用癌抗原(hTERT、WT-1和PSMA)、佐剂、程序性死亡受体-1(PD-1)检查点抑制剂(例如抗PD-1抗体)。在某些实施例中，所述方法防止肿瘤生长。在某些实施例中，所述方法可以减少肿瘤生长和/或质量。在某些实施例中，所述方法可以防止肿瘤细胞转移。在某些实施例中，所述方法可以提高受试者体内的细胞免疫反应。在某些实施例中，所述方法可以提高受试者的无肿瘤生存期、无进展生存期、总体生存期或其任何组合。
在某些实施例中，IL-12由DNA质粒编码，例如INO-9012或其生物仿制药或生物等效物。在某些实施例中，hTERT、WT-1和PSMA由一个或多个DNA质粒编码，例如INO-5401或其生物仿制药或生物等效物。在某些实施例中，抗PD-1抗体为西米普利单抗或其生物仿制药或生物等效物。在某些实施例中，所述方法进一步包括施用放疗和/或化疗剂，例如替莫唑胺或其生物等效物。
在某些实施例中，所述方法临床证明安全、临床证明有效或两种兼有。
重组癌抗原可诱导抗原特异性T细胞和/或高效价抗体反应，从而诱导或诱发针对表达抗原的癌症或肿瘤的免疫反应。在某些实施例中，所述诱导或诱发的免疫反应可以是细胞免疫反应、体液免疫反应或细胞免疫反应和体液免疫反应。在某些实施例中，所述诱导或诱发的细胞免疫反应可包括干扰素-γ(IFN-γ)和/或肿瘤坏死因子α(TNF-α)的诱导或分泌。在其他实施例中，所述诱导或诱发的免疫反应可减少或抑制一种或多种免疫抑制因子，这些因子促进表达抗原的肿瘤或癌症的生长，包括但不限于，下调MHC呈递的因子、上调抗原特异性调节性T细胞(Treg)的因子、PD-L1、FasL、细胞因子(例如IL-10和TFG-β)、肿瘤相关巨噬细胞、肿瘤相关成纤维细胞、免疫抑制细胞产生的可溶性因子、CTLA-4、PD-1、MDSC、MCP-1和免疫检查点分子。
除非另有说明，否则本发明所用的所有技术和科学术语均具有本领域普通技术人员公知的相同含义。如有冲突，应以本发明文件(包括定义)为准。示例性方法和材料如下所述，尽管与本发明所述的方法和材料类似或等效的方法和材料可用于本发明的实践或测试。本发明提及的所有出版物、专利申请、专利和其他参考通过本发明的整体引用，成为本发明的一部分。本发明所述的材料、方法和示例仅仅用于说明，而非对其进行限制。本发明使用的术语仅用于描述特定实施例，而非加以限制。
在本发明中，术语“包括(comprise)”、“包括(include)”、“具有(having)”、“具有(has)”、“可以”、“包含”及其变体应视为不排除其他动作或结构可能性的开放式过渡短语、术语或词语。除非上下文另有明确说明，否则单数形式“一个(a)”、“一个(an)”和“所述(the)”包括复数指称对象。本发明还考虑了“包括本发明所述实施例或要素”、“由本发明所述实施例或要素构成”和“基本上由本发明所述实施例或要素构成”的其他实施例，无论是否明确规定。
为了复述本发明的数值范围，明确考虑了具有相同精确度的数值范围其间的每个中间数字。例如，对于范围6-9，除6和9之外，还考虑了7和8，对于范围6.0-7.0，明确考虑了数字6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9和7.0。
本发明给出的一些定量表达不限定于术语“约”。应理解的是，无论是否明确使用术语“约”，给出的每个数量是指实际的给定值，也是指根据本领域普通技术合理推断的此类值的近似值，包括由于此类值的实验和/或测量条件而产生的近似值。
在本发明中，“佐剂”是指添加到本发明所述的免疫原性合成物中以增强由核酸分子编码的抗原和下文所述的编码核酸序列的免疫原性。
“生物仿制药”(经批准的参考产品/生物药物，即参考上市药物)是指与参考产品高度相似的生物产品，尽管临床非活性成分上存在细微差异，但生物仿制药和参考产品在安全性、纯度和效力方面没有临床意义差异，基于以下来源的数据(a)分析研究证明生物产品与参考产品高度相似，尽管临床非活性成分上存在细微差异；(b)动物研究(包括毒性评估)；和/或(c)临床研究(包括免疫原性和药代动力学或药效学的评估)，足以证明在一种或多种适当使用条件下的安全性、纯度和效力，其中参考产品已获得许可并预计使用，并且为生物仿制药寻求许可。生物仿制药可以是一种可互换的产品，可以在药房替代参考产品，而无需开具处方的医护专业人员的干预。为了满足“可互换性”的其他标准，预计生物仿制药将在任何特定患者中产生与参考产品相同的临床结果，如果生物仿制药对个体进行多次给药，则在使用生物仿制药和参考产品之间交替或切换的安全性或疗效降低方面的风险不大于在没有此类交替或切换的情况下使用参考产品的风险。生物仿制药在参考产品已知机制的范围内，对拟议的使用条件采用相同的作用机制。对于参考产品，先前已批准了生物仿制药拟议的标签中规定、推荐或建议的使用条件。生物仿制药的给药途径、剂型和/或强度与参考产品相同，生物仿制药在符合标准的环境中生产、加工、包装或保存，旨在确保生物仿制药继续保持安全、纯净和有效。与参考产品相比，生物仿制药可能包含氨基酸序列中的微小修饰，例如预计不会改变生物仿制药性能的N端或C端截断。
在本发明中，术语“抗体”包括免疫球蛋白分子(包含四个多肽链、通过二硫键互连的两个重(H)链和两个轻(L)链)及其多聚体(例如IgM)。在典型抗体中，每个重链包含一个重链可变区(在本发明中简称为HCVR或VH)和一个重链恒定区。重链恒定区包含三个结构域，CH1、CH2和CH3。每个轻链包含一个轻链可变区(在本文中简称为LCVR或VL)和一个轻链恒定区。轻链恒定区包含一个结构域(CL1)。VH和VL区可进一步细分为高可变性区(称为互补决定区(CDR))以及散布的更保守区域(称为框架区(FR))。每个VH和VL由三个CDR和四个FR组成，从氨基末端到羧基末端的排列顺序如下：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本发明的不同实施例中，抗体的FR(或其抗原结合部分)可与人种系序列相同，或可进行天然或人工修饰。可根据两个或多个CDR的并排分析，定义氨基酸共有序列。
在本发明中，术语“抗体”还包括完整抗体分子的抗原结合片段。在本发明中，抗体的“抗原结合部分”、抗体的“抗原结合片段”等包括任何天然、可酶促获得、合成或基因工程多肽或糖蛋白，其可特异性结合抗原形成复合物。采用任何适当的标准技术，如蛋白水解或重组基因工程技术(涉及DNA编码抗体可变结构域和可选恒定结构域的操作和表达)，抗体的抗原结合片段可衍生自完整抗体分子。此类DNA已知和/或容易从商业来源、DNA库(包括噬菌体库)获得，也可合成。可通过化学方式或采用分子生物学技术对DNA进行测序和操作，例如，以将一个或多个可变结构域和/或恒定结构域安排到适当的构型中，或引入密码子，形成半胱氨酸残基，修饰、添加或删除氨基酸等。
抗原结合片段的非限制性示例包括：(i)Fab片段；(ii)F(ab')2片段；(iii)Fd片段；(iv)Fv片段；(v)单链Fv(scFv)分子；(vi)dAb片段；以及(vii)由模拟抗体高变区的氨基酸残基组成的最小识别单位(例如分离互补决定区(CDR)，如CDR3肽)，或受限的FR3-CDR3-FR4肽。其他工程分子，例如结构域特异性抗体、单结构域抗体、域缺失抗体、嵌合抗体、CDR移植抗体、双体、三体、四体、微抗体、纳米抗体(例如单价纳米抗体，二价纳米抗体等)、小模块化免疫药物(SMIP)和鲨鱼可变IgNAR结构域，还包括在本发明所用的表达“抗原结合片段”中。
抗体的抗原结合片段通常包含至少一个可变结构域。可变结构域可以是任何大小或氨基酸合成物，并且通常包含至少一个与一个或多个框架序列相邻或在其中的CDR。在具有与VL结构域相关的VH结构域的抗原结合片段中，VH和VL结构域可以相对彼此位于任何合适的排列中。例如，可变区可以是二聚体并且包含VH-VH、VH-VL或VL-VL二聚体。或者，抗体的抗原结合片段可包含单体VH或VL结构域。
在某些实施例中，抗体的抗原结合片段可包含至少一个可变结构域，所述可变结构域与至少一个恒定结构域共价连接。可在本发明抗体的抗原结合片段内发现的可变结构域和恒定结构域的非限制性示例性构型包括：(i)VH-CH1；(ii)VH-CH2；(iii)VH-CH3；(iv)VH-CH1-CH2；(V)VH-CH1-CH2-CH3；VH-CH2-CH3；(vii)VH-CL；(Viii)VL-CH1；(ix)VL-CH2；(x)VL-CH3；(xi)VL-CH1-CH2；(xii)VL-CH2-CH2-CH3；(xiii)VL-CH2-CH3；以及(xiv)VL-CL。在可变结构域和恒定结构域的任何构型(包括上述任何示例性构型)中，可变结构域和恒定结构域可以直接相互连接，也可以通过完全或部分铰链区或连接区连接。铰链区可由至少2个(例如5、10、15、20、40、60或更多)氨基酸组成，这些氨基酸在单个多肽分子中相邻可变结构域和/或恒定结构域之间产生柔性或半柔性连接。此外，本发明中抗体的抗原结合片段可包含上述任何可变区和恒定区构型的同源二聚体或异源二聚体(或其他多聚体)，这些聚体彼此和/或与一个或多个单体VH或VL结构域非共价结合(例如通过二硫键)。
在本发明中，“编码序列”或“编码核酸”是指包含编码蛋白的核苷酸序列的核酸(RNA或DNA分子)。编码序列可进一步包含与调节元件可操作连接的起始和终止信号，包括能够引导在接受核酸的个体或哺乳动物的细胞中表达的启动子和多聚腺苷酸化信号。
在本发明中，“补体”或“互补”是指核酸可以表示Watson-Crick(例如A-T/U和C-G)或核苷酸分子的核苷酸或核苷酸类似物之间的Hoogsteen碱基配对。
在本发明中，“共有”或“共有序列”是指基于对来自不同生物体的相同基因的多个序列进行比对分析的多肽序列。可以制备编码共有多肽序列的核酸序列。可采用免疫原性合成物(包含含有共有序列的蛋白和/或编码此类蛋白的核酸分子)诱导针对抗原的广泛免疫。
在本发明中交替使用的“电穿孔”、“电通透”或“电动增强”(“EP”)是指使用跨膜电场脉冲在生物膜中诱导微观通路(孔)；它们允许生物分子(例如质粒、寡核苷酸、siRNA、药物、离子和水)从细胞膜的一侧传递到另一侧。
在本发明中，与核酸序列相关的“片段”是指编码多肽的核酸序列或其部分，所述多肽能够在哺乳动物中诱发与本发明所述抗原交叉反应的免疫反应。片段可以是选自编码下述蛋白片段的各种核苷酸序列中至少一种的DNA片段。片段可包含至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或至少95％的一个或多个下述核酸序列。在某些实施例中，片段可包含具有至少一种下述核酸序列的至少20个或更多核苷酸、至少30个或更多核苷酸、至少40个或更多核苷酸、至少50个或更多核苷酸、至少60个或更多核苷酸、至少70个或更多核苷酸、至少80个或更多核苷酸、至少90个或更多核苷酸、至少100个或更多核苷酸、至少150个或更多核苷酸、至少200个或更多核苷酸、至少250个或更多核苷酸、至少300个或更多核苷酸、至少350个或更多核苷酸、至少400个或更多核苷酸、至少450个或更多核苷酸、至少500个或更多核苷酸、至少550个或更多核苷酸、至少600个或更多核苷酸、至少650个或更多核苷酸、至少700个或更多核苷酸、至少750个或更多核苷酸、至少800个或更多核苷酸、至少850个或更多核苷酸、至少900个或更多核苷酸、至少950个或更多核苷酸或至少1000个或更多核苷酸。
在本发明中，与多肽序列相关的“片段”或“免疫原性片段”是指能够在哺乳动物中诱发与本发明所述抗原交叉反应的免疫反应的多肽。片段可以是选自以下各种氨基酸序列中至少一种的多肽片段。片段可包含至少10％、至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％或至少95％的共有蛋白。在某些实施例中，共有蛋白的片段可包含具有本发明所述蛋白序列的至少20个或更多氨基酸、至少30个或更多氨基酸、至少40个或更多氨基酸、至少50个或更多氨基酸、至少60个或更多氨基酸、至少70个或更多氨基酸、至少80个或更多氨基酸、至少90个或更多氨基酸、至少100个或更多氨基酸、至少110个或更多氨基酸、至少120个或更多氨基酸、至少130个或更多氨基酸、至少140个或更多氨基酸、至少150个或更多氨基酸、至少160个或更多氨基酸、至少170个或更多氨基酸、至少180个或更多氨基酸。
在本发明中，术语“基因构建体”是指包含编码蛋白的核苷酸序列的DNA或RNA分子。所述编码序列包含与调节元件可操作连接的起始和终止信号，包括能够引导在接受核酸分子的个体细胞中表达的启动子和多聚腺苷酸化信号。在本发明中，术语“表现形式”是指包含必要调节元件的基因构建体，所述调节元件与编码蛋白的编码序列可操作连接，以便在个体细胞中存在时，可以表达编码序列。
在本发明中，术语“同源”是指一定程度的互补性。可以是部分同源或完全同源(即一致性)。至少部分抑制完全互补序列杂交到靶核酸的部分互补序列称为使用功能术语“基本同源”。当用于指代双链核酸序列(例如cDNA或基因组克隆)时，本发明中使用的术语“基本同源”是指在低严格条件下可以与双链核酸序列中的一条链杂交的探针。当用于指代单链核酸序列时，本发明中使用的术语“基本同源”是指在低严格条件下能够杂交(即互补)单链核酸模板序列的探针。
在本发明中，在两个或以上核酸或多肽序列背景中“相同”或“一致性”是指序列在指定区域上具有指定百分比的相同残基。可以通过以下方式计算所述百分比：以最佳方式对齐两个序列，比较指定区域上的两个序列，确定两个序列中出现相同残基的位置数量以得到匹配位置数量，将匹配位置数量除以指定区域的位置总数，并将结果乘以100得到序列一致性的百分比。如果两个序列的长度不同或者序列产生一个或多个交错末端，并且指定的比较区域仅包含单个序列，则单个序列的残基包含在分母中，但不包含在计算的分子中。在比较DNA和RNA时，可将胸腺嘧啶(T)和尿嘧啶(U)视为等效。可以手动或使用计算机序列算法(例如BLAST或BLAST 2.0)计算一致性。
在本发明中，“基本互补”是指第一序列在8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、180、270、360、450、540个或更多核苷酸或氨基酸的区域上与第二序列的补体至少60％、65％、70％、75％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同，或者两个序列在严格杂交条件下杂交。
在本发明中，“基本相同”是指第一序列和第二序列在8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、180、270、360、450、540个或更多核苷酸或氨基酸的区域上至少60％、65％、70％、75％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同，或者相对于核酸，第一序列与第二序列的补体基本互补。
术语“治疗有效量”是指可在人类受试者中产生治疗效果的生物制剂、化合物或合成物的治疗有效量。治疗有效量是可以治疗、改善或预防确诊的疾病或病症，或表现出可检测治疗效果的用量。治疗有效量是产生以下一项或多项效果的用量：(a)癌症(例如胶质母细胞瘤)症状或适应症的严重程度或持续时间降低；(b)抑制肿瘤生长，或增加肿瘤坏死、肿瘤缩小和/或肿瘤消失；(c)延缓肿瘤的生长和发展；(d)抑制肿瘤转移；(e)预防肿瘤生长的复发；(f)提高癌症患者的生存期；和/或(g)与未治疗的受试者或接受单一疗法的抗癌疗法的受试者相比，常规抗癌疗法的使用或需求减少(例如减少或消除化疗剂或细胞毒素剂的使用)。受试者的精确有效量取决于受试者的体重、体型和健康状况；病症的性质和程度；以及选择给药的治疗药物。可以通过临床医生的技能和判断范围内的常规实验来确定给定情况的治疗有效量。
在本发明中，“治疗效果”是任何一种医学治疗的结果，其结果判定为理想和有益。无论结果是预期、意外、甚至是治疗的意外结果，都是如此。治疗效果也可以是临床医生或其他合格观察者指出的客观可识别的改善。
在本发明中，与核酸相关的“变体”是指(i)参考核苷酸序列的一部分或片段；(ii)参考核苷酸序列或其部分的补体；(iii)与参考核酸或其补体基本相同的核酸；或者(iv)在严格条件下与参考核酸、其补体或与其基本相同的序列杂交的核酸。变体可以是在完整基因序列或其片段的完整长度上基本相同的核酸序列。所述核酸序列可以是在基因序列或其片段的完整长度上80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％相同。
与多肽相关的“变体”是指通过氨基酸的插入、缺失或保守取代而在氨基酸序列上有所不同但保留参考多肽中至少一种生物活性的变体。变体还可以指具有氨基酸序列的蛋白，所述蛋白与具有保留至少一种生物活性的氨基酸序列的参考蛋白基本相同。变体可以是在氨基酸序列或其片段的完整长度上基本相同的氨基酸序列。所述氨基酸序列可以是在氨基酸序列或其片段的完整长度上80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％相同。
在本发明中，“载体”是指含有复制原点的核酸序列。载体可以是病毒载体、噬菌体、细菌人工染色体或酵母人工染色体。载体可以是DNA或RNA载体。载体可以是自我复制的染色体外载体，在一个实施例中，载体可以是表达质粒。所述载体可包含或包括一个或多个异源核酸序列。
在本发明中，“免疫反应”是指响应抗原引入而激活宿主免疫系统(例如哺乳动物的免疫系统)。所述免疫反应可以是细胞或体液反应，或两者兼有。
在本发明中，“核酸”或“寡核苷酸”或“多核苷酸”是指至少两个共价连接的核苷酸。单链的描述还定义了互补链的序列。因此，核酸还包含所述单链的互补链。核酸的许多变体可用于与给定核酸相同的目的。因此，核酸还包含基本相同的核酸及其补体。单链提供可以在严格杂交条件下与靶序列杂交的探针。因此，核酸还包含在严格杂交条件下杂交的探针。
核酸可以是单链或双链核酸，也可包含双链和单链序列的一部分。核酸可以是DNA(包含基因组和cDNA)、RNA或杂交，其中核酸可包含脱氧核糖核苷酸和核糖核苷酸的组合，以及碱基组合，包括尿嘧啶、腺嘌呤、胸腺嘧啶、胞嘧啶、鸟嘌呤、肌苷、黄嘌呤次黄嘌呤、异胞嘧啶和异鸟嘌呤。核酸可以通过化学合成方法或重组方法获得。
在本发明中，“可操作连接”是指基因的表达在与其空间连接的启动子的控制下。启动子可以位于其控制下的基因的5'端(上游)或3'端(下游)。在启动子所衍生的基因中，启动子和基因之间的距离可以与该启动子与其控制的基因之间的距离大致相同。如本领域已知，可以在不损失启动子功能的情况下适应此距离的变化。
在本发明中，“肽”、“蛋白”或“多肽”是指氨基酸的连接序列，并且可以是天然、合成、或天然和合成的修饰或组合。
在本发明中，“启动子”是指能够给予、激活或增强细胞中核酸表达的合成或天然衍生的分子。启动子可包含一个或多个特异性转录调控序列，进一步增强表达和/或改变其空间表达和/或时间表达。启动子还可包含末端增强子或阻遏子元件，这些元件可位于距转录起始位点多达数千个碱基对的位置。启动子可来自病毒、细菌、真菌、植物、昆虫和动物等。启动子可以在细胞、表达发生的组织或器官方面，或在表达发生的进展阶段方面，或在对外部刺激(如生理应激、病原体、金属离子或诱导剂)的反应方面，构成性或差异性调节基因成分的表达。启动子的代表性示例包括噬菌体T7启动子、噬菌体T3启动子、SP6启动子、lac操作启动子、tac启动子、SV40后期启动子、SV40早期启动子、RSV-LTR启动子、CMV IE启动子、SV40早期启动子或SV40晚期启动子以及CMV IE启动子。
“信号肽”和“前导序列”在本发明中可互换使用，并且是指可在本发明所述的蛋白氨基末端连接的氨基酸序列。信号肽/前导序列通常引导蛋白的定位。本发明使用的信号肽/前导序列可促进蛋白从其产生的细胞中分泌。信号肽/前导序列通常在从细胞分泌时从蛋白的其余部分(通常称为成熟蛋白)中切割出来。信号肽/前导序列连接在蛋白的氨基末端(即N端)。
在本发明中，短语“有需要的受试者”是指表现出一种或多种脑癌症状或适应症的人类或非人类哺乳动物，和/或已诊断患有脑癌(包括例如胶质母细胞瘤)并需要治疗的人类或非人类哺乳动物。在许多实施例中，术语“受试者”可与术语“患者”互换使用。例如，人类受试者可能确诊为患有原发性或转移性肿瘤和/或具有一种或多种症状或适应症，包括但不限于不明原因的体重减轻、全身无力、持续疲劳、食欲不振、发烧、盗汗、骨痛、呼吸短促、腹部肿胀、胸痛/压迫感、脾脏肿大和癌症相关生物标志物水平升高(例如CA125)。此短语包括具有原发性或已确诊肿瘤的受试者。此短语包括原发性或转移性肿瘤(晚期恶性肿瘤)的受试者。例如，此短语包括新诊断的受试者。在某些实施例中，此短语包括根据本发明方法进行的治疗是初始治疗的受试者(例如，“一线”治疗，患者之前没有接受过针对癌症的全身治疗)。在某些实施例中，此短语包括根据本发明方法进行的治疗是“二线”治疗的受试者，其中患者之前接受了“标准护理”治疗，包括但不限于化疗、手术和放疗。
在本发明中，术语“治疗(treat)”、“治疗(treating)”等是指暂时或永久缓解症状、消除症状原因、延缓或抑制肿瘤生长、减少肿瘤细胞负荷或肿瘤负荷、促进肿瘤消退、引起肿瘤缩小、坏死和/或消失、预防肿瘤复发、预防或抑制肿瘤转移、抑制转移性肿瘤生长和/或增加受试者的生存期。
在本发明中，短语“组合”是指在接受佐剂、程序性死亡受体-1(PD-1)检查点抑制剂、放疗和/或化疗剂的同时、之前或之后向受试者施用癌抗原hTERT、PSMA和WT-1。在某些实施例中，所述癌抗原作为与佐剂的共制剂给药。
在本发明中，除非另有说明，否则术语“临床证明”(独立使用或修饰术语“安全”和/或“有效”)应指此术语已经过临床试验证明，其中临床试验符合美国食品和药物管理局、EMA或相应国家监管机构的批准标准。例如，可以通过本发明提供的示例中描述的临床试验来提供证据。
术语“临床证明安全”是指与标准治疗或另一比较对象相比，具有可接受的频率和/或可接受的治疗紧急不良事件(称为AE或TEAE)严重程度的有利风险:获益比，因为此术语涉及与癌抗原hTERT、PSMA、WT1(例如作为INO-5401或其生物仿制药或生物等效物施用)与佐剂(如IL-12(例如作为INO-9012或其生物仿制药或生物等效物施用)和程序性死亡受体1(PD-1)检查点抑制剂(如抗PD-1抗体(如抗PD-1抗体REGN2810或其生物仿制药或生物等效物))组合的剂量、剂量方案、治疗或方法。不良事件是向患者施用药物时发生的不良医学事件。一个安全指标是美国国家癌症研究所(NCI)根据不良事件常见毒性标准CTCAE v4.03分级的不良事件(AE)发生率。
在本发明中，在剂量、剂量方案、治疗或方法背景下使用的术语“临床证明疗效”和“临床证明有效”是指特定剂量、剂量方案或治疗方案的有效性。可根据与本发明药剂相对应的病程变化来衡量疗效。例如，将癌抗原hTERT、PSMA、WT1和佐剂(例如INO-5401或其生物仿制药或生物等效物与INO-9012或其生物仿制药或生物等效物的组合)与PD-1检查点抑制剂(例如抗PD-1抗体(例如抗PD-1抗体西米普利单抗或其生物仿制药或生物等效物))组合，以足以诱导改善(优选持续改善)至少一种指标(反映正在治疗疾病的严重程度)的用量和时间向患者施用。可以评估反映受试者病情、疾病或病症程度的各种指标，确定治疗的用量和时间是否足够。例如，此类指标包括临床公认的疾病严重程度、症状或相关疾病表现的指标。改善程度通常由医生决定，医生可根据体征、症状、活检或其他测试结果做出决定，医生还可以对受试者进行问卷调查，例如针对特定疾病开发的生活质量问卷调查。例如，将癌抗原hTERT、PSMA、WT1和佐剂(例如INO-5401或其生物仿制药或生物等效物与INO-9012或其生物仿制药或生物等效物的组合)与PD-1抗体(例如抗PD-1抗体西米普利单抗或其生物仿制药或生物等效物)组合向受试者施用，从而改善与脑癌(如胶质母细胞瘤(GBM))相关的患者症状。改善可以通过疾病活动指数的改善、临床症状的改善或任何其他疾病活动的测量来表示。
在本发明中，“INO-5401”是指三个DNA质粒的免疫原性合成物：包含由启动子操作控制的编码hTERT的插入片段的DNA质粒、包含由启动子操作控制的编码WT1的插入片段的DNA质粒以及包含由启动子操作控制的编码PSMA的插入片段的DNA质粒。
在本发明中，术语“放疗”(也称为“XRT”)是指使用电离辐射杀死癌细胞，通常作为抗癌治疗的一部分。采用X射线、伽马射线或带电粒子(例如质子或电子)产生电离辐射。
放疗可通过放置在患者体外的机器(外照射放疗)或放置在患者体内的放射源(内部放疗或近距放疗)或通过静脉内或口服的全身放射性同位素(全身放射性同位素治疗)进行。放疗可与基于成像的技术(例如计算机断层扫描(CT)、磁共振成像(MRI))一起计划和施用，准确确定要施用的放射剂量和位置。在各实施例中，放疗选自以下几项：全身放疗、常规外照射放疗、立体定向放疗、立体定向身体放疗、三维适形放疗、调强放疗、图像引导放疗、断层放疗、近距放疗和全身放疗。根据不同意图，在某些实施例中，放疗具有治愈性、辅助性或姑息性。在特定实施例中，术语“放疗”是指低分割放疗。低分割放疗是指一种放疗方案，其中将放射总剂量分为大剂量，每天进行一次或更少频率的治疗。与标准放疗相比，低分割放疗次数更少，每次放射剂量更大。在各实施例中，每次分割包括2-20Gy。例如，50Gy的放射剂量可分成10次分割，每次分割包括5Gy。在某些实施例中，在连续或顺序天数内施用2个或多个分割。在某些其它实施例中，每2天施用一次、每3天一次、每4天一次、每5天一次、每6天一次、每7天一次或以其组合施用2个或多个分割。
根据某些实施例，本发明提供的方法用于治疗受试者的癌症，例如脑癌(例如胶质母细胞瘤)。本发明所述方法包括向受试者施用癌抗原人端粒酶逆转录酶(hTERT)、Wilms肿瘤-1(WT-1)和前列腺特异性膜抗原(PSMA)的免疫原性合成物；佐剂；以及抗程序性细胞死亡受体1(PD-1)抗体或其抗体结合片段。
本发明公开了癌抗原hTERT、WT-1和PSMA的优化共有序列。在一个实施例中，由优化共有序列编码的抗原能够在哺乳动物中诱发免疫反应。在一个实施例中，由优化共有序列编码的抗原可包含表位，使其作为可以诱导免疫反应的免疫原特别有效。
在一个实施例中提供了一种优化共有PSMA，旨在打破对天然人PSMA的耐受性。在一个实施例中，人优化共有PSMA编码序列如SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:21或SEQ ID NO:28中所示。在一个实施例中，人优化共有PSMA编码抗原具有SEQ ID NO:13、SEQID NO:14或SEQ ID NO:28中所示的氨基酸序列。
在一个实施例中，优化共有WT-1旨在打破对天然人WT-1的耐受性。在一个实施例中，人优化共有WT-1编码序列如SEQ ID NO:15或SEQ ID NO:27中所示。在一个实施例中，人优化共有WT-1编码抗原具有SEQ ID NO:16或SEQ ID NO:26中所示的氨基酸序列。
在一个实施例中，优化共有TERT旨在打破对天然人TERT的耐受性。在一个实施例中，人优化共有TERT编码序列如SEQ ID NO:17或SEQ ID NO:19中所示。在一个实施例中，人优化共有TERT编码抗原具有SEQ ID NO:18和SEQ ID NO:20中所示的氨基酸序列。
本发明所述疫苗可进一步包含佐剂。在某些实施例中，本发明所述的治疗方法进一步包括向受试者施用佐剂。在某些实施例中，佐剂为IL12。IL12可能以其p35和p40亚基的形式包含在疫苗中。佐剂IL12可作为其p35和p40亚基向受试者施用。IL12 p35和p40亚基可由相同的表达载体编码，也可由单独的表达载体编码。在一个实施例中，IL12 p35编码序列如SEQ ID NO:22中所示。在一个实施例中，IL12 p35亚基具有SEQ ID NO:23中所示的氨基酸序列。在一个实施例中，IL12 p40编码序列如SEQ ID NO:24中所示。在一个实施例中，IL12p40亚基具有SEQ ID NO:25中所示的氨基酸序列。
癌抗原TERT、WT-1、PSMA和/或佐剂可存在于疫苗中或作为多肽、其片段、其变体、编码多肽、其片段或变体的核酸序列或者其任意组合向受试者施用。所述癌抗原可以是在受试者中诱导免疫反应的任何形式。所述核酸序列可以是DNA、RNA、cDNA、其变体、其片段或其组合。所述核酸序列还可包括对通过肽键与抗原连接的连接子或标记序列进行编码的附加序列。所述氨基酸序列可以是蛋白、肽、其变体、其片段或其组合。
癌抗原TERT、WT-1、PSMA和/或佐剂可存在于疫苗中或作为多肽、其片段、其变体、编码多肽、其片段或变体的核酸序列或者其任意组合向受试者施用。所述癌抗原可以是在受试者中诱导免疫反应的任何形式。所述核酸序列可以是DNA、RNA、cDNA、其变体、其片段或其组合。所述核酸序列还可包括对通过肽键与抗原连接的连接子或标记序列进行编码的附加序列。所述氨基酸序列可以是蛋白、肽、其变体、其片段或其组合。
癌抗原TERT、WT-1、PSMA和/或IL-12可包含在疫苗中或作为一个或多个核酸分子(包括但不限于表达载体)施用。表达载体可以是环状质粒或线性核酸。表达载体能够引导特定核苷酸序列在适当受试者细胞中的表达。表达载体可具有与抗原编码核苷酸序列可操作连接的启动子，所述启动子可与终止信号可操作连接。表达载体还可包含正确翻译核苷酸序列所需的序列。包含目标核苷酸序列的表达载体可以是嵌合载体，这意味着载体的至少一种成分相对于载体的至少一种其他成分异源。表达盒中核苷酸序列的表达可能受组成型启动子或诱导型启动子的控制，所述启动子仅在宿主细胞暴露于某些特定外部刺激时才开始转录。在多细胞生物体的情况下，启动子也可以对特定组织或器官或进展阶段具有特异性。
在一个实施例中，所述核酸为RNA分子。因此，在一个实施例中，本发明提供了编码一种或多种目标多肽的RNA分子。所述RNA可能是正链RNA。因此，在某些实施例中，所述RNA分子可通过细胞翻译，而不需要任何干预复制步骤，例如逆转录。本发明使用的RNA分子可能具有5'端帽(例如7-甲基鸟苷)。此端帽可以增强RNA的体内翻译。本发明使用的RNA分子的5'核苷酸可具有5'三磷酸基团。在加帽RNA中，这可能通过5'-5'桥与7-甲基鸟苷相连。RNA分子可具有一个3'端多聚A尾。还可能包含靠近其3'端的多聚A聚合酶识别序列(例如AAUAAA)。本发明使用的RNA分子可能是单链分子。在某些实施例中，RNA分子为裸露RNA分子。在一个实施例中，RNA分子包含在载体内。
在一个实施例中，RNA具有5'和3'UTR。在一个实施例中，5'UTR的长度在0和3000个核苷酸之间。可通过不同方法改变要添加到编码区域的5'和3'UTR序列的长度，包括但不限于设计用于退火UTR不同区域的PCR引物。使用这种方法，本领域普通技术人员可以在转染转录RNA后修饰实现最佳翻译效率所需的5'和3'UTR长度。
5'和3'UTR可以是目标基因的天然存在内源性5'和3'UTR。或者，通过将UTR序列合并到正向和反向引物中或通过对模板的任何其他修饰来添加对目标基因非内源性的UTR序列。使用对目标基因非内源性的UTR序列可以修饰RNA的稳定性和/或翻译效率。例如，众所周知，3'UTR序列中AU富含元件会降低RNA的稳定性。因此，可以根据本领域众所周知的UTR性质选择或设计3'UTR，提高转录RNA的稳定性。
在一个实施例中，5'UTR可包含内源基因的Kozak序列。或者，当如上所述通过PCR添加对目标基因非内源性的5'UTR时，可以通过添加5'UTR序列来重新设计共有Kozak序列。Kozak序列可提高某些RNA转录本的翻译效率，但似乎并非所有RNA都需要Kozak序列才能实现有效翻译。在本领域众所周知，许多RNA需要Kozak序列。在其它实施例中，5'UTR可衍生自其RNA基因组在细胞中稳定的RNA病毒。在其他实施例中，在3'或5'UTR中可以使用各种核苷酸类似物来阻止RNA的外切核酸酶降解。
在一个实施例中，所述RNA有一个5'端的端帽和一个3'端多聚(A)尾，它们决定了细胞中的核糖体结合、翻译开始和RNA稳定性。
在一个实施例中，所述RNA为核苷修饰的RNA。与非修饰的RNA相比，核苷修饰的RNA具有特殊优势，包括稳定性增加、先天免疫原性低或缺失以及翻译增强。
表达载体可以是环状质粒，所述环状质粒可通过整合到细胞基因组中来转化靶细胞或存在于染色体外(例如具有复制原点的自主复制质粒)。载体可以是pVAX、pcDNA3.0或provax，或任何其他能够表达编码抗原的DNA并使细胞能够将序列翻译成免疫系统可识别抗原的表达载体。
本发明还提供了一种线性核酸免疫原性合成物或线性表达盒(“LEC”)，其能够通过电穿孔有效递送给受试者并表达一种或多种所需抗原。所述LEC可以是不含任何磷酸主链的线性DNA。所述DNA可编码一种或多种抗原。LEC可能包含启动子、内含子、终止密码子和/或多聚腺苷酸化信号。抗原表达可由启动子控制。LEC可能不包含任何抗生素抗性基因和/或磷酸主链。LEC可能不包含与所需抗原基因表达无关的其他核苷酸序列。LEC可衍生自能够线性化的任何质粒。所述质粒能够表达抗原。质粒可以是pNP(Puerto Rico/34)或pM2(New Caledonia/99)。质粒可以是WLV009、pVAX、pcDNA3.0或provax，或任何其他能够表达编码抗原的DNA并使细胞能够将序列翻译成免疫系统可识别的抗原的表达载体。LEC可以是pcrM2。LEC可以是pcrNP。pcrNP和pcrMR可分别衍生自pNP(Puerto Rico/34)和pM2(NewCaledonia/99)。
载体可包含编码上述抗原的异源核酸，并可进一步包含起始密码子和终止密码子，起始密码子可位于一种或多种癌抗原编码序列的上游，终止密码子可位于上述抗原的编码序列的下游。
所述载体可具有启动子。启动子可以是能够驱动基因表达和调节分离核酸表达的任何启动子。此类启动子是通过DNA依赖性RNA聚合酶转录所需的顺式作用序列元件，所述元件转录本发明所述的抗原序列。用于引导异源核酸表达的启动子的选择取决于特定应用。所述启动子在载体中与转录起始位点的距离可以与其在自然环境中与转录起始位点的距离大致相同。然而，在不损失启动子功能的情况下可以适应此距离的变化。
所述起始和终止密码子可以是在具有上述抗原编码序列的框架中。载体还可包含与上述抗原编码序列可操作连接的启动子。与上述抗原编码序列可操作连接的启动子可以是以下来源的启动子：猿猴病毒40(SV40)、小鼠乳瘤病毒(MMTV)启动子、人类免疫缺陷病毒(HIV)启动子(例如牛免疫缺陷病毒(BIV)长末端重复(LTR)启动子)、莫洛尼病毒启动子、禽类白血病病毒(ALV)启动子、巨细胞病毒(CMV)启动子(例如CMV立即早期启动子)、爱泼斯坦-巴尔病毒(EBV)启动子或劳氏肉瘤病毒(RSV)启动子。所述启动子也可以是来自人类基因的启动子，例如人肌动蛋白、人肌球蛋白、人血红蛋白、人肌肉肌酸或人金属硫蛋白。启动子也可以是组织特异性启动子，例如天然或合成的肌肉或皮肤特异性启动子。第US20040175727号美国专利申请公开对此类启动子的示例进行了描述，所述专利通过本发明的整体引用，成为本发明的一部分。
载体还可包含多聚腺苷酸化信号，所述信号可位于上述抗原和/或抗体的编码序列的下游。多聚腺苷酸化信号可以是SV40多聚腺苷酸化信号、LTR多聚腺苷酸化信号、牛生长激素(bGH)多聚腺苷酸化信号、人生长激素(hGH)多聚腺苷酸化信号或β-珠蛋白多聚腺苷酸化信号。SV40多聚腺苷酸化信号可以是来自apCEP4载体(加利福尼亚州圣地亚哥市Invitrogen公司)的多聚腺苷酸化信号
载体还可包含上述抗原的上游增强子。
所述增强子可能是表达所必需的。增强子可以是人肌动蛋白、人肌球蛋白、人血红蛋白、人肌肉肌酸或病毒增强子，例如来自CMV、HA、RSV或EBV中的一种。
载体可包含增强子和具有功能性剪接供体和受体位点的内含子。载体可包含结构基因下游的转录终止区，从而提供有效的终止。可从与启动子序列相同的基因中获得所述终止区，也可从不同的基因获得所述终止区。
本发明所述方法可包括施用单个核酸分子(例如单个质粒)的多个拷贝或两个或多个不同核酸分子(例如两个或多个不同质粒)的多个拷贝。例如，所述方法可包括施用两个、三个、四个、五个、六个、七个、八个、九个或十个或更多不同的核酸分子。
按照本发明所述方法使用的核酸分子(例如质粒)可共同包含单个抗原或多个抗原的编码序列。例如，在一个实施例中，所述抗原为选自TERT和一种或多种其他癌抗原的多种抗原。在一个示例性实施例中，所述抗原为TERT和WT-1。在一个示例性实施例中，所述抗原为TERT和PSMA。在一个示例性实施例中，所述抗原为PSMA和一种或多种其他癌抗原。在一个示例性实施例中，所述抗原为PSMA和WT-1。在另一个示例性实施例中，所述抗原为TERT、WT-1和PSMA。
载体可进一步包含抑制其整合到染色体中的元件或试剂。载体可包含哺乳动物复制原点，从而将载体维持在染色体外并在细胞中产生载体的多个拷贝。载体可以是来自Invitrogen公司(加利福尼亚州圣地亚哥)的pVAXl、pCEP4或pREP4，它们可包含爱泼斯坦-巴尔病毒复制原点和核抗原EBNA-1编码区，从而在不整合的情况下产生高拷贝游离型复制。载体可以是pVAXl或变化的pVAXl变体，例如本发明所述的变体质粒。变体pVAXl质粒为主链载体质粒pVAXl(加利福尼亚州卡尔斯巴德市Invitrogen公司)的2998碱基对变体。CMV启动子位于碱基137-724。T7启动子/引发位点位于碱基664-683。多个克隆位点位于碱基696-811。
牛GH多聚腺苷酸化信号位于碱基829-1053。卡那霉素抗性基因位于碱基1226-2020。pUC原点位于碱基2320-2993。
基于Invitrogen公司提供的pVAXl序列，在用作本发明所述质粒1-6主链的pVAXl序列中发现了以下突变：
C>G241，在CMV启动子中
C>T 1942主链，在牛生长激素多聚腺苷酸化信号(bGHpolyA)下游
A>-2876主链，在卡那霉素基因下游
C>T 3277，在pUC复制原点(Ori)高拷贝数突变(见核酸研究1985)
G>C 3753，在RNASeH位点pUC Ori上游的末端
碱基对2、3和4从ACT变为CTG，在CMV启动子上游的主链中。载体主链可为pAV0242。载体可以是复制缺陷5型腺病毒(Ad5)载体。
载体还可包含调控序列，所述调控序列非常适合接受载体的哺乳动物或人类细胞中的基因表达。本发明所述的一种或多种癌抗原序列可包含允许编码序列在宿主细胞中更有效转录的密码子。
载体可以是pSE420(加利福尼亚州圣地亚哥市Invitrogen公司)，可用于大肠杆菌(E.coli)中的蛋白生产。载体也可以是pYES2(加利福尼亚州圣地亚哥市Invitrogen公司)，可用于酿酒酵母菌株中的蛋白生产。载体也可以是MAXBACTM完整杆状病毒表达系统(加利福尼亚州圣地亚哥市Invitrogen公司)，可用于昆虫细胞中的蛋白生产。载体也可以是pcDNA I或pcDNA3(加利福尼亚州圣地亚哥市Invitrogen公司)，可用于哺乳动物细胞(例如中国仓鼠卵巢(CHO)细胞)中的蛋白生产。载体可以是表达载体或系统，通过常规技术和现有起始材料生产蛋白，包括Sambrook等人，《分子克隆和实验室手册》，第二版，冷泉港(1989)，其通过整体引用成为本发明的一部分。
在2019年9月12日提交的第62/899,543号美国申请中公开了编码癌抗原hTERT、WT-1和/或PSMA的示例性DNA质粒编码，所述美国申请通过本发明的整体引用，成为本发明的一部分。
根据所公开的方法，可以向受试者施用约5纳克-20mg编码一种或多种抗原的核酸分子。在某些实施例中，可以向受试者施用约5mg-15mg编码一种或多种抗原的核酸分子。在某些实施例中，可以向受试者施用约9mg-11mg编码一种或多种抗原的核酸分子。在某些实施例中，可以向受试者施用约10mg编码一种或多种抗原的核酸分子。
可通过多种途径递送DNA质粒。典型的递送途径包括肠胃外给药，例如皮内、肌肉或皮下递送。其他途径包括口服给药、鼻内和阴道内途径。特别是对于疫苗的DNA，疫苗可以递送到个体组织的间质空间(Felgner等人，第5,580,859号和第5,703,055号美国专利，所述专利通过本发明的整体引用，成为本发明的一部分)。DNA质粒也可施用于肌肉，或者可通过皮内或皮下注射或透皮给药，例如通过离子电渗疗法。也可采用DNA质粒的表皮给药。表皮给药可涉及机械或化学刺激表皮的最外层以刺激对刺激物的免疫反应(Carson等人，第5,679,647号美国专利，所述专利通过本发明的整体引用，成为本发明的一部分)。
DNA质粒可以是液体制剂，例如悬浮液、糖浆或酏剂。疫苗还可以是用于肠胃外、皮下、皮内、肌肉或静脉给药(例如注射给药)的制剂，例如无菌混悬剂或乳液。
DNA质粒可以掺入脂质体、微球体或其他聚合物基质中(Felgner等人，第5,703,055号美国专利；Gregoriadis，脂质体技术，第I卷至第III卷(第2版，1993)，所述专利通过本发明的整体引用，成为本发明的一部分)。脂质体可由磷脂或其他脂类组成，并且是相对容易生产和给药的无毒、生理上可接受和可代谢的载体。
DNA质粒可通过电穿孔给药，例如通过第7,664,545号美国专利中描述的方法，所述专利通过本发明的整体引用，成为本发明的一部分。可通过第6,302,874号、第5,676,646号、第6,241,701号、第6,233,482号、第6,216,034号、第6,208,893号、第6,192,270号、第6,181,964号、第6,150,148号、第6,120,493号、第6,096,020号、第6,068,650号和第5,702,359号美国专利中描述的方法和/或装置进行电穿孔，所述专利通过本发明的整体引用，成为本发明的一部分。可通过微创装置进行电穿孔。
微创电穿孔装置(“MID”)可以是将上述疫苗和相关流体注射到身体组织的装置。所述装置可包括空心针、DNA盒和流体递送工具，其中所述装置适用于驱动使用中的流体递送工具，以便在将针插入身体组织的同时(例如自动)将DNA注入身体组织。这样做的优势在于在插入针头时逐渐注入DNA和相关流体，使流体更均匀地分布在身体组织中。由于注射的DNA分布在更大的区域，所以可减少注射时体验的疼痛。
MID可在不使用针头的情况下将DNA质粒注射到组织中。MID可以小流或射流的形式注射疫苗，其力度足以使疫苗穿透组织表面并进入下层组织和/或肌肉。可通过压缩气体(例如二氧化碳)膨胀在几分之一秒内通过微孔来提供小流或射流后面的力量。在发布的第20080234655号、第6,520,950号、第7,171,264号、第6,208,893号、第6,009,347号、第6,120,493号、第7,245,963号、第7,328,064号和第6,763,264号美国专利申请中描述了微创电穿孔装置的示例及其使用方法，所述专利通过本发明的整体引用，成为本发明的一部分。
MID可包括一个注射器，所述注射器产生可以无痛刺穿组织的高速液体射流。此类无针注射器可在市场上买到。本发明中使用的无针注射器示例包括第3,805,783号、第4,447,223号、第5,505,697号和第4,342,310号美国专利申请中描述的无针注射器，所述专利申请的内容通过本发明的整体引用，成为本发明的一部分。
使用无针注射器将适合直接或间接电迁移的所需疫苗引入(例如注射)到待治疗的组织中，通常通过将组织表面与注射器接触来驱动药剂射流的递送，以足够的力使疫苗渗透到组织中。例如，如果要治疗的组织为黏膜、皮肤或肌肉，则以足够的力将药剂投射到黏膜或皮肤表面，使药剂穿透角质层进入真皮层，或分别进入下层组织和肌肉。
无针注射器非常适合将DNA质粒递送到所有组织类型中，特别是皮肤和黏膜。在某些实施例中，无针注射器可用于将含有DNA质粒的液体推向表面并进入受试者的皮肤或黏膜。可使用本发明方法治疗的各种组织类型的代表性示例包括胰腺、喉、鼻咽、下咽、口咽、唇、喉咙、肺、心脏、肾脏、肌肉、乳房、结肠、前列腺、胸腺、睾丸、皮肤、黏膜组织、卵巢、血管或其任意组合。
MID可具有电穿孔组织的针状电极。通过在多电极阵列中的多对电极之间产生脉冲，例如设置成矩形或方形图案，提供比在一对电极之间产生脉冲更好的结果。例如，第5,702,359号美国专利申请“用于介导药物和基因递送的针状电极”公开了一组针头，其中在治疗期间可脉冲多对针头。在上述申请(通过本发明的整体引用，成为本发明一部分)中，针头布置成圆形阵列，但具有连接器和开关装置，能够在相对的针状电极对之间产生脉动。可以使用一对针状电极将重组表达载体递送到细胞。第6,763,264号美国专利申请中描述了此类装置和系统，所述专利通过本发明的整体引用，成为本发明的一部分。或者，可使用单针装置，所述装置允许用类似于普通注射针的单针进行DNA注射和电穿孔，并施加比当前使用装置递送的电压更低的脉冲，从而减少患者体验的触电感。
MID可包括一个或多个电极阵列。所述阵列可包括两个或多个相同直径或不同直径的针头。所述针头可均匀或不均匀分开。针头可能介于0.005英寸和0.03英寸之间、介于0.01英寸和0.025英寸之间；或介于0.015英寸和0.020英寸之间。针头的直径可能为0.0175英寸。针头的间隔可为0.5mm、1.0mm、1.5mm、2.0mm、2.5mm、3.0mm、3.5mm、4.0mm或以上。
MID可由脉冲发生器和两个或多个针头注射器组成，其可一步递送DNA质粒和电穿孔脉冲。脉冲发生器可通过运行闪存卡的个人计算机操作灵活编程脉冲和注射参数，以及全面记录和存储电穿孔和患者数据。脉冲发生器可在短时间内递送各种电压脉冲。例如，脉冲发生器可递送三个持续时间为100ms的15伏脉冲。此类MID的示例为Inovio生物医药公司的Elgen 1000系统，所述系统在第7,328,064号美国专利申请中进行了描述，所述申请通过本发明的整体引用，成为本发明的一部分。
MID可以是
(Inovio生物医药公司，宾夕法尼亚州布卢市)装置和系统，它是一种模块化电极系统，可以将大分子(例如DNA)引入到身体或植物中选定组织的细胞中。所述模块化电极系统可包括多个针状电极；一个皮下注射针头；一个电连接器，可在可编程恒流脉冲控制器和多个针状电极之间提供导电链路；和一个电源。操作员可以抓住安装在支撑结构上的多个针状电极，并将它们牢固插入身体或植物的选定组织中。然后通过皮下注射针头将大分子递送到选定的组织中。激活可编程恒流脉冲控制器，将恒流电脉冲施加到多个针状电极上。施加的恒流电脉冲可将大分子引入到多个电极之间的细胞中。利用恒流脉冲限制组织中的功耗，可以最大限度地减少因细胞过热而导致的细胞死亡。第7,245,963号美国专利申请中描述了
装置和系统，所述申请通过本发明的整体引用，成为本发明的一部分。
MID可以是Elgen 1000系统(Inovio生物医药公司)。Elgen 1000系统可包括提供空心针的装置；和流体递送工具，其中所述装置适用于驱动使用中的流体递送工具，以便在将流体(本发明所述的DNA质粒)注入身体组织的同时(例如自动)将针插入所述身体组织。这样做的优势在于在插入针头时逐渐注入流体，使流体更均匀地分布在身体组织中。人们还认为，由于注射流体的体积分布在更大的区域，所以可减少注射时体验的疼痛。
此外，自动流体注射便于自动监测和记录实际注射的流体剂量。如需记录，这些数据可由控制单元存储。
应理解的是，注射速率可以是线性或非线性的，并且可在针头穿过待治疗受试者的皮肤之后、在针头进一步插入身体组织中时进行注射。
通过本发明装置将流体注入的适当组织包括肿瘤组织、皮肤或肝脏组织，也可能是肌肉组织。
所述装置进一步包括引导针头插入人体组织的进针工具。由进针速率控制流体注射速率。这样做的优势在于可以控制进针和流体注射，使插入速率根据需要与注射速率相匹配。还可以使装置更便于用户操作。如需要，可提供将针头自动插入身体组织的工具。
用户可选择流体注射的开始时间。然而，理想情况下，当针尖到达肌肉组织时开始注射，并且所述装置可包括用于感应针头插入到足够深度时开始注射流体的工具。这意味着当针头达到所需深度(通常是肌肉组织开始的深度)时，可以提示自动开始注射流体。例如，肌肉组织开始的深度可视为预设进针深度，例如值为4mm，其足以使针头穿过皮肤层。
所述感应工具可包括超声波探头。感应工具可包括用于感应阻抗或电阻变化的工具。在这种情况下，这些工具可能不会记录针头在身体组织中的深度，而是当针头从不同类型的身体组织移动到肌肉时，感应阻抗或电阻的变化。任何一种替代方案均提供了一种相对准确且易于操作的感应注射开始的工具。如需要，可进一步记录进针深度，此深度可用于控制流体注射，以便在记录进针深度时确定要注射的流体体积。
所述装置可进一步包括：一个支撑针头的底座；和一个容纳底座的壳体，其中，所述底座可相对于外壳移动，当底座相对于外壳处于第一向后位置时，针头缩回外壳内，当底座在外壳内处于第二向前位置时，针头伸出外壳。这对用户来说是有利的，因为外壳可以排列在患者的皮肤上，然后可以通过相对于底座移动外壳将针头插入患者的皮肤。
如上所述，最好实现受控的流体注射速率，使流体在针头插入皮肤时均匀分布在针头的长度上。流体递送工具可包括适合以受控速率注射流体的活塞驱动工具。例如，活塞驱动工具可由伺服电机激活。然而，活塞驱动工具的致动可由底座相对于外壳沿轴向方向移动来实现。应理解的是，可提供替代的流体递送工具。因此，例如，可在注射器和活塞系统的位置提供以受控或非受控速率挤压进行流体递送的封闭容器。
上述装置可用于任何类型的注射。然而，预计所述装置在电穿孔领域特别有用，因此还进一步包括向针头施加电压的工具。这使针头不仅可用于注射，还可以在电穿孔过程中用作电极。特别有利的是这意味着将电场施加到与注射流体相同的区域。传统上，电穿孔存在一个问题，即很难将电极与先前注射的流体准确对齐，因此用户倾向于在较大区域注射超过所需体积的更大体积流体，并在较高区域上施加电场以试图保证注入的物质和电场之间重叠。使用本发明，注射的流体体积和施加的电场大小均可减小，同时实现电场与流体之间的良好配合。
在向受试者施用编码癌抗原hTERT、PSMA和WT-1的核酸分子时，转染细胞将表达和分泌一种或多种癌抗原。免疫系统将这些分泌的蛋白或合成抗原识别为外来物质，从而产生免疫反应，包括：针对一种或多种癌抗原的抗体，以及特异性针对一种或多种癌抗原的T细胞反应。在某些示例中，施用本发明所述的免疫原性合成物的哺乳动物将具有激活的免疫系统，并且在受到本发明所述的一种或多种癌抗原激发时，激活的免疫系统将允许快速清除本发明所述的后续癌抗原，无论是通过体液、细胞或者是细胞和体液免疫反应。
重组癌抗原可诱导抗原特异性T细胞和/或高效价抗体反应，从而诱导或诱发针对表达抗原的癌症或肿瘤的免疫反应。在某些实施例中，所述诱导或诱发的免疫反应可以是细胞免疫反应、体液免疫反应或细胞免疫反应和体液免疫反应。在某些实施例中，所述诱导或诱发的细胞免疫反应可包括干扰素-γ(IFN-γ)和/或肿瘤坏死因子α(TNF-α)的诱导或分泌。在其他实施例中，所述诱导或诱发的免疫反应可减少或抑制一种或多种免疫抑制因子，这些因子促进表达抗原的肿瘤或癌症的生长，包括但不限于，下调MHC呈递的因子、上调抗原特异性调节性T细胞(Treg)的因子、PD-L1、FasL、细胞因子(例如IL-10和TFG-β)、肿瘤相关巨噬细胞、肿瘤相关成纤维细胞、免疫抑制细胞产生的可溶性因子、CTLA-4、PD-1、MDSC、MCP-1和免疫检查点分子。
所述疫苗可进一步包含一种抗PD-1抗体。本发明公开的治疗方法可进一步包括向受试者施用PD-1抗体。根据本发明的某些实施例，所述抗PD-1抗体包含重链可变区(HCVR)、轻链可变区(LCVR)和/或互补决定区(CDR)，这些区域包含第20150203579号美国专利公开中所述的任何抗PD-1抗体的氨基酸序列，所述专利公开通过本发明的整体引用成为本发明的一部分。在某些示例性实施例中，可在本发明所述方法的背景下使用的抗PD-1抗体包含重链可变区(HCVR)(包含氨基酸序列SEQ ID NO:1)的重链互补决定区(HCDR)以及轻链可变区(LCVR)(包含氨基酸序列SEQ ID NO:2)的轻链互补决定区(LCDR)。根据某些实施例，所述抗PD-1抗体包含三个HCDR(HCDR1、HCDR2和HCDR3)和三个LCDR(LCDR1、LCDR2和LCDR3，其中，HCDR1包含氨基酸序列SEQ ID NO:3；HCDR2包含氨基酸序列SEQ ID NO:4；HCDR3包含氨基酸序列SEQ ID NO:5；LCDR1包含氨基酸序列SEQ ID NO:6；LCDR2包含氨基酸序列SEQ ID NO:7；以及LCDR3包含氨基酸序列SEQ ID NO:8。在其他实施例中，所述抗PD-1抗体包含含有SEQID NO:1的HCVR和含有SEQ ID NO:2的LCVR。在某些实施例中，本发明方法包括使用抗PD-1抗体，其中，所述抗体包含含有氨基酸序列SEQ ID NO:9的重链。在某些实施例中，所述抗PD-1抗体包含含有氨基酸序列SEQ ID NO:10的轻链。包含氨基酸序列SEQ ID NO:9的重链和包含氨基酸序列SEQ ID NO:10的轻链的示例性抗体是称为REGN2810的全人抗PD-1抗体，也称为西米普利单抗或西米普利单抗注射溶液。
根据某些示例性实施例，本发明所述方法包括使用REGN2810或其生物仿制药或生物等效物。在本发明中，术语“生物等效”是指抗PD-1抗体或PD-l结合蛋白或其片段，它们是药物等效物或药物替代品，其吸收速率和/或程度在相似实验条件下以相同的摩尔剂量(单剂量或多剂量)施用时与REGN2810没有显著差异。在本发明背景下，此术语是指与PD-1结合的抗原结合蛋白，其在安全性，纯度和/或效力方面与REGN2810不存在临床意义的差异。
根据本发明的某些实施例，所述抗人PD-1抗体包含与SEQ ID NO:1具有90％、95％、98％或99％序列一致性的HCVR。
根据本发明的某些实施例，所述抗人PD-1抗体包含与SEQ ID NO:2具有90％、95％、98％或99％序列一致性的LCVR。
根据本发明的某些实施例，所述抗人PD-1抗体包含HCVR，所述HCVR包含具有不超过5个氨基酸取代的氨基酸序列SEQ ID NO:1。根据本发明的某些实施例，所述抗人PD-1抗体包含LCVR，所述LCVR包含具有不超过2个氨基酸取代的氨基酸序列SEQ ID NO:2。
可通过本领域已知的任何方法测量序列一致性(例如GAP、BESTFIT和BLAST)。
本发明还包括在方法中使用抗PD-1抗体治疗癌症，其中，所述抗PD-1抗体包含本发明所述的任何HCVR、LCVR和/或CDR氨基酸序列的变体，这些序列具有一个或多个保守氨基酸取代。例如，本发明包括使用具有HCVR、LCVR和/或CDR氨基酸序列的抗PD-1抗体，相对于本发明公开的任何HCVR、LCVR和/或CDR氨基酸序列，这些序列具有10个或更少、8个或更少、6个或更少、4个或更少等的保守氨基酸取代。
根据本发明所述方法，向受试者施用的抗PD-1抗体量可以是治疗有效量。在本发明中，抗PD-1抗体的“治疗有效量”短语是导致以下一项或多项的用量：(a)癌症(例如胶质母细胞瘤)症状或适应症的严重程度或持续时间降低；(b)抑制肿瘤生长，或增加肿瘤坏死、肿瘤缩小和/或肿瘤消失；(c)延缓肿瘤的生长和发展；(d)抑制肿瘤转移；(e)预防肿瘤生长的复发；(f)提高癌症患者的生存期；和/或(g)与未治疗的受试者或施用所述抗体作为单一疗法的受试者相比，常规抗癌疗法的使用或需求减少(例如减少或消除化疗剂或细胞毒素剂的使用)。
在抗PD-1抗体或其抗原结合片段的情况下，治疗有效量可以是约0.05mg-约600mg、约1mg-约500mg、约10mg-约450mg、约50mg-约400mg、约75mg-约350mg或约100mg-约300mg的抗体。例如，在各实施例中，抗PD-1抗体的用量约为0.05mg、约0.1mg、约1.0mg、约1.5mg、约2.0mg、约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg、约210mg、约220mg、约230mg、约240mg、约250mg、约260mg、约270mg、约280mg、约290mg、约300mg、约310mg、约320mg、约330mg、约340mg、约350mg、约360mg、约370mg、约380mg、约390mg、约400mg、约410mg、约420mg、约430mg、约440mg、约450mg、约460mg、约470mg、约480mg、约490mg、约500mg、约510mg、约520mg、约530mg、约540mg、约550mg、约560mg、约570mg、约580mg、约590mg或约600mg的抗PD-1抗体。在一个实施例中，根据本发明所述方法施用250mg抗PD-1抗体。在一个实施例中，根据本发明所述方法施用200mg抗PD-1抗体。在一个实施例中，根据本发明所述方法施用350mg抗PD-1抗体。
抗PD-1抗体可多剂量向受试者施用，例如，作为特异性治疗给药方案的一部分。例如，治疗给药方案可包括向受试者施用一剂或多剂的抗PD-1抗体，施用频率约为一天一次、两天一次、三天一次、四天一次、五天一次、六天一次、一周一次、两周一次、三周一次、四周一次、一个月一次、两个月一次、三个月一次、四个月一次或更少频率。
在某些实施例中，所述抗PD-1抗体包含在药物合成物中。本发明的药物合成物可与合适的载体、赋形剂和提供合适的转移、递送、耐受性等的其他试剂一起配制。在所有药物化学家已知的处方集中可以找到大量合适的配方：《雷明登氏药学全书》，Mack出版社公司，宾夕法尼亚州伊斯顿。这些制剂包括粉末、糊剂、软膏、凝胶剂、蜡、油、脂类、含有囊泡(例如LIPOFECTINTM)的脂类(阳离子或阴离子)、DNA偶联物、无水吸浆、水包油和油包水乳液、乳液碳蜡(各种分子量的聚乙二醇)、半固体凝胶和含有碳蜡的半固体混合物。另见Powell等人，“肠胃外制剂赋形剂简编”PDA(1998)，《药学科学与技术杂志》，52:238-311。
各种递送系统已知并可用于施用抗PD-1抗体，例如封装在脂质体、微粒、微囊剂、能够表达突变病毒的重组细胞、受体介导的内吞作用(见Wu等人，1987，《生物化学杂志》，262:4429-4432)。给药方法包括但不限于皮内、肌肉、腹膜内、静脉、皮下、鼻内、硬膜外和口服途径。合成物可通过任何适当途径给药，例如通过输注或推注，通过上皮或皮肤黏膜内膜吸收(例如口腔黏膜、直肠和肠黏膜等)，并且可与其它生物活性试剂一起给药。
抗PD-1抗体可通过标准针头和注射器皮下或静脉给药。此外，关于皮下递送，笔型递送装置随时可用于递送抗PD-1抗体。此类笔型递送装置可重复使用或一次性使用。可重复使用的笔型递送装置通常使用可更换药筒，所述药筒包含抗PD-1抗体的药物合成物。一旦药筒中的所有药物合成物已施用并且药筒清空，则可丢弃空药筒并更换包含药物合成物的新药筒。然后可重复使用笔型递送装置。在一次性笔型递送装置中，没有可更换药筒。相反，一次性笔型递送装置预先填充有药物合成物，药物合成物保存在装置内的储药槽中。一旦储药槽中的药物合成物清空，丢弃整个装置。
在某些情况下，所述抗PD-1抗体可在控释系统中递送。在一个实施例中，可使用泵。在另一实施例中，可使用聚合材料；见《控释的医学应用》，Langer和Wise(编辑)，1974，CRC出版社，佛罗里达州波卡拉顿市。在另一实施例中，控释系统可放置在目标附近，因此只需要一小部分的全身剂量(见Goodson，1984，《控释的医学应用》，同上，第2卷，第115页-第138页)。其他控释系统的讨论见Langer，1990，《科学杂志》，249:1527-1533。
所述抗PD-1抗体的注射制剂可包括静脉、皮下、皮内和肌肉注射、点滴注射等剂型。这些注射制剂可通过已知方法制备。例如，通过将上述抗体或其盐在常规用于注射的无菌水性介质或油性介质中溶解、悬浮或乳化，来制备注射制剂。作为注射用水性介质，包括生理盐水、包含葡萄糖和其他助剂的等渗溶液等，它们可与合适的增溶剂(如酒精(例如乙醇)、聚醛醇(例如丙二醇、聚乙二醇)、非离子型表面活性剂[例如聚山梨醇酯80、HCO-50(氢化蓖麻油的聚氧乙烯(50摩尔)加合物]等)组合使用。作为油性介质，包括芝麻油、大豆油等，它们可与苯甲酸苄酯、苯甲醇等加溶剂组合使用。由此制备的注射剂优选灌装在适当的安瓿中。
在某些实施例中，所述抗PD-1抗体配制为用于静脉内给药的药物合成物。
在某些实施例中，所述方法进一步包括向受试者施用放疗。在某些实施例中，向受试者施用一剂或多剂放疗的频率约为：一天一次、两天一次、三天一次、四天一次、五天一次、六天一次、一周一次、两周一次、三周一次、四周一次、一个月一次、两个月一次、三个月一次、四个月一次或更少频率。
在某些实施例中，所述放疗为低分割放疗。在某些实施例中，所述受试者在2-20次分割中施用20-60Gy。在某些实施例中，所述低分割放疗包括15次分割。在某些实施例中，在连续15-25天内施用15次分割。在某些实施例中，在连续21天内施用15次分割。
在某些实施例中，所述方法进一步包括向受试者施用化疗剂，例如替莫唑胺(TMZ)。化疗剂可与放疗一起施用。例如，TMZ的每日剂量为75mg/m2，同时进行低分割放疗。在某些实施例中，对具有甲基化MGMT启动子的肿瘤的受试者施用化疗剂的维持治疗。例如，在放疗后，具有甲基化MGMT启动子的肿瘤的受试者可在28天周期的前5天(5天“进行”，23天“不进行”)以150mg/m2/天的起始剂量接受TMZ，持续6个周期，在没有血液毒性的情况下，每个维持周期增加50mg/m2/剂，最大200mg/m2/剂。在某些实施例中，维持治疗将在最后一剂放疗后约三至五周(优选约四周)开始。
在特定实施例中，本发明所述方法可介导清除或预防肿瘤细胞的生长，方法是(1)通过B细胞反应诱导体液免疫来产生阻断单核细胞趋化蛋白-1(MCP-1)生成的抗体，从而延缓髓源抑制细胞(MDSC)并抑制肿瘤生长；(2)增加细胞毒性T淋巴细胞(例如CD8+(CTL))攻击和杀死肿瘤细胞；(3)增加T辅助细胞反应；(4)以及通过IFN-γ和TFN-α增加炎症反应；或(5)上述任意组合。所述方法可将无进展生存期提高30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％和45％。免疫后，所述方法可将肿瘤质量减少30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％和60％。所述方法可预防和阻断单核细胞趋化蛋白1(MCP-1)(即一种由髓源抑制细胞分泌的细胞因子)的增加。所述方法可将肿瘤生存期提高30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％和60％。
与未施用所述方法或施用标准护理治疗方法的受试者的细胞免疫反应相比，本发明所述方法可将受试者的细胞免疫反应提高约50倍-约6000倍、约50倍-约5500倍、约50倍-约5000倍、约50倍-约4500倍、约100倍-约6000倍、约150倍-约6000倍、约200倍-约6000倍、约250倍-约6000倍或约300倍-约6000倍。在某些实施例中，与未施用所述方法或施用标准护理治疗方法的受试者中的细胞免疫反应相比，所述方法可将受试者的细胞免疫反应提高约50倍、100倍、150倍、200倍、250倍、300倍、350倍、400倍、450倍、500倍、550倍、600倍、650倍、700倍、750倍、800倍、850倍、900倍、950倍、1000倍、1100倍、1200倍、1300倍、1400倍、1500倍、1600倍、1700倍、1800倍、1900倍、2000倍、2100倍、2200倍、2300倍、2400倍、2500倍、2600倍、2700倍、2800倍、2900倍、3000倍、3100倍、3200倍、3300倍、3400倍、3500倍、3600倍、3700倍、3800倍、3900倍、4000倍、4100倍、4200倍、4300倍、4400倍、4500倍、4600倍、4700倍、4800倍、4900倍、5000倍、5100倍、5200倍、5300倍、5400倍、5500倍、5600倍、5700倍、5800倍、5900或6000倍。
在某些实施例中，所述方法可提高受试者的无肿瘤生存期、减少肿瘤质量、提高无进展生存期、提高总体生存期或其组合。所述方法可将受试者的无肿瘤生存期提高20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％和60％。所述方法可将受试者的肿瘤质量减少20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％、60％、61％、62％、63％、64％、65％、66％、67％、68％、69％和70％。所述方法可将受试者的无进展生存期提高20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％和60％。所述方法可将受试者的总体生存期提高20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％和60％。
在某些实施例中，所述方法临床证明安全、临床证明有效或两种兼有。
示例
目标
主要目标：通过肌肉(IM)注射递送INO-5401和INO-9012后使用
2000进行EP，联合西米普利单抗注射溶液，在新诊断GBM的成人受试者中评价此组合的安全性和耐受性。
主要终点和评估：
●不良事件(AE)发生率根据不良事件常见毒性标准(CTCAE)v4.03进行分级，按系统器官类别、优选术语、严重程度以及与试验治疗的关系进行分类。
●实验室安全性参数与基线相比出现的临床显著变化。
次要目标：
■通过IM注射递送INO-5401和INO-9012后使用
2000进行EP，联合西米普利单抗注射溶液，在新诊断GBM的成人受试者中评价此组合的初步临床疗效和免疫原性。
■通过IM注射递送INO-5401和INO-9012后使用
2000进行EP，联合REGN2810，在新诊断GBM的成人受试者中评价该组合的初步免疫原性。
次要终点和评估：
●18个月的总体生存期(OS18)；
●通过以下方法评估的抗原特异性细胞免疫反应：
○通过ELISpot在外周血单核细胞(PBMC)中分泌干扰素-γ的T淋巴细胞；
○通过流式细胞术在PBMC中评估T细胞表型(例如活化和溶细胞细胞、髓源抑制细胞频率(MDSC))；
○来自PBMC的T细胞受体(TCR)测序，以评估多样性和推定的抗原特异性；
●抗原特异性体液反应(例如B细胞活化/抗体分泌)。
探索性目标
■探索临床疗效与肿瘤遗传学和/或生物标志物之间的相关关联。
■通过IM注射递送INO-5401和INO-9012后使用
2000进行EP，联合REGN2810和低分割放疗，在新诊断GBM的成人受试者中进一步评价此组合的疗效。探索性终点：
■在可行的情况下，肿瘤浸润淋巴细胞(TIL)和免疫抑制元件；
■肿瘤癌蛋白的表达，包括但不限于通过IHC、免疫荧光(IF)或基因组测序对hTERT，、WT1和PSMA的肿瘤表达；
■血浆和/或血清中的MicroRNA特征；
■在可行的情况下，循环肿瘤细胞、循环内皮细胞和/或循环来自外周血的癌症相关巨噬细胞样细胞；
■通过RNAseq评估肿瘤相关抗原(TAA)特异性外周T细胞；
■评估来自血浆和/或血清的细胞因子谱；
■根据RANO(神经肿瘤学反应评估)标准和神经肿瘤学免疫治疗反应评估(iRANO)标准评估的无进展生存期；
■总体生存期(OS)。
研究设计
本示例中描述的研究与ClinicalTrials_gov标识符NCT03491683相对应。本发明提供的与本研究相关的数据反映了本研究截至本申请时的状态。在本研究中，向新诊断GBM的患者施用抗原特异性T细胞生成治疗、INO-5401和INO-9012，然后使用
2000设备进行电穿孔，联合PD-1检查点抑制剂、西米普利单抗注射溶液，结合放疗和替莫唑胺，评估此组合的耐受性、免疫原性和抗肿瘤活性。获得纽约大学(NYU)伦理委员会的伦理批准；批准号i 17-00764。
这是一项1/2期、开放标签、多中心试验，旨在评价INO-5401和INO-9012联合西米普利单抗(也称为REGN2810)在新诊断GBM的受试者中的安全性、免疫原性和初步疗效。所有患者均提供书面知情同意书。
受试者在确定性组织病理学诊断GBM并从手术干预中充分恢复后开始使用REGN2810进行免疫治疗。根据在CLIA认证实验室(在RT完成之前进行)进行的MGMT基因甲基化测定的结果为受试者分配队列。将第0天指定为免疫治疗的开始。REGN2810每三周静脉给药(IV)一次，直至出现iRANO(神经肿瘤学中的免疫反应评估)定义的疾病进展、不可接受的毒性、撤回同意书或死亡为止。
在第0天，受试者接受肌肉注射(IM)INO-5401和INO-9012，然后进行电穿孔(EP)。施用INO-5401和INO-9012，然后进行EP，每三周施用一次，共四剂，然后每9周施用一次，直至出现iRANO定义的疾病进展、不可接受的毒性、撤回同意书或死亡为止。
在放疗期间，除非存在临床禁忌，否则所有受试者施用替莫唑胺，无论其是否具有MGMT启动子甲基化。在手术干预后42天内开始放疗(RT)。放疗在第0天后约1-2周开始，并持续约3周。在放疗(TMZ/RT)期间每天施用替莫唑胺(TMZ)。从TMZ/RT恢复后，具有MGMT启动子甲基化的受试者接受6个周期的维持(辅助)TMZ。在28天周期的前5天施用维持(辅助)TMZ。本研究有两个队列：由具有未甲基化MGMT启动子的受试者组成的队列A以及由具有甲基化MGMT启动子的受试者组成的队列B。
研究人群
每个潜在受试者均满足以下所有标准才能入选研究：患者资格概述
在确定性手术后新诊断GBM的成人并且能够接受标准治疗。估计受试者数量：52。队列A：MGMT启动子未甲基化(N＝32，30名可评价受试者)。队列B：MGMT启动子甲基化(N＝20，19名可评价受试者)。
入选标准：
●受试者必须根据机构指导提供IRB批准的书面知情同意书；
●在签署知情同意书之日年满18周岁，能够并愿意遵守所有试验程序；
●新诊断脑癌伴病理组织学诊断为胶质母细胞瘤(GBM)；
●卡氏性能状态(KPS)评分≥基线70；
●在第0天接受地塞米松等效剂量≤2mg/天，≥三天稳定或减少；
●从研究者定义的先前GBM手术的影响中恢复；
●在签署知情同意书(ICF)后28天内进行ECG，并经研究者评估没有临床显著发现；
●在第一次试验治疗前28天内获得下表中定义的血液学、肾脏、肝脏参数，证明器官功能充分；
*肌酐清除率应根据Cockcroft-Gault公式计算
●同意在试验期间，男性不能繁衍后代，女性如果有生育能力，则不能怀孕。受试者必须具有非生育潜力(如果未进行激素替代治疗，通过促卵泡激素[FSH]确认非治疗引起的闭经≥12个月)；或手术导致的不孕不育(男性输精管结扎或女性没有卵巢和/或子宫)；或同意在治疗期间和至少在最后一次给药后的第12周内使用一种失败率<1％/年的高效或联合的避孕方法。周期性禁欲(例如日历、排卵、共热或排卵后方法)和戒断是不可接受的避孕方法。预计失败率<1％/年的避孕方法示例包括男性绝育和激素植入物。或者，正确使用联合口服或注射激素避孕药和某些宫内避孕器(IUD)或者可以结合使用两种方法(例如两道屏障法，如避孕套和子宫帽)实现每年＜1％的失败率(屏障法必须始终辅以杀精剂)；
●耐受磁共振成像(MRI)的能力。
排除标准：
●术后MRI显示大于1cm×1cm的残余肿瘤强化；
●术后MRI显示多病灶疾病或软脑膜疾病(LM)；
●在手术切除肿瘤后42天内无法开始放疗；
●接受地塞米松等效剂量大于>2mg/天；
●在过去任何时候使用阻断PD-1/PD-L1通路的药物进行先前治疗；
●在接受首剂治疗后28天内，接受先前批准的或研究的免疫调节剂(例如抗TNF、治疗性抗癌疫苗、细胞因子治疗(G-CSF或红细胞生成素除外)或靶向细胞毒性T淋巴细胞抗原4(CTLA-4)、4-1BB(CD137)、PI3K-δ或OX-40的药剂)；
●在过去任何时候接受过艾地拉利昔的先前治疗；
●过去、现在或计划中的肿瘤治疗领域(Optune；NovoTTF)的治疗；溶瘤细胞病毒治疗；或先前接触过研究药剂或装置，包括用于化疗的Gliadel晶片(卡莫司汀)植入物；在接受首剂治疗后28天内；
●对REGN2810或其任何赋形剂过敏或有超敏反应；
●有记录的过敏反应或归因于抗体治疗的急性超敏反应的病史；
●需要全身免疫抑制治疗的自身免疫疾病的持续或近期(5年内)证据，这可能表示免疫相关不良事件(irAE)的风险，但白癜风、已治愈的儿童哮喘、1型糖尿病、仅需要激素替代治疗的残余甲状腺功能减退症或不需要全身治疗的牛皮癣除外；
●如入选标准中所述，在首剂试验治疗前28天内诊断出免疫缺陷或接受全身免疫抑制治疗，但使用地塞米松治疗研究中的基础疾病除外；
●人类免疫缺陷病毒(HIV)血清检测阳性，或HIV感染史；或乙型肝炎病毒表面抗原(HB V sAg)或丙型肝炎病毒核糖核酸(HCV RNA)检测阳性，表明活动性或慢性感染，因为这些感染可能会干扰对疫苗接种产生适当免疫反应的能力；
●目前其他部位存在恶性肿瘤，除了经过充分治疗的基底或鳞状细胞皮肤癌或3年内没有疾病证据的原位子宫颈癌。接受过恶性肿瘤治愈治疗、3年无疾病证据且复发风险较低的癌症生存者有资格参加试验；
●在首剂试验治疗前4周内接受任何疫苗，但灭活流感疫苗(可在2周前暂停)除外；
●存在临床显著、医学上不稳定的疾病史，根据研究者的判断，这些疾病会危及受试者的安全、干扰试验评估或终点评估，或以其他方式影响试验结果的有效性(例如慢性肾功能衰竭、心绞痛、心肌缺血或梗塞、纽约心脏协会(NYHA)III/IV类心脏病)；或任何心脏预激综合征(例如Wolff-Parkinson-White综合征；心肌病或临床显著的心律失常)；
●近5年内有肺炎病史；
●急性或慢性出血或凝血障碍，在第0天后2周内禁用IM注射或使用血液稀释剂(例如抗凝剂或抗血小板药物，不包括非处方阿司匹林或非甾体抗炎药，如布洛芬)；
●考虑到三角肌和前外侧股四头肌，可用于IM注射的可接受部位少于两个。不可接受的部位如下：
○纹身、瘢痕疙瘩或增生性瘢痕位于预期治疗部位2cm内；
○心脏除颤器或起搏器(防止危及生命的心律失常)位于三角肌注射部位同侧的(除非心脏病专家认为可接受)；
○预期治疗部位(即EP区域)内存在金属植入物或可植入医疗器械；
●主动吸毒或酗酒或研究者认为对毒品或酒精的依赖会干扰对试验要求的遵守；
●监禁或为治疗精神或身体(即传染病)疾病而强制拘留(非自愿监禁)；
●怀孕或正在哺乳；
●根据研究者的决定，任何可能干扰受试者参与能力或影响受试者安全的身体或心理或非身体状况。
剂量和给药
研究药品
INO-5401中的活性药物成分(API)是使用专有合成共有
技术设计和构建的DNA质粒序列。此过程涉及在多个菌株中合成衍生共有基因，并在遗传水平上优化DNA插入物，以允许在人类细胞中高表达。INO-5401质粒如下：
■pGX1108，一种用于表达前列腺特异性膜抗原的质粒(PSMA；SEQ ID NO:28)。每10mg剂量的试验治疗中存在3mg pGX1108(INO-5401+INO-9012)。
■pGX1404，一种用于表达Wilms肿瘤基因-1(WT1)抗原的质粒(SEQ ID NO:26)。每10mg剂量的试验治疗中存在3mg pGX1404。
■pGX1434，一种用于表达人端粒酶逆转录酶(hTERT)的质粒(SEQ ID NO:20)。每10mg剂量的试验治疗中存在3mg pGX1434。
药品INO-9012中的API为pGX6001，这是一种用于表达人IL-12p35和p40亚基蛋白的DNA质粒。每10mg剂量的试验治疗中存在1mg pGX6001。DNA质粒产物INO-5401和INO-9012均使用注射器和研究的
2000电穿孔(EP)装置给药。
西米普利单抗注射溶液(REGN2810)是一种共价异四聚体，由两个二硫键连接的人重链组成，每个重链均通过二硫键与人κ轻链共价结合。基于一级序列，抗体的分子量约为143.6kDa。每个重链上都有一个单一N连接糖基化位点，位于分子Fc部分的恒定区域内。
REGN2810重链具有IgG4同种型恒定区。重链和轻链的可变结构域结合在抗体内形成PD-1结合位点。在使用PD-1免疫后，使用标准技术通过
小鼠产生抗体。将编码REGN2810重链和轻链的基因引入CHO细胞，并为所述抗体开发具有较高效价的稳定表达细胞系(细胞系2)。对于两种细胞系，重组CHO细胞在悬浮培养中生长并进行化学诱导，从而启动抗体表达和分泌到细胞培养基中。通过过滤收获抗体，并通过一系列制备色谱柱和过滤步骤纯化，进而生成原料药。然后配制原料药并进行无菌过滤，生成最终药品。
在含有10mM组氨酸、5％(w/v)蔗糖、1.5％(w/v)L-脯氨酸和0.2％(w/v)聚山梨醇酯80的水缓冲溶液(pH 6.0)中配制REGN2810(50mg/mL)。REGN2810为用于IV给药封装在10或20mL玻璃瓶中的5.5mL无菌液体溶液。从含有250mg REGN2810的每个瓶中可取出的最大体积为5.0mL。需要7mL才能提供350mg剂量的REGN2810，因此在提供5mL西林瓶时，必须使用2瓶。REGN2810(50mg/mL)也可为为用于IV给药封装在10或20mL玻璃瓶中的7.44mL无菌液体溶液。从含有350mg REGN2810的每个瓶中可取出的最大体积为7.0mL。
治疗
符合所有入选标准且无排除标准的受试者在第0天开始使用REGN2810和INO-5401+INO-9012进行免疫治疗。在不保持剂量的情况下，每三周IV注射REGN2810，每剂量350mg，直至出现iRANO定义的疾病进展、不可接受的毒性、撤回同意书或死亡为止。在不保持剂量的情况下，IM注射INO-5401和INO-9012，然后进行EP，每三周施用一次，共四剂，然后每9周施用一次，每剂10mg/DNA，直至出现iRANO定义的疾病进展、不可接受的毒性、撤回同意书或死亡为止。在手术干预后42天内开始RT，大约在第0天后1-2周开始。RT持续大约三周。在3周内施用的RT总剂量为40Gy。
在手术干预后42天内开始每日TMZ和放疗(TMZ/RT)，大约在第0天后2周开始。TMZ/RT持续大约三周。在没有减少剂量的情况下，以75mg/m2/剂的剂量施用TMZ。然后，受试者应再接受6个周期的维持(辅助)TMZ。队列B在放疗后接受长达六个周期的TMZ。根据标准TMZ治疗指导，在TMZ/RT外周血细胞计数恢复后，在28天周期的前5天以150-200mg/m2/剂向队列B中的受试者施用维持(辅助)TMZ。
第0天(首剂INO 5401、INO 9012和REGN2810)为原发性肿瘤切除完成后至少14天，受试者已从手术中恢复，但不迟于术后第28天。
对于因进展以外的原因停止一种治疗(INO-5401+INO-9012或REGN2810)的受试者，在咨询医学监督员后允许继续进行另一种治疗。
图1显示了队列A和队列B的试验设计。
●INO-5401(hTERT、WT-1和PSMA质粒各3mg)加上1mg INO-9012(IL-12)，共10mgDNA，通过肌肉注射(IM)给药，然后用
2000装置进行电穿孔(EP)，每3周施用一次，共四剂，然后每9周施用一次。
●放化疗：以低分割时间表(3周内40Gy)施用放疗(RT)
●替莫唑胺(TMZ)与放疗同时进行(队列A和队列B)，然后进行六个维持(辅助)周期(仅队列B)
从第0天开始，以每三周(Q3W)350mg的剂量在约30分钟内IV注射西米普利单抗注射溶液(REGN2810)，并持续至出现iRANO定义的疾病进展、不可接受的毒性、撤回同意书或死亡为止。
INO-5401是三种靶向WT1、PSMA和hTERT蛋白的独立合成质粒的混合物。每种质粒以3mg DNA施用，每剂INO-5401共有9mg DNA。在第0天、第3周、第6周和第9周施用INO-5401，然后每9周施用一次，并持续至出现iRANO定义的疾病进展、不可接受的毒性、撤回同意书或死亡为止。INO-9012是一种表达人IL-12的合成质粒，以1mg DNA给药，并与INO-5401一起经IM注射。当混合和一起给药时，每剂INO-5401+INO-9012中的DNA总剂量为10mg。INO-5401(hTERT、WT-1和PSMA质粒各3mg)加上1mg INO-9012(IL-12)，共10mg DNA，通过肌肉注射(IM)给药，然后用
2000装置进行电穿孔(EP)，每3周施用一次，共四剂，然后每9周施用一次。
所有受试者在15次分割(三周)中共接受了40Gy。
低分割放疗(hfRT)在手术后42天内开始。放疗持续三周。
除非存在临床禁忌证，否则所有患者在放疗期间接受TMZ，无论MGMT甲基化状态如何。TMZ每天口服剂量为75mg/m2，施用21天，同时(每周7天，持续3周)伴随hfRT治疗。
放疗后，具有MGMT启动子甲基化(队列B)的受试者在28天周期的前5天(5天“进行”，23天“不进行”)以150mg/m2/天的起始剂量继续TMZ维持治疗，持续6个周期，并在没有血液毒性的情况下，每个维持周期增加50mg/m2/剂，最大200mg/m2/剂。根据TMZ治疗指导，在最后一剂RT(±3天)后四周和外周血细胞计数恢复后开始维持(辅助)TMZ。使用在每个治疗周期开始时以平方米计算的实际体表面积(BSA)确定剂量。
每日剂量四舍五入至最接近的5mg。
疗效评价/终点ELISpot
ELISpot用于定性测量外周血单核细胞(PBMC)样本中是否存在抗原特异性T细胞。在研究第0周、第3周、第6周、第9周、第12周和第24周，从受试者中收集PBMC，并通过IFN-gELISpot测定。在12个月数据截止时，在第24周采样的8名受试者在治疗前(前段)和使用INO-5401和西米普利单抗注射溶液治疗后在最高量级(峰值)处显示了每百万PBMC的抗原特异性IFNg斑点形成单位(SFU)。每名受试者用空心圆圈表示，条形表示平均值。各抗原图与11名被测受试者以及8名在第24周采样的受试者显示了从前段到峰值的差异(Δ)。在18个月数据截止时，39名受试者在治疗前(前段)和使用INO-5401和西米普利单抗注射溶液治疗后在最高量级(峰值)处显示了每百万PBMC的抗原特异性IFNg斑点形成单位(SFU)。每名受试者用空心圆圈表示，条形表示平均值。显示了每个抗原图以及39名受试者从前段到峰值的差异(Δ)。INO-5401是WT1、PSMA和hTERT的总和。箱形图从第25个百分位延伸到第75个百分位数，中位数为水平线，平均值为“+”。
裂解性颗粒加载
进行裂解性颗粒加载测定，探索在研究第0周、第3周、第6周、第9周、第12周和第24周从受试者采集的PBMC样本中存在的抗原特异性T细胞的活化状态和裂解潜力。在没有任何外源细胞因子的情况下，用INO-5401抗原(hTERT、PSMA和WT1)或相关对照的重叠肽库刺激PBMC。5天后，用抗体染色细胞并通过流式细胞术进行评估。在12个月数据截止时，针对8名受试者，在治疗前(前段)和使用INO-5401和西米普利单抗注射溶液治疗后在最高量级(峰值)处测定了具有裂解潜力(表达颗粒酶A、穿孔素)的活性、抗原特异性、活化(CD38+)CD3+CD8+T细胞的频率，在18个月数据截止时，对29名受试者进行了相同操作。
安全性评估
不良事件(AE)根据不良事件常见毒性标准(CTCAE)v4.03进行分级，按系统器官类别、优选术语、严重程度以及与试验治疗的关系进行分类；实验室安全性参数与基线相比出现的临床显著变化。
使用修饰的Rolling 6设计进行安全导入，每个队列最多入选六名受试者(队列A和队列B总共最多12名受试者)。入选时间错开，每个队列中第一名和第二名受试者的入选间隔为一周，第二名和第三名受试者之间也等待一周。每名受试者都进行了评估，直到第9周。到第9周，受试者接受三剂REGN2810，三剂INO-5401+INO-9012，并完成了RT。
在没有剂量限制性毒性(DLT)的情况下，每个队列中六名受试者的前三名受试者完成第9周的评估后，在由申办方和再生元制药公司的医学监督员以及协调主要研究者对这些患者的所有可用安全数据进行审查，该队列的入选工作已全面开始。然而，如果在每个队列中前三名受试者完成第9周之前，该队列中前六名受试者中一名受试者出现DLT，那么入选人数将限制在该队列中的六名受试者，直到所有六名受试者都达到第9周并接受DLT评估。
如果前6名受试者中的第二名受试者在前9周内在同一个队列中出现DLT，则将停止该队列的入选，并且除了受试者所在地的主要研究者(PI)和研究者之外，申办方的医学监督员将讨论该病例，并决定是否在修改该队列的试验药物或伴随药物(RT/TMZ)剂量，或停止进一步入选该队列。如果需要更改方案，则只有在方案修改并由IRB批准修改的方案后才能重新开始入选。
DLT定义为：
非血液毒性
●≥2级葡萄膜炎。
●≥3级非血液毒性；但以下情况除外：
■3级恶心、呕吐或腹泻，除非持续存在(持续时间>7天)，尽管根据主治医生的规定已采取最大限度的支持性护理措施。
■≥3级实验室异常，临床上认为这些异常不显著且不符合AE标准。
■对药物治疗有反应的3级输液相关反应。
■除葡萄膜炎外，3级免疫相关不良事件(IRAE)，在14天内通过药物治疗(包括类固醇治疗)改善至≤2级。
血液毒性
●4级中性粒细胞减少症，>7天。
●4级血小板减少症，或伴出血的3级血小板减少症。
●≥3级发热性中性粒细胞减少症(发热≥38.5℃，中性粒细胞绝对计数[ANC]<1000/mm3)，或≥3级中性粒细胞减少症伴有明确感染。
治疗研究者认为与潜在肿瘤、并发药物或合并症事件相关的事件，以及不太可能与试验治疗相关的事件(INO-5401、INO-9012或REGN 2810)，但至少可能与替莫唑胺或RT相关，不应将这些事件视为DLT。出现DLT的患者将停止进一步的试验治疗，并进入试验的试验后随访阶段。符合DLT标准但在DLT窗口之外发生的不良事件将归类为不可接受的AE，并停止试验治疗。
在安全导入期后，如果在本临床研究过程中的任何时间点，任一队列中≥30％的受试者出现了与研究试验药物相关的剂量限制性毒性，则停止入选一个队列或两个队列，并且除了受试者所在地的主要研究者(PI)和研究者之外，申办方的医学监督员将讨论试验药物的安全性，并决定是否修改一个队列或两个队列的试验药物或伴随药物(RT/TMZ)剂量，或停止进一步入选一个队列或两个队列。如果需要更改方案，则只有在方案修改并由IRB批准修改的方案后才能重新开始入选。
医疗和临床评估
从签署ICF时开始并在所有随后的试验访视中(直至试验结束)，收集伴随药物。
从签署ICF时开始收集所有AE的评估，直到最后一剂INO-5401+INO-9012或REGN2810后30天(以较晚者为准)，但AESI和本方案中定义的SAE除外，其将在最后一剂INO-5401+INO-9012或REGN2810后6个月(以较晚者为准)进行收集。使用NCI CTCAEv4.03评估AE。
物理评估
每3周进行一次全面检查，包括完整的神经检查(颅神经评估、深部腱反射、肌肉力量和感觉)以及卡氏性能评分(KPS)。
医疗治疗后反应评估
在第0天，在REGN2810和INO-5401+INO-9012治疗前、在REGN2810输注结束时、在REGN2810输注后前4小时的每30分钟以及在INO-5401+INO-9012输注伴EP后30分钟收集生命体征。在所有其他访视中，研究者在每次治疗(REGN2810和/或INO-5401+INO-9012)后以及根据事件时间表在指定访视中评估30分钟内的局部和全身反应。
生命体征
在所有试验治疗访视中测量生命体征，包括体温、呼吸频率、血压和心率。
体重、身高和体重指数
在筛查访视中收集体重(kg)和身高(cm)。从第0天到治疗结束，在每次额外的治疗访视时收集体重。
在第0天、第3周、第6周、第9周、第18周以及第18周后每9周评估体重指数的同时受试者接受EP程序，其次是需要评估针规。
12导联ECG
在第0天之前28天的筛查时对受试者进行ECG，以确定受试者的资格。异常ECG应解释为临床显著或非临床显著。将与试验医学监督员讨论筛查时发现的异常ECG，确定受试者的资格。
妊娠试验
对于具有生殖潜力的女性，在筛查访视时和每次施用INO-5401+INO-9012和REGN2810之前，血清妊娠试验(试验必须具有至少25mIU/mL的敏感性)的结果为阴性。如果在任何时候，β-HCG(妊娠)试验呈阳性，表明受试者怀孕，则无需进行额外的试验治疗，但在试验期间及以后应对受试者进行跟踪以确定怀孕结果(经受试者同意)。
实验室评价
按照试验事件时间表中的规定收集血液样本。
如果在第0天后的7天内进行筛查实验室试验，则可采用筛查实验室进行第1次访视(第0天)。否则，在治疗前不超过72小时收集与任何治疗访视(CBC和化学分析)相关的所有实验室结果，并在治疗前由研究者审查/评价。
全血细胞计数(CBC)应包括：
●白细胞(WBC)计数与差异
●红细胞(RBC)计数
●血红蛋白、红细胞压积
●血小板计数
血清化学分析应包括：
●葡萄糖
●白蛋白
●总蛋白
●SGPT(血清谷氨酸-丙酮酸转氨酶；ALT)
●SGOT(血清谷氨酸-谷草转氨酶；AST)
●碱性磷酸酶
●胆红素(总)
●直接胆红素
●BUN(血尿素氮)
●钙
●肌酸
●电解质(钠、钾、氯化物、二氧化碳或碳酸氢盐)
●脂肪酶
●淀粉酶
●CPK
在筛查时进行的评估仅包括：
●HIV筛查测试(抗体免疫测定测试)；或在医疗记录中记录这些结果；
●乙型肝炎血清学：HBsAg(乙型肝炎表面抗原)；或在医疗记录中记录这些结果；
●丙型肝炎抗体免疫测定；或在医疗记录中记录这些结果；
●尿液分析包括比重、葡萄糖、血液和酮；
●活化部分凝血致活酶时间(aPTT)、INR。
外周血免疫原性评估
获得全血和血清样本。在筛查时、第0天、第3周、第6周、第9周、第12周和之后每12周(第24周、第36周、第48周等)抽取免疫样本。
使用覆盖INO-5401抗原(hTERT、WT-1和PSMA)的重叠肽库，使用抗原特异性IFN-γELISpot测定评估T细胞反应。此外，评估了PBMC对来自巨细胞病毒、爱泼斯坦-巴尔病毒和流行性感冒(CEF)的已知抗原表位的反应，以便在试验期间跟踪一般细胞免疫能力。
通过流式细胞仪重叠肽库(覆盖INO-5401抗原)评估T细胞反应。流式细胞术测定可包括检查免疫治疗对受试者T细胞在由与INO-5401抗原对应的肽刺激后表现出与细胞溶解潜力、活化或耗竭相关表型标志物的能力的影响。为此使用的标志物包括CD3、CD4、CD8、CD137、CD69、CD38、PD-1、粒溶素、颗粒酶A、颗粒酶B和穿孔素。这些标志物可能会随着新数据的出现而发生变化，这些数据可为本评估提供信息。
可应用流式细胞术评估是否存在已知在免疫抑制中起作用的细胞。流式细胞术测定可包括检查这些细胞对免疫治疗后免疫反应的诱导或扩增的影响。为此使用的标志物包括CD3、CD16、CD19、CD20、CD56、CD11b、CD14、CD15、CD33和HLA-DR。这些标志物可能会随着新数据的出现而发生变化，这些数据可为本评估提供信息。
对整个PBMC进行PBMC的TCR测序以评估多样性和推定的抗原特异性，无论是否进行事先体外刺激。
通过应用酶联免疫吸附测定(ELISA)或用于检测抗原特异性抗体分泌的其他方法和/或使用流式细胞术进行B细胞表型分析来评估体液反应。可通过基于CD137等标志物的表达分离这些细胞来进行TAA特异性T细胞的分析。分离后，可以进行RNAseq，进而了解这些细胞的唯一转录组。使用Luminex等评估平台进行外周血细胞因子谱的分析。
组织免疫学
通过一系列评估检查在INO-5401给药之前和之后肿瘤组织中的免疫浸润以及是否存在免疫调节因子，这些评估包括：
●通过IHC、免疫荧光(IF)或基因组测序在肿瘤和浸润免疫细胞中表达PD-L1和肿瘤癌蛋白
●RNAScope对TIL浸润(CD3、CD8、CD4)的表征
●通过RNAScope评估肿瘤Treg、骨髓免疫抑制人群和T细胞免疫检查点表达
●切除肿瘤组织中的T细胞受体测序，将任何已有克隆T细胞群与外周血中T细胞多样性的治疗相关变化相关联
生物标志物
根据上述外周和组织样本进行生物标志物评估，并根据实验室手册说明进行收集。对入选受试者组织样本中hTERT、WT1和/或PSMA蛋白表达进行免疫组织化学评估取决于是否存在足够的样本量和现有数据支持的持续相关性。如可以，对肿瘤组织进行IDH-1状态检查。评估血浆和/或血清中的微RNA特征，从而确定疾病和/或治疗特异性特征，这些特征可预测病程和/或对INO-5401以及INO-5401驱动变化的治疗反应。此方法中可采用RNAseq。
可能会评估来自外周血的循环肿瘤细胞、循环内皮细胞和/或循环癌症相关巨噬细胞样细胞。为此可使用基于尺寸排阻的过滤器，标志物可包括GFAP、CD45、波形蛋白、PD-L1、CD146、TIE-2和其他可能的标志物。
临床评估
在所有试验访视中对疾病反应进行临床评价(通过临床体征和疾病进展症状进行评估)。在第0天后9周(±3天)和之后每3个月对所有受试者进行疾病进展MRI，除非通过iRANO评估认为假性进展。在此类情况下，应在疑似假性进展后的3个月内进行重复确认性MRI扫描。
总体生存期
跟踪所有受试者的生存期。完成治疗结束访视后，每6个月和第0天后的第18个月需要记录生存状态。可采用以下方法记录生存期：电话；私下联系；确认函；或医疗记录中确认的访视记录。
进展
通过RANO和iRANO对进展进行评估。对进展前退出的患者进行进展和生存期随访。
RANO和IRANO：神经肿瘤学(免疫治疗)反应评估
本试验同时使用了RANO和iRANO标准。神经肿瘤学放射评估(RANO)标准于2010年提出，用于改善对恶性胶质瘤受试者成像复杂性不断发展的评估[Wen等人，《临床肿瘤学杂志》2010，28:1963-1972]。RANO标准为假性进展的出现提供了指南，在放疗和TMZ治疗后大约有10-20％的新诊断GBM受试者出现假性进展。临床益处，包括长期生存和肿瘤消退，仍然可在疾病初始进展或出现新病灶后出现。iRANO标准由多国和多学科的神经肿瘤学免疫治疗专家小组(RANO工作组)制定，该小组为确定神经肿瘤学免疫治疗试验中的肿瘤进展制定了指南[Okada等人，《柳叶刀肿瘤学》，2015，16:e534-542；Reardon等人，《神经肿瘤学》，2014，16(增补2)]。iRANO工作委员会建议，对于有早期进展发现的受试者(免疫治疗少于6个月)，包括出现新病灶但没有实质性神经功能衰退的受试者，应在取得进行性疾病的初始放射学证据后3个月通过随访影像来确认放射学进展，以降低在假性进展或反应延迟的受试者中过早宣布进行性疾病的可能性。在此类受试者中，那些通过与首次显示疾病进展证据的扫描进行比较而确认进一步放射学进展的受试者，或随时出现实质性临床下降的受试者，被归类为患有进行性疾病，疾病进展的日期可追溯到受试者符合放射学进展标准的第一个日期。
在本研究中，研究者在面对疑似进展时决定是否停止研究药物时使用了iRANO标准，然而，所有受试者都要通过RANO和iRANO的进展标准进行进展评估。
NANO量表：神经肿瘤学中的神经评估
NANO量表仅与iRANO和RANO标准结合使用。
虽然RANO和iRANO量表规定必须将临床状态纳入整体评估，但两种量表均没有提供这样做的具体参数。召集一个国际神经肿瘤学家小组起草NANO标准，作为可在常规检查中评价神经功能的客观和可量化指标。NANO量表包括根据在例行办公室访视期间进行的直接观察/测试，对八个相关的神经领域进行评估。评分定义了反应、进展、疾病稳定和“未评估”的特定领域和总体评分的标准。这些标准提供了神经功能的详细和客观衡量，可通过临床试验和治疗干预进行评估[Nayak等人，《神经肿瘤学》，2017，19:625-635]。此试验包括在评估RANO和iRANO时使用NANO量表的临床评估。
AE定义为向患者或临床研究受试者施用药品发生的任何不良医学事件，并且不一定必须与治疗有因果关系。因此，AE可以是任何不利和意外迹象(例如，包括异常的实验室发现)、症状或与使用药品暂时相关的疾病，无论是否与药品有关。
在本研究中，对AE进行监测、分类和总结。只有在开始研究治疗后恶化时，才认为在开始使用研究产品之前存在的病症/疾病属于AE。意外AE是在研究药物的参考安全性文件或IB的相应部分中未确定的AE。在整个研究过程中，对所有AE进行监测并在AE CRF中报告，包括事件的严肃性、严重性、采取的措施以及与IP的关系。跟踪不良事件直至其解决或稳定，并在适当的CRF中记录结果。所有AE记录均采用标准医学术语，而非受试者自己的叙述。
AE包括以下内容：
●由于方案规定的程序而发生的治疗前或治疗后并发症。
●在人类临床试验的试验药物阶段或作为人类临床试验的试验药物的结果，导致严重程度增加或性质发生变化的任何已有病症。
●妊娠并发症。AE不包括以下内容：
●进行医疗或外科手术(例如手术、内窥镜检查、拔牙、输血)；导致此程序的病症可视为AE。
●在筛查访视之前出现或发现的不会恶化的疾病、病症或实验室异常。
●未发生不良医学事件的情况(例如，选择性手术住院、社交和/或方便入院)。
●研究药物过量，无临床后遗症。
●在签署ICF之前出现的病症或临床显著实验室异常均不属于AE，除非情况恶化。在病史CRF上记录。
●无并发症妊娠。
●无医学原因终止妊娠的选择性流产(记录在妊娠CRF上)。
记录从签署同意书到整个试验期间以及最后一次给药后30天(免疫相关AE为6个月；irAE)发生的所有AE。
严重不良事件(SAE)是指符合以下条件的任何AE：
●在方案规定的监督期间死亡(不包括由于疾病进展导致的死亡)；
●直接危及生命(例如在研究者看来，受试者在事件发生时处于直接死亡风险)；
●在方案定义的监督期间要求受试者住院治疗或延长现有住院治疗时间(包括在医院过夜，无论时间长短，即使住院只是为了继续观察而采取的预防措施)。然而，因未恶化的已有病症而住院(包括选择性手术住院)不构成SAE；
●导致持续或严重的残疾/丧失能力(严重破坏一个人进行正常生活机能的能力)；
●导致先天性异常或天生缺陷；
●否则是可能不会导致死亡、危及生命或需要住院的重要医疗事件，但根据适当的医学判断，可能会危及受试者，并可能需要医疗或手术干预以防止发生上述一种结果。此类医疗事件的示例包括：
○需要在急诊室或家中进行强化治疗过敏性支气管痉挛；
○不会导致住院治疗的恶血质或抽搐；
○药物依赖或药物滥用的发展。注意以下SAE的说明：
●死亡是AE的结果，而不是AE本身。
●事件发生时，受试者可能未采用IP。
●可能已作为治疗周期提供给药或在SAE开始前暂时中断给药，但可能促成该事件。
●“危及生命”是指受试者在事件发生时处于直接死亡风险。这不包括更严重时可能导致死亡的事件。
●住院期间发生的并发症是AE。如果并发症延长了住院时间，则为SAE。
●住院是指受试者因医疗原因正式入院，时间不限。
研究者试图根据体征、症状和/或其他临床信息确定事件的诊断。在此类情况下，诊断应记录为AE和/或SAE，而不是个体体征/症状。
统计和分析计划
这是一项单臂(INO-5401+INO 9012与REGN2810组合)、开放标签、多中心试验，适用于新诊断GBM的患者，这些患者具有未甲基化MGMT启动子的肿瘤(队列A)和MGMT甲基化启动子的肿瘤(队列B)。试验的主要分析涉及INO-5401和INO-9012与REGN2810组合的安全性和耐受性。试验的次要分析使用OS18和免疫原性生物标志物(ELISpot/流式细胞术/TCR测序/抗原特异性体液反应)评估了INO-5401和INO-9012与REGN2810组合的疗效。
探索性分析涉及临床反应与肿瘤遗传学和生物标志物之间的相关关联。通过RANO(神经肿瘤学反应评估)标准评估的无进展生存期和总体生存期也作为探索性终点进行评估。
统计假设
该试验的每个队列都有一个单独的独立假设，评估18个月时的次要终点总体生存期(OS18)。OS18的真正治疗效果定义为p，其中p表示每个队列中OS18的真实人群概率。然后，对于MGMT启动子未甲基化的受试者(队列A)，优于历史对照的假设为：H0：p≤0.45与H1：p>0.45，对于MGMT启动子甲基化的受试者(队列B)，优于历史对照的假设为：H0：p≤0.60与H1：p>0.60。
分析人群/数据集
分析人群为：
○改良意向性治疗(mITT)人群包括接受至少一剂试验治疗的所有受试者。mITT人群将用于分析OS18的次要终点以及所有探索性疗效终点，包括OS和PFS。
○符合方案(PP)人群由接受前四剂试验治疗中至少三剂的受试者组成，并且这些受试者没有违反方案。对PP群体的分析将视为支持相应的mITT群体，以分析疗效。在锁定试验数据库之前，确定和记录从PP人群中排除的受试者。
○安全性分析集包括接受至少一剂INO-5401或INO-9012或REGN2810试验治疗的所有受试者。根据受试者接受的治疗对其进行分析。
主要安全终点的统计方法分析说明
该试验的主要分析是治疗紧急不良事件(TEAE)的安全性分析以及实验室安全参数与基线相比的显著变化。
该试验的TEAE定义为在第0天至最后一剂试验治疗后30天内出现的任何AE，但irAE、AESI和SAE除外，这些事件可能在最后一剂试验治疗后6个月内出现。所有TEAE将按每个队列内和两个队列相结合的频率、百分比和95％Clopper-Pearson置信区间对安全性分析集中的受试者进行总结。
这些频率将按剂量数整体和单独表示，并按系统器官类别和优选术语整体描述受影响受试者的百分比。将针对最大严重程度和与试验治疗的最强关系表示其他频率。在严重程度和与试验治疗的关系方面，按照最坏情况的方法，单个受试者中多次出现相同AE仅计为一次。所有严重TEAE也将按照上文进行总结。
将任何缺失或部分开始/停止日期的AE纳入整体AE总结中，但从AE持续时间的计算中排除。AE持续时间将按照AE停止日期-AE开始日期+1天计算。不属于TEAE或严重TEAE的AE、irAE、AESI和SAE将在列表中列出。
实验室反应变量将按时间点和相对于基线的变化进行描述性汇总，包括95％置信区间。还显示了根据CTCAE相对于基线的变化情况。列表还显示了具有临床显著性的实验室值。
对安全性分析集中的受试者进行所有安全性分析。
次要疗效终点分析
使用每个队列的频率、百分比、95％Clopper-Pearson置信区间和p值对OS18的次要终点进行总结。如果受试者在18个月(548天)后确定为存活，则视为生存者。
如果单侧p值<0.025，则结论为具有优势。在mITT和符合方案人群中对受试者进行OS18分析，将所有mITT/PP受试者均纳入OS18分母中。
使用每个时间点的描述性统计数据和相对于基线的变化表示细胞和体液免疫反应。
其他安全数据的分析
对于安全人群中的受试者，具有异常病史结果的受试者百分比将按每个队列的身体系统和优选术语进行总结。
先前的药物是指在试验开始之前(在第0天之前的28天内)使用的药物。伴随药物是指在试验过程中(在第0天或之后)使用的药物。先前和伴随药物的部分开始日期将假定为与部分日期一致的最早可能日期。先前和伴随药物的部分停止日期将假定为与部分日期一致的最晚可能日期。对于安全人群中的受试者，所有先前和伴随药物的数据将按每个队列的百分比进行总结。
对于安全性分析集中的受试者，生命体征的测量以及相对于基线的变化将按每个队列的时间点进行描述性总结。对于安全性分析集中的受试者，每个时间点身体检查结果异常的受试者百分比将按身体系统在每个队列内进行整体描述性总结。
筛查时的ECG和病毒血清学以及每个时间点的血清妊娠将在每个队列中进行整体描述性总结。
处置
受试者处置将按队列和整体对所有入选受试者进行总结，并包括入组人数和百分比、接受每个计划剂量的人数和百分比以及完成试验的人数。停止治疗的受试者人数和百分比将按原因进行整体总结。还将显示每个分析人群中的人数。
人口统计和其他基线特征
在安全性分析集中，按队列对人口统计和基线特征数据进行描述性总结。
探索性分析
使用Kaplan-Meier统计方法在每个队列和整体中总结了通过RANO(定义为从第0天到因任何原因或进展导致的死亡日期的时间，以先发生者为准)和OS(定义为从第0天到因任何原因导致的死亡日期的时间)评估的无进展生存期。在撤回同意书或最后一次进展评估日期(认为受试者没有进展)时，删失受试者的PFS。在撤回同意书或已知受试者存活的最后日期，删失未记录为死亡的受试者的OS。在mITT和符合方案人群中分析无进展生存期和OS。
对于mITT人群和符合方案人群，使用每个时间点的描述性统计数据和相对于基线的变化来表示探索性肿瘤遗传学和/或生物标志物反应。
使用逻辑回归模型和Cox PH模型根据探索性反应对OS18、PFS和OS进行建模，以检查关联性。基线变量(例如患者人口统计数据或患者疾病特征)作为潜在的混杂因素包含在模型中。另外，将细胞和体液免疫反应用作解释变量。
结果
入组患者的人口统计数据如图2(人口统计数据表)所示。诊断时对肿瘤基因转录本的评估证实了由INO-5401编码的抗原表达和多种免疫基因表达谱。47名受试者中有5人(8.11％)具有可用于评估的组织，表现出由INO-5401(WT1、PSMA和hTERT)编码的一种或多种肿瘤相关抗原的转录本表达。47名受试者中有43人(89％)具有可用于评估的组织，表现出由INO-5401(WT1、PSMA和hTERT)编码的两种(2)或多种肿瘤相关抗原的转录本表达。47名受试者中有19人(40％)表现出所有三种肿瘤相关抗原的转录本表达。没有受试者表现出PD-1表达，无伴随PD-L1表达。47名受试者中有27人(57％)表现出PD-L1表达，而没有伴随PD-1表达。47名受试者中有20人(43％)表现出PD-1和PD-L1的共表达。归一化转录本读取计数>1属于“正数”。
MRI成像
一些患者出现假性进展，在MRI上显示进展的放射学证据，但在重复活检时没有肿瘤证据。患者示例的图像表明在首剂INO-5401+INO-9012和西米普利单抗注射溶液后的时间点上MRI信号增加，有水肿或肿瘤迹象。对几名患者的活检显示治疗相关的变化，伴有坏死和混合炎症；没有有丝分裂活性；并且没有存活肿瘤的证据。图3显示了两名患者的代表性图像。
ELISpot
ELISpot用于定性测量外周血单核细胞(PBMC)样本中是否存在抗原特异性T细胞。在研究第0周、第3周、第6周、第9周、第12周和第24周，从受试者中收集PBMC，并通过IFN-gELISpot测定。在12个月数据截止时，在第24周采样的8名受试者在治疗前(前段)和使用INO-5401和西米普利单抗注射溶液治疗后在最高量级(峰值)处显示了每百万PBMC的抗原特异性IFNg斑点形成单位(SFU)(图4)。每名受试者用空心圆圈表示，条形表示平均值。各抗原图与11名被测受试者以及8名在第24周采集样本的受试者显示了从前段到峰值的差异(Δ)。INO-5401是WT1、PSMA和hTERT的总和。箱形图从第25个百分位延伸到第75个百分位数，中位数为水平线，平均值为“+”。ELISpot结果支持INO-5401和西米普利单抗注射溶液的组合具有免疫原性，5/11名受试者对所有3种抗原的IFN-g量级高于基线，9名受试者对至少一种抗原的IFN-g量级高于基线，如图4所示。
在18个月数据截止时，按队列总结的INO-5401后外周免疫反应的评估显示了通过干扰素γELISpot(与INO-5401各成分相对应的细胞因子产生)测定的抗原特异性T细胞反应。图16A和16B提供了通过ELISpot按队列总结的INO-5401后外周免疫反应的评估结果。对治疗后峰值时间点的基线值进行绘制。在队列A中，迄今为止测试的19/22(86％)名受试者对一种或多种INO-5401抗原的IFN-g量级高于基线(图16A)。在队列B中，迄今为止测试的16/17(94％)名受试者对一种或多种INO-5401抗原的IFN-g量级高于基线(图16B)。
裂解性颗粒加载
进行裂解性颗粒加载测定，探索在研究第0周、第3周、第6周、第9周、第12周和第24周从受试者收集的PBMC样本中存在的抗原特异性T细胞的活化状态和裂解潜力。在没有任何外源细胞因子的情况下，用INO-5401抗原(hTERT、PSMA和WT1)或相关对照的重叠肽库刺激PBMC。5天后，用抗体染色细胞并通过流式细胞术进行评估。该图针对8名受试者的每种抗原，显示了治疗前在基线处(前段)以及使用INO-5401和西米普利单抗注射溶液治疗后在最高量级(峰值)处具有裂解潜力(表达颗粒酶A、穿孔素)的活性、抗原特异性、活化(CD38+)CD3+CD8+T细胞的频率(图5A)。每名受试者用空心圆圈表示，条形表示平均值。在12个月数据截止时，针对8名被测受试者显示了各抗原与INO-5401从前段到峰值的差异(图5B)，以及5/8名在第12周采集样本的受试者从前段到峰值的差异(图5C)。INO-5401是WT1、PSMA和hTERT的总和。箱形图从第25个百分位延伸到第75个百分位数，中位数为水平线，平均值为“+”。五名受试者具有裂解潜力(CD38+Prf+GrzA+)的活化CD8+T细胞的频率，对多种抗原产生的反应高于基线(前段)；三名受试者具有裂解潜力(CD38+Prf+GrzA+)的活化CD8+T细胞的频率，对所有三种抗原产生的反应高于基线。三名受试者在任何时候对任何抗原产生的反应都没有高于基线。
在18个月数据截止时，按队列总结的INO-5401后外周免疫反应的评估显示了通过流式细胞术(具有裂解潜力的抗原特异性CD8+T细胞的扩增)测定的抗原特异性T细胞反应。在队列A中，迄今为止测试的13/19(68％)名受试者对一种或多种INO-5401抗原的CD38+GrzA+Prf+CD8+T细胞频率高于基线(图17A)。在队列B中，迄今为止测试的8/10(80％)名受试者对一种或多种INO-5401抗原的CD38+GrzA+Prf+CD8+T细胞频率高于基线(图17B)。在Q3周采样4次，然后在Q12周采样。对治疗后峰值时间点的基线值进行绘制。
无进展生存期
图6显示了队列A(O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)6个月无进展生存期(PFS6)的Kaplan-Meier估计量的可视化表示。此曲线显示事件在特定时间间隔内的概率。y轴以数字形式表示事件概率，x轴表示时间间隔。显示的事件为无进展生存期。无进展生存期是指给定受试者在给定时间点没有疾病进展。
图7显示了队列B(具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)6个月无进展生存期(PFS6)的Kaplan-Meier估计量的可视化表示。此曲线显示事件在特定时间间隔内的概率。y轴以数字形式表示事件概率，x轴表示时间间隔。显示的事件为无进展生存期。无进展生存期是指给定受试者在给定时间点没有疾病进展。
图8显示了队列A(具有O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)和队列B(具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)6个月无进展生存期(PFS6)的Kaplan-Meier估计量的可视化表示。此曲线显示事件在特定时间间隔内的概率。y轴以数字形式表示事件概率，x轴表示时间间隔。显示的事件为无进展生存期。无进展生存期是指给定受试者在给定时间点没有疾病进展。
图9显示了队列A、队列B和两个队列组合在6个月内无进展生存期(PFS6)的Kaplan-Meier估计量的表格表示。此图提供了每个队列的受试者总数、事件数量、事件(PFS6)估计以及事件(PFS6)的数值估计存在的95％置信区间(CI)。
确诊的进行性疾病(PD)通过≥4周的连续PD扫描确定，或根据活检手术进展确定。在6个月前因PD以外的任何原因终止的受试者归纳为确诊的进行性事件，包括队列B中的两(2)名受试者，他们在第三(3)周退出研究并拒绝长期随访。
总体生存期
对改良意向性治疗(mITT)人群中的受试者进行所有疗效分析(OS12、OS18和Kaplan-Meier)，该人群定义为接受至少一剂计划治疗的所有受试者。将12个月时的总体生存期(OS12)制成表格，作为在研究开始时所有存在死亡风险的受试者中12个月时存活受试者的比例。退出的受试者视为失败(即死亡)。队列A中在12个月前退出研究的所有受试者，也在12个月的随访前死亡。使用Cloper-Pearson精确方法计算95％置信区间(CI)。将18个月时的总体生存期(OS18)制成表格，作为在研究开始时所有存在死亡风险的受试者中12个月时存活受试者的比例。使用Cloper-Pearson精确方法计算95％置信区间(CI)。
图10A显示了队列A(具有O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)12个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。图10B显示了队列A(具有O6-甲基鸟嘌呤甲基转移酶基因启动子未甲基化的肿瘤细胞的患者)18个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。队列A的中位随访时间为17.8个月。mITT包括接受≥1剂研究治疗的任何受试者。阴影表示在该时间点上基于生存点估计值的置信带。
图11A显示了队列B(具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)12个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。图11B显示了队列B(具有O6-甲基鸟嘌呤甲基转移酶基因启动子甲基化的肿瘤细胞的患者)18个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。队列B的中位随访时间为15.6个月。删失；队列B中的两名受试者在第3周撤回随访同意书。mITT包括接受≥1剂研究治疗的任何受试者。阴影表示在该时间点上基于生存点估计值的置信带。
图12显示了队列A+B 12个月总体生存概率的Kaplan-Meier估计量的可视化表示。逐步回归曲线显示了在特定时间点之前和之后的生存概率。y轴以数字形式表示生存概率，x轴表示生存时间(单位：天)。
图13显示了队列A、队列B和两个队列组合在12个月和18个月时总体生存期的疗效数据。此图显示了在12个月和18个月时报告存活的受试者总数。此图提供了受试者总数、事件(OS12或OS18)估计以及事件(OS12或OS18)的数值估计存在的95％置信区间(CI)。使用Clopper-Pearson精确方法计算95％CI。
安全性数据
根据安全性分析人群成员的受试者将安全性数据制成表格，定义为接受至少一剂研究产品(IP)。
≥NCI CTCAE 3级的临床研究方案定义的所有不良事件如图14所示。临床研究方案定义的免疫相关不良事件如图15所示。
受试者中报告的最常见≥3级不良事件为：血小板计数下降(11.5％)、淋巴细胞计数减少(11.5％)、肿瘤炎症(7.7％)、癫痫(7.7％)、ALT增加(7.7％)。报告了一例5级不相关事件(即尿脓毒病)。只报告了一例INO-5401+INO-9012相关的SAE(即发热)。48％的受试者报告了irAE，最常见的是ALT增加(9.6％)、AST增加(7.7％)、腹泻(7.7％)、发热(7.7％)和肿瘤炎症(7.7％)。71％报告的SAE和irAE发生在治疗前12周。
结论
在新诊断GBM的患者中，INO-5401+INO-9012与西米普利单抗注射溶液联合放疗和替莫唑胺具有可接受的安全性和免疫原性，并且对新诊断GBM的患者可能有效。常见的AE包括注射部位给药事件；≥3级AE主要由TMZ或放射引起，免疫相关AE与西米普利单抗注射溶液特征一致。SAE与GBM(癫痫)患者中的SAE一致。
在迄今为止测试的几乎所有患者中，都观察到了对INO-5401中包括的一个或多个抗原的抗原特异性T细胞反应。在MGMT启动子未甲基化和甲基化的患者中，PFS6超过了本研究的历史对照，并且OS12超过了MGMT启动子未甲基化的患者的历史对照[Stupp R，MasonWP，van den Bent MJ等人，放疗加伴随和辅助替莫唑胺治疗胶质母细胞瘤。《新英格兰医学杂志》，2005，352:987-996]。
应理解的是，上述详细描述和所附示例仅用于说明，不应视为对本发明范围的限制，本发明的范围仅由所附权利要求书及其等同内容限定。
对于本领域的技术人员而言，本发明公开的实施例的各种更改和修改显而易见。此类更改和修改，包括但不限于与本发明的化学结构、取代基、衍生物、中间体、综合体、合成物、制剂或使用方法有关的更改和修改，不应脱离本发明的精神和范围。
SEQUENCE LISTING
<110> 艾诺奥医药品有限公司(INOVIO PHARMACEUTICALS, INC.)
瑞泽恩制药公司(REGENERON PHARMACEUTICALS, INC.)
严健(YAN, JIAN)
贝尔纳黛特·费拉罗(FERRARO, BERNADETTE)
朱厄尔·沃尔特斯(WALTERS, JEWELL)
<120> 治疗脑癌的联合疗法
<130> 104409.000581
<140>
<141>
<150> 63/070,987
<151> 2020-08-27
<150> 63/018,060
<151> 2020-04-30
<150> 62/988,102
<151> 2020-03-11
<150> 62/930,417
<151> 2019-11-04
<160> 29
<170> PatentIn version 3.5
<210> 1
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 1
Glu Val Gln Leu Leu Glu Ser Gly Gly Val Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Gly Gly Arg Asp Thr Tyr Phe Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 2
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Leu Ser Ile Asn Thr Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu His Gly Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Thr Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Asn Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Val Val Asp Phe Arg
100 105
<210> 3
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
肽
<400> 3
Gly Phe Thr Phe Ser Asn Phe Gly
1 5
<210> 4
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
肽
<400> 4
Ile Ser Gly Gly Gly Arg Asp Thr
1 5
<210> 5
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
肽
<400> 5
Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr
1 5 10
<210> 6
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
肽
<400> 6
Leu Ser Ile Asn Thr Phe
1 5
<210> 7
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
肽
<400> 7
Ala Ala Ser
1
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
肽
<400> 8
Gln Gln Ser Ser Asn Thr Pro Phe Thr
1 5
<210> 9
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 9
Glu Val Gln Leu Leu Glu Ser Gly Gly Val Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Gly Gly Arg Asp Thr Tyr Phe Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 10
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Leu Ser Ile Asn Thr Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu His Gly Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Thr Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Asn Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Val Val Asp Phe Arg Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 11
<211> 2283
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 11
atgtggaacg cactgcatga gactgattct gctgtcgcac tgggacggag accccggtgg 60
ctgtgcgctg gagcactggt gctggccggc gggggattcc tgctgggatt cctgtttggc 120
tggtttatca aaagctccag cgaggctacc aatattaccc ctaagcacaa taagaaagca 180
ttcctggatg aactgaaagc cgagaacatc aagaaattcc tgtacaactt cacaagaatt 240
ccacatctgg ctggcactga gcagaacttc cagctggcaa aacagatcca gagtcagtgg 300
aaggaatttg ggctggactc agtggagctg acccactacg atgtcctgct gtcctatcca 360
aataagactc atcccaacta catctctatc attaacgaag acggaaatga gattttcaac 420
acctctctgt ttgaaccccc tccacccggc tatgagaatg tcagtgacgt ggtccctcca 480
ttctcagcct tcagccccca ggggatgcct gagggagatc tggtgtacgt caattatgct 540
agaacagaag acttctttaa gctggagagg gatatgaaaa tcaactgttc cggcaagatc 600
gtgattgccc ggtacgggaa ggtgttcaga ggaaataagg tcaaaaacgc tcagctggcc 660
ggagctaccg gcgtgatcct gtacagcgac cccgctgatt attttgcacc tggcgtgaag 720
tcctatccag acggatggaa tctgcccggc gggggagtgc agaggggaaa catcctgaac 780
ctgaatggag ccggcgatcc tctgactcca ggataccccg ccaacgaata cgcttatcgc 840
cggggaattg cagaggccgt gggcctgcct agcatcccag tccatcccat tggctattac 900
gatgcccaga agctgctgga gaaaatgggc gggagcgctc cccctgactc tagttggaag 960
ggctccctga aagtgcctta caatgtcggg ccaggattca ctgggaactt ttctacccag 1020
aaggtgaaaa tgcacatcca tagtaccagc gaggtgacac gaatctacaa cgtcattggc 1080
accctgagag gcgccgtgga gcctgatcgc tatgtcattc tgggaggcca cagagactca 1140
tgggtgttcg ggggaatcga tccacagagc ggagcagctg tggtccatga aattgtgcgc 1200
agctttggga ccctgaagaa agagggatgg cgacccaggc gcacaatcct gttcgcatcc 1260
tgggacgccg aggaatttgg gctgctgggc agcacagaat gggccgagga aaattctcgc 1320
ctgctgcagg agcgaggggt ggcttacatc aatgcagact caagcattga aggaaactat 1380
accctgcggg tggattgcac acccctgatg tacagtctgg tctataacct gacaaaggag 1440
ctgaaatcac ctgacgaggg cttcgaaggg aaaagcctgt acgaatcctg gactgagaag 1500
agcccatccc ccgaattcag cggcatgcct aggatctcta agctgggcag tgggaacgat 1560
tttgaggtgt tctttcagcg cctgggaatt gcctctggcc gagctcggta cacaaaaaat 1620
tgggagacta acaagttctc ctcttaccca ctgtatcaca gcgtgtacga gacttatgaa 1680
ctggtcgaga aattctacga ccccactttt aagtatcatc tgaccgtggc acaggtcagg 1740
ggcgggatgg tgttcgaact ggccaatagc atcgtcctgc catttgactg tcgagattac 1800
gctgtggtcc tgcggaagta cgcagacaag atctataaca tctccatgaa gcacccccag 1860
gagatgaagg cctattctgt gagtttcgat tccctgtttt ctgccgtcaa aaatttcacc 1920
gaaatcgcta gtaagttttc agagcgcctg caggacctgg ataagtccaa tcccatcctg 1980
ctgcggatta tgaacgatca gctgatgttc ctggaaagag cctttatcga ccctctgggc 2040
ctgcctgata gaccattcta caggcacgtg atctacgcac ctagttcaca taacaagtac 2100
gccggcgagt ctttcccagg gatctatgac gctctgtttg atattgaatc aaaggtggac 2160
cccagcaaag catggggcga ggtcaagaga cagatcagca ttgcagcctt tacagtgcag 2220
gccgccgccg aaaccctgtc cgaagtcgct tacccatacg atgtccccga ttacgcatga 2280
taa 2283
<210> 12
<211> 2334
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 12
atggactgga catggattct gttcctggtc gccgccgcaa ctcgcgtgca ttcctggaac 60
gcactgcatg agactgattc tgctgtcgca ctgggacgga gaccccggtg gctgtgcgct 120
ggagcactgg tgctggccgg cgggggattc ctgctgggat tcctgtttgg ctggtttatc 180
aaaagctcca gcgaggctac caatattacc cctaagcaca ataagaaagc attcctggat 240
gaactgaaag ccgagaacat caagaaattc ctgtacaact tcacaagaat tccacatctg 300
gctggcactg agcagaactt ccagctggca aaacagatcc agagtcagtg gaaggaattt 360
gggctggact cagtggagct gacccactac gatgtcctgc tgtcctatcc aaataagact 420
catcccaact acatctctat cattaacgaa gacggaaatg agattttcaa cacctctctg 480
tttgaacccc ctccacccgg ctatgagaat gtcagtgacg tggtccctcc attctcagcc 540
ttcagccccc aggggatgcc tgagggagat ctggtgtacg tcaattatgc tagaacagaa 600
gacttcttta agctggagag ggatatgaaa atcaactgtt ccggcaagat cgtgattgcc 660
cggtacggga aggtgttcag aggaaataag gtcaaaaacg ctcagctggc cggagctacc 720
ggcgtgatcc tgtacagcga ccccgctgat tattttgcac ctggcgtgaa gtcctatcca 780
gacggatgga atctgcccgg cgggggagtg cagaggggaa acatcctgaa cctgaatgga 840
gccggcgatc ctctgactcc aggatacccc gccaacgaat acgcttatcg ccggggaatt 900
gcagaggccg tgggcctgcc tagcatccca gtccatccca ttggctatta cgatgcccag 960
aagctgctgg agaaaatggg cgggagcgct ccccctgact ctagttggaa gggctccctg 1020
aaagtgcctt acaatgtcgg gccaggattc actgggaact tttctaccca gaaggtgaaa 1080
atgcacatcc atagtaccag cgaggtgaca cgaatctaca acgtcattgg caccctgaga 1140
ggcgccgtgg agcctgatcg ctatgtcatt ctgggaggcc acagagactc atgggtgttc 1200
gggggaatcg atccacagag cggagcagct gtggtccatg aaattgtgcg cagctttggg 1260
accctgaaga aagagggatg gcgacccagg cgcacaatcc tgttcgcatc ctgggacgcc 1320
gaggaatttg ggctgctggg cagcacagaa tgggccgagg aaaattctcg cctgctgcag 1380
gagcgagggg tggcttacat caatgcagac tcaagcattg aaggaaacta taccctgcgg 1440
gtggattgca cacccctgat gtacagtctg gtctataacc tgacaaagga gctgaaatca 1500
cctgacgagg gcttcgaagg gaaaagcctg tacgaatcct ggactgagaa gagcccatcc 1560
cccgaattca gcggcatgcc taggatctct aagctgggca gtgggaacga ttttgaggtg 1620
ttctttcagc gcctgggaat tgcctctggc cgagctcggt acacaaaaaa ttgggagact 1680
aacaagttct cctcttaccc actgtatcac agcgtgtacg agacttatga actggtcgag 1740
aaattctacg accccacttt taagtatcat ctgaccgtgg cacaggtcag gggcgggatg 1800
gtgttcgaac tggccaatag catcgtcctg ccatttgact gtcgagatta cgctgtggtc 1860
ctgcggaagt acgcagacaa gatctataac atctccatga agcaccccca ggagatgaag 1920
gcctattctg tgagtttcga ttccctgttt tctgccgtca aaaatttcac cgaaatcgct 1980
agtaagtttt cagagcgcct gcaggacctg gataagtcca atcccatcct gctgcggatt 2040
atgaacgatc agctgatgtt cctggaaaga gcctttatcg accctctggg cctgcctgat 2100
agaccattct acaggcacgt gatctacgca cctagttcac ataacaagta cgccggcgag 2160
tctttcccag ggatctatga cgctctgttt gatattgaat caaaggtgga ccccagcaaa 2220
gcatggggcg aggtcaagag acagatcagc attgcagcct ttacagtgca ggccgccgcc 2280
gaaaccctgt ccgaagtcgc ttacccatac gatgtccccg attacgcatg ataa 2334
<210> 13
<211> 750
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 13
Met Trp Asn Ala Leu His Glu Thr Asp Ser Ala Val Ala Leu Gly Arg
1 5 10 15
Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val Leu Ala Gly Gly Gly
20 25 30
Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile Lys Ser Ser Ser Glu
35 40 45
Ala Thr Asn Ile Thr Pro Lys His Asn Lys Lys Ala Phe Leu Asp Glu
50 55 60
Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr Asn Phe Thr Arg Ile
65 70 75 80
Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile
85 90 95
Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser Val Glu Leu Thr His
100 105 110
Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile
115 120 125
Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe
130 135 140
Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser Asp Val Val Pro Pro
145 150 155 160
Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr
165 170 175
Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met
180 185 190
Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val
195 200 205
Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu Ala Gly Ala Thr Gly
210 215 220
Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys
225 230 235 240
Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly
245 250 255
Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr
260 265 270
Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly
275 280 285
Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys
290 295 300
Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Lys
305 310 315 320
Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn
325 330 335
Phe Ser Thr Gln Lys Val Lys Met His Ile His Ser Thr Ser Glu Val
340 345 350
Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro
355 360 365
Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly
370 375 380
Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val His Glu Ile Val Arg
385 390 395 400
Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile
405 410 415
Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr
420 425 430
Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala
435 440 445
Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val
450 455 460
Asp Cys Thr Pro Leu Met Tyr Ser Leu Val Tyr Asn Leu Thr Lys Glu
465 470 475 480
Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser
485 490 495
Trp Thr Glu Lys Ser Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile
500 505 510
Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu
515 520 525
Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn
530 535 540
Lys Phe Ser Ser Tyr Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu
545 550 555 560
Leu Val Glu Lys Phe Tyr Asp Pro Thr Phe Lys Tyr His Leu Thr Val
565 570 575
Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val
580 585 590
Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala
595 600 605
Asp Lys Ile Tyr Asn Ile Ser Met Lys His Pro Gln Glu Met Lys Ala
610 615 620
Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr
625 630 635 640
Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln Asp Leu Asp Lys Ser
645 650 655
Asn Pro Ile Leu Leu Arg Ile Met Asn Asp Gln Leu Met Phe Leu Glu
660 665 670
Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr Arg
675 680 685
His Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu Ser
690 695 700
Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys Val Asp
705 710 715 720
Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Ser Ile Ala Ala
725 730 735
Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val Ala
740 745 750
<210> 14
<211> 767
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 14
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Trp Asn Ala Leu His Glu Thr Asp Ser Ala Val Ala Leu Gly
20 25 30
Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val Leu Ala Gly Gly
35 40 45
Gly Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile Lys Ser Ser Ser
50 55 60
Glu Ala Thr Asn Ile Thr Pro Lys His Asn Lys Lys Ala Phe Leu Asp
65 70 75 80
Glu Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr Asn Phe Thr Arg
85 90 95
Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln
100 105 110
Ile Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser Val Glu Leu Thr
115 120 125
His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr
130 135 140
Ile Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu
145 150 155 160
Phe Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser Asp Val Val Pro
165 170 175
Pro Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu Gly Asp Leu Val
180 185 190
Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp
195 200 205
Met Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys
210 215 220
Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu Ala Gly Ala Thr
225 230 235 240
Gly Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val
245 250 255
Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly Val Gln Arg
260 265 270
Gly Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly
275 280 285
Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val
290 295 300
Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr Tyr Asp Ala Gln
305 310 315 320
Lys Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp
325 330 335
Lys Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly
340 345 350
Asn Phe Ser Thr Gln Lys Val Lys Met His Ile His Ser Thr Ser Glu
355 360 365
Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly Ala Val Glu
370 375 380
Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp Ser Trp Val Phe
385 390 395 400
Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val His Glu Ile Val
405 410 415
Arg Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr
420 425 430
Ile Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser
435 440 445
Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu Arg Gly Val
450 455 460
Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg
465 470 475 480
Val Asp Cys Thr Pro Leu Met Tyr Ser Leu Val Tyr Asn Leu Thr Lys
485 490 495
Glu Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu
500 505 510
Ser Trp Thr Glu Lys Ser Pro Ser Pro Glu Phe Ser Gly Met Pro Arg
515 520 525
Ile Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe Gln Arg
530 535 540
Leu Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr
545 550 555 560
Asn Lys Phe Ser Ser Tyr Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr
565 570 575
Glu Leu Val Glu Lys Phe Tyr Asp Pro Thr Phe Lys Tyr His Leu Thr
580 585 590
Val Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn Ser Ile
595 600 605
Val Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr
610 615 620
Ala Asp Lys Ile Tyr Asn Ile Ser Met Lys His Pro Gln Glu Met Lys
625 630 635 640
Ala Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe
645 650 655
Thr Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln Asp Leu Asp Lys
660 665 670
Ser Asn Pro Ile Leu Leu Arg Ile Met Asn Asp Gln Leu Met Phe Leu
675 680 685
Glu Arg Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr
690 695 700
Arg His Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu
705 710 715 720
Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys Val
725 730 735
Asp Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Ser Ile Ala
740 745 750
Ala Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val Ala
755 760 765
<210> 15
<211> 1332
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 15
ggatccgcca ccatggactg gacctggatt ctgttcctgg tcgccgccgc aacacgggtg 60
catagtggga gtgatgtgag agacctgaac gccctgctgc cagcagtgcc atccctgcct 120
ggcgggggag gctgcgctct gccagtctct ggagcagctc agtgggctcc cgtgctggac 180
tttgcacccc ctgcagcccc ttacggaagt ctgggcggcc cacactcatt catcaaacag 240
gagccaagct ggggcggggc agatcctcat gaggaacagt gcctgtcagc cttcacagtc 300
cactttagcg ggcagttcac tggaaccgca ggagcttgta gatacggacc ctttggagca 360
ccaccccctt cccaggcacc ttctggacag gcacgcatgt tcccaaacgc tccctatctg 420
cctaattgtc tggaaagcca gcccgctatt aggaaccagg gctactccac agtggcattt 480
gacgggactc ctagctatgg acatacccca tcccaccatg ctgcacagtt tcctaatcac 540
tccttcaagc atgaggaccc catgggacag caggggtccc tgggagaaca gcagtactct 600
gtgccccctc ccgtgtacgg atgccacaca ccaactgaca gttgtacagg ctcacaggcc 660
ctgctgctgc gaactccata caacagtgat aatctgtatc agatgacctc acagctggag 720
tgcatgacat ggaaccagat gaatctgggc agcacactga aaggccatgc cactgggtac 780
gaatctgaca accacaccac acctatgctg tacagttgtg gagcccagta tagaatccac 840
actcatggag tcttcagagg cattcaggat gtgcggagag tcccaggagt ggcaccaact 900
atcgtgcgga gcgcctccga gaccaacgaa aagcgcccct ttatgggcgc ctaccctgga 960
ggcaataagc ggtatttcaa actgtctcac ctgcagatgg ggagtagaaa ggggaccgga 1020
gagaaacctt atcagggcga ctttaaagat ggggaaaggc gcttctctcg cagtgaccag 1080
ctgaagcgag gacagcgacg aggaaccggg gtgaagccat ttcagtgcaa aacatgtcag 1140
agaaagttct caaggagcga tcacctgaag acccatacaa gaactcacac cggcaagacc 1200
agcgagaaac cattttcctg ccgatggccc tcttgtcaga agaaattcgc ccgctccgac 1260
gaactggtcc gacaccacaa tatgcatcag agaaatatga caaaactgca gctggctctg 1320
tgataactcg ag 1332
<210> 16
<211> 436
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 16
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val
20 25 30
Pro Ser Leu Pro Gly Gly Gly Gly Cys Ala Leu Pro Val Ser Gly Ala
35 40 45
Ala Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Ala Ala Pro Tyr
50 55 60
Gly Ser Leu Gly Gly Pro His Ser Phe Ile Lys Gln Glu Pro Ser Trp
65 70 75 80
Gly Gly Ala Asp Pro His Glu Glu Gln Cys Leu Ser Ala Phe Thr Val
85 90 95
His Phe Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly
100 105 110
Pro Phe Gly Ala Pro Pro Pro Ser Gln Ala Pro Ser Gly Gln Ala Arg
115 120 125
Met Phe Pro Asn Ala Pro Tyr Leu Pro Asn Cys Leu Glu Ser Gln Pro
130 135 140
Ala Ile Arg Asn Gln Gly Tyr Ser Thr Val Ala Phe Asp Gly Thr Pro
145 150 155 160
Ser Tyr Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Asn His
165 170 175
Ser Phe Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu
180 185 190
Gln Gln Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr
195 200 205
Asp Ser Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Asn
210 215 220
Ser Asp Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp
225 230 235 240
Asn Gln Met Asn Leu Gly Ser Thr Leu Lys Gly His Ala Thr Gly Tyr
245 250 255
Glu Ser Asp Asn His Thr Thr Pro Met Leu Tyr Ser Cys Gly Ala Gln
260 265 270
Tyr Arg Ile His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg
275 280 285
Arg Val Pro Gly Val Ala Pro Thr Ile Val Arg Ser Ala Ser Glu Thr
290 295 300
Asn Glu Lys Arg Pro Phe Met Gly Ala Tyr Pro Gly Gly Asn Lys Arg
305 310 315 320
Tyr Phe Lys Leu Ser His Leu Gln Met Gly Ser Arg Lys Gly Thr Gly
325 330 335
Glu Lys Pro Tyr Gln Gly Asp Phe Lys Asp Gly Glu Arg Arg Phe Ser
340 345 350
Arg Ser Asp Gln Leu Lys Arg Gly Gln Arg Arg Gly Thr Gly Val Lys
355 360 365
Pro Phe Gln Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His
370 375 380
Leu Lys Thr His Thr Arg Thr His Thr Gly Lys Thr Ser Glu Lys Pro
385 390 395 400
Phe Ser Cys Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp
405 410 415
Glu Leu Val Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu
420 425 430
Gln Leu Ala Leu
435
<210> 17
<211> 3447
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 17
atggattgga catggattct gttcctggtc gcagccgcca cacgagtgca tagccctaga 60
gccccacggt gtagagcagt ccgcagcctg ctgcgcagcc gataccggga agtgctgcct 120
ctggccacct ttgtccggag actgggacca cagggcaggc gcctggtgca gcgcggcgac 180
cccgcagctt tccgagcact ggtggcacag tgcctggtgt gcgtgccatg ggatgcacgg 240
ccccctccag cagcccctag ctttagacag gtgtcctgcc tgaaagaact ggtcgcaagg 300
gtggtccagc ggctgtgcga gagaggcgcc aggaacgtgc tggcattcgg ctttgcactg 360
ctggacggag ctaggggcgg gccccctgag gcattcacca caagcgtgcg ctcctacctg 420
ccaaatacag tcactgatac cctgcgaggc tccggagcat ggggactgct gctgcgacgg 480
gtgggggacg atgtgctggt ccacctgctg gctagatgcg cactgtatgt gctggtcgct 540
ccctcttgcg cataccaggt gtgcggacca cccctgtatg acctgggcgc tgcaacccag 600
gcaagacctc caccccacgc ctctggcact agaaggggac tgggcaccga acaggcatgg 660
aaccatagtg tcagggaggc aggagtgcca ctgggactgc cagcacctgg ggctcgccga 720
cggagaggga gtgccggacg gtcactgcca ctggctaaga gaccaaggcg cggagccgct 780
ccagaaccag agaggacacc tgtgggacag ggaagctggg cacaccctgg aagaactagg 840
gggccaagtg ataggggctt ctgcgtggtc tcaccagcac gaccagcaga ggaagctact 900
tctctggagg gagctctgag tggcacccgg cactctcatc ctagtgtggg aagacagcac 960
catgcaggcc ctccaagcac cagccggcct ccccggccat gggacactcc ttgtccaccc 1020
gtgtacgctg aaaccaaaca ctttctgtat agctccggag ataaggagca gctgcggccc 1080
tctttcctgc tgtctagtct gagacctagt ctgaccggag cacgacggct ggtggaaaca 1140
atctttctgg ggtcccgccc ttggatgcca ggaaccccca gaaggacacc tcgactgcca 1200
cagcggtact ggcagatgcg gccactgttc ctggagctgc tgggcaatca cgctcagtgc 1260
ccctatgggg cactgctgcg aacacattgt cctctgcggg cagccgtgac tccagctgca 1320
ggagtctgcg ccagggaaaa gccacagggc agcgtggcag ctcctgagga agaggacacc 1380
gatccacgcc gactggtgca gctgctgaga cagcactcaa gcccctggca ggtgtacgga 1440
tttctgaggg cctgtctgcg gagactggtg cctccaggac tgtgggggtc caggcacaac 1500
gaaaggcgct ttctgcgcaa tactaagaaa ttcatcagcc tgggcaagca tgctaaactg 1560
tccctgcagg agctgacctg gaaaatgagt gtgcgcgact gcgcatggct gcgacggtca 1620
ccaggagtcg ggtgcgtgcc tgcagccgag caccgcctgc gagaagagat tctggccaag 1680
tttctgcatt ggctgatgtc agtgtacgtg gtcgaactgc tgcggagctt cttttatgtg 1740
acagagacta ccttccagaa aaactacctg ttcttttatc gcaagtcagt gtggagcaaa 1800
ctgcagtcaa tcggcattcg gcagcacctg aagagagtgc agctgaggga actgagtgaa 1860
gccgaggtcc ggcagcatag agaggcaagg cctgccctgc tgacctcccg gctgagattc 1920
ctgcctaagc cagacgggct gagaccaatc gtgaacatgg attacgtggt cggagcacgg 1980
accttccgga gggaaaaacg cgctgagcga ctgacatccc gcgtgaagac tctgttctct 2040
gtcctgaatt atgagcgagc tcgccgaccc ggactgctgg gagcatctgt gctgggactg 2100
gacgatattc accgggcttg gagagcattt gtcctgaggg tgcgcgcaca ggaccctccc 2160
ccagaactgt acttcgtgaa agtcgccgtg accggggctt atgacacaat ccctcaggat 2220
cggctgactg aagtgatcgc ctccatcatt aagccacaga atacctactg cgtgcggaga 2280
tatgctgtgg tcaggcgcgc tgcacacggc catgtgagga agagcttcaa gcgccacgtc 2340
agcacactga ctgatctgca gccctacatg agacagttcg tggctcatct gcaggagacc 2400
agccctctga gggacgcagt ggtcatcgaa cagtcctcta gtctgaacga ggcatcaagc 2460
gggctgttcg atgtctttct gcggttcgtg tgccaccatg ccgtcagaat tggaggcaaa 2520
tcttacgtgc agtgtcaggg catcccccag ggcagcattc tgtctaccct gctgtgcagc 2580
ctgtgctatg gcgacatgga aaataagctg tttgccggaa tccgacggga tggcctgctg 2640
ctgagactgg tggccgcttt tctgctggtc actccacacc tgacccatgc caaagctttc 2700
ctgcgcacac tggtccgagg ggtgccagag tacggatgcg tggtcaacct gaggaagacc 2760
gtggtcaatt tcccagtgga agacgaggcc ctgggcggca cagcatttgt ccagctgcca 2820
gcacacggac tgttcccatg gtgtggactg ctgctggaca cccgcacact ggaggtgcag 2880
tccgattact cctcttatgc ccggacaagc atcagagctt ccctgacttt taacagaggc 2940
ttcaaggccg ggaggaatat gagaaggaaa ctgtttggcg tgctgcgcct gaagtgccat 3000
tccctgttcc tgtatctgca ggtgaactct ctgcagactg tctgtaccaa cgtgtacaaa 3060
atttttctgc tgcaggccta tcggttccac gcttgcgtgc tgcagctgcc attccatcag 3120
caggtcagga agaaccccac cttctttctg cgcgtgatct ctgatacagc tagtctgtgc 3180
tactcaattc tgaaggccaa aaatgctggc atgagcctgg gagcaaaagg agcagcagga 3240
ccatttcctt ccgaggctgc acagtggctg tgccaccagg cattcctgct gaagctggcc 3300
cgacatcggg tgacatatag gtgcctgctg ggcgcactgc gaacagcaca gactcagctg 3360
tgcagaaagc tgcccggggc cactctggct gccctggaag ccgctgccga ccctgccctg 3420
acctccgatt tcaagactat tctggac 3447
<210> 18
<211> 1149
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 18
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg
20 25 30
Ser Arg Tyr Arg Glu Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu
35 40 45
Gly Pro Gln Gly Arg Arg Leu Val Gln Arg Gly Asp Pro Ala Ala Phe
50 55 60
Arg Ala Leu Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg
65 70 75 80
Pro Pro Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys Leu Lys Glu
85 90 95
Leu Val Ala Arg Val Val Gln Arg Leu Cys Glu Arg Gly Ala Arg Asn
100 105 110
Val Leu Ala Phe Gly Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro
115 120 125
Pro Glu Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr Val
130 135 140
Thr Asp Thr Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg
145 150 155 160
Val Gly Asp Asp Val Leu Val His Leu Leu Ala Arg Cys Ala Leu Tyr
165 170 175
Val Leu Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu
180 185 190
Tyr Asp Leu Gly Ala Ala Thr Gln Ala Arg Pro Pro Pro His Ala Ser
195 200 205
Gly Thr Arg Arg Gly Leu Gly Thr Glu Gln Ala Trp Asn His Ser Val
210 215 220
Arg Glu Ala Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg
225 230 235 240
Arg Arg Gly Ser Ala Gly Arg Ser Leu Pro Leu Ala Lys Arg Pro Arg
245 250 255
Arg Gly Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser
260 265 270
Trp Ala His Pro Gly Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys
275 280 285
Val Val Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu Gly
290 295 300
Ala Leu Ser Gly Thr Arg His Ser His Pro Ser Val Gly Arg Gln His
305 310 315 320
His Ala Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro Trp Asp Thr
325 330 335
Pro Cys Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser
340 345 350
Gly Asp Lys Glu Gln Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg
355 360 365
Pro Ser Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu Gly
370 375 380
Ser Arg Pro Trp Met Pro Gly Thr Pro Arg Arg Thr Pro Arg Leu Pro
385 390 395 400
Gln Arg Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu Leu Gly Asn
405 410 415
His Ala Gln Cys Pro Tyr Gly Ala Leu Leu Arg Thr His Cys Pro Leu
420 425 430
Arg Ala Ala Val Thr Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro
435 440 445
Gln Gly Ser Val Ala Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg Arg
450 455 460
Leu Val Gln Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly
465 470 475 480
Phe Leu Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly Leu Trp Gly
485 490 495
Ser Arg His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile
500 505 510
Ser Leu Gly Lys His Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys
515 520 525
Met Ser Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Pro Gly Val Gly
530 535 540
Cys Val Pro Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys
545 550 555 560
Phe Leu His Trp Leu Met Ser Val Tyr Val Val Glu Leu Leu Arg Ser
565 570 575
Phe Phe Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Tyr Leu Phe Phe
580 585 590
Tyr Arg Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln
595 600 605
His Leu Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg
610 615 620
Gln His Arg Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe
625 630 635 640
Leu Pro Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp Tyr Val
645 650 655
Val Gly Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr
660 665 670
Ser Arg Val Lys Thr Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg
675 680 685
Arg Pro Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His
690 695 700
Arg Ala Trp Arg Ala Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro
705 710 715 720
Pro Glu Leu Tyr Phe Val Lys Val Ala Val Thr Gly Ala Tyr Asp Thr
725 730 735
Ile Pro Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro
740 745 750
Gln Asn Thr Tyr Cys Val Arg Arg Tyr Ala Val Val Arg Arg Ala Ala
755 760 765
His Gly His Val Arg Lys Ser Phe Lys Arg His Val Ser Thr Leu Thr
770 775 780
Asp Leu Gln Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr
785 790 795 800
Ser Pro Leu Arg Asp Ala Val Val Ile Glu Gln Ser Ser Ser Leu Asn
805 810 815
Glu Ala Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Val Cys His
820 825 830
His Ala Val Arg Ile Gly Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile
835 840 845
Pro Gln Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr Gly
850 855 860
Asp Met Glu Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu
865 870 875 880
Leu Arg Leu Val Ala Ala Phe Leu Leu Val Thr Pro His Leu Thr His
885 890 895
Ala Lys Ala Phe Leu Arg Thr Leu Val Arg Gly Val Pro Glu Tyr Gly
900 905 910
Cys Val Val Asn Leu Arg Lys Thr Val Val Asn Phe Pro Val Glu Asp
915 920 925
Glu Ala Leu Gly Gly Thr Ala Phe Val Gln Leu Pro Ala His Gly Leu
930 935 940
Phe Pro Trp Cys Gly Leu Leu Leu Asp Thr Arg Thr Leu Glu Val Gln
945 950 955 960
Ser Asp Tyr Ser Ser Tyr Ala Arg Thr Ser Ile Arg Ala Ser Leu Thr
965 970 975
Phe Asn Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe
980 985 990
Gly Val Leu Arg Leu Lys Cys His Ser Leu Phe Leu Tyr Leu Gln Val
995 1000 1005
Asn Ser Leu Gln Thr Val Cys Thr Asn Val Tyr Lys Ile Phe Leu
1010 1015 1020
Leu Gln Ala Tyr Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe
1025 1030 1035
His Gln Gln Val Arg Lys Asn Pro Thr Phe Phe Leu Arg Val Ile
1040 1045 1050
Ser Asp Thr Ala Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn
1055 1060 1065
Ala Gly Met Ser Leu Gly Ala Lys Gly Ala Ala Gly Pro Phe Pro
1070 1075 1080
Ser Glu Ala Ala Gln Trp Leu Cys His Gln Ala Phe Leu Leu Lys
1085 1090 1095
Leu Ala Arg His Arg Val Thr Tyr Arg Cys Leu Leu Gly Ala Leu
1100 1105 1110
Arg Thr Ala Gln Thr Gln Leu Cys Arg Lys Leu Pro Gly Ala Thr
1115 1120 1125
Leu Ala Ala Leu Glu Ala Ala Ala Asp Pro Ala Leu Thr Ser Asp
1130 1135 1140
Phe Lys Thr Ile Leu Asp
1145
<210> 19
<211> 3399
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 19
cctagagccc cacggtgtag agcagtccgc agcctgctgc gcagccgata ccgggaagtg 60
ctgcctctgg ccacctttgt ccggagactg ggaccacagg gcaggcgcct ggtgcagcgc 120
ggcgaccccg cagctttccg agcactggtg gcacagtgcc tggtgtgcgt gccatgggat 180
gcacggcccc ctccagcagc ccctagcttt agacaggtgt cctgcctgaa agaactggtc 240
gcaagggtgg tccagcggct gtgcgagaga ggcgccagga acgtgctggc attcggcttt 300
gcactgctgg acggagctag gggcgggccc cctgaggcat tcaccacaag cgtgcgctcc 360
tacctgccaa atacagtcac tgataccctg cgaggctccg gagcatgggg actgctgctg 420
cgacgggtgg gggacgatgt gctggtccac ctgctggcta gatgcgcact gtatgtgctg 480
gtcgctccct cttgcgcata ccaggtgtgc ggaccacccc tgtatgacct gggcgctgca 540
acccaggcaa gacctccacc ccacgcctct ggcactagaa ggggactggg caccgaacag 600
gcatggaacc atagtgtcag ggaggcagga gtgccactgg gactgccagc acctggggct 660
cgccgacgga gagggagtgc cggacggtca ctgccactgg ctaagagacc aaggcgcgga 720
gccgctccag aaccagagag gacacctgtg ggacagggaa gctgggcaca ccctggaaga 780
actagggggc caagtgatag gggcttctgc gtggtctcac cagcacgacc agcagaggaa 840
gctacttctc tggagggagc tctgagtggc acccggcact ctcatcctag tgtgggaaga 900
cagcaccatg caggccctcc aagcaccagc cggcctcccc ggccatggga cactccttgt 960
ccacccgtgt acgctgaaac caaacacttt ctgtatagct ccggagataa ggagcagctg 1020
cggccctctt tcctgctgtc tagtctgaga cctagtctga ccggagcacg acggctggtg 1080
gaaacaatct ttctggggtc ccgcccttgg atgccaggaa cccccagaag gacacctcga 1140
ctgccacagc ggtactggca gatgcggcca ctgttcctgg agctgctggg caatcacgct 1200
cagtgcccct atggggcact gctgcgaaca cattgtcctc tgcgggcagc cgtgactcca 1260
gctgcaggag tctgcgccag ggaaaagcca cagggcagcg tggcagctcc tgaggaagag 1320
gacaccgatc cacgccgact ggtgcagctg ctgagacagc actcaagccc ctggcaggtg 1380
tacggatttc tgagggcctg tctgcggaga ctggtgcctc caggactgtg ggggtccagg 1440
cacaacgaaa ggcgctttct gcgcaatact aagaaattca tcagcctggg caagcatgct 1500
aaactgtccc tgcaggagct gacctggaaa atgagtgtgc gcgactgcgc atggctgcga 1560
cggtcaccag gagtcgggtg cgtgcctgca gccgagcacc gcctgcgaga agagattctg 1620
gccaagtttc tgcattggct gatgtcagtg tacgtggtcg aactgctgcg gagcttcttt 1680
tatgtgacag agactacctt ccagaaaaac tacctgttct tttatcgcaa gtcagtgtgg 1740
agcaaactgc agtcaatcgg cattcggcag cacctgaaga gagtgcagct gagggaactg 1800
agtgaagccg aggtccggca gcatagagag gcaaggcctg ccctgctgac ctcccggctg 1860
agattcctgc ctaagccaga cgggctgaga ccaatcgtga acatggatta cgtggtcgga 1920
gcacggacct tccggaggga aaaacgcgct gagcgactga catcccgcgt gaagactctg 1980
ttctctgtcc tgaattatga gcgagctcgc cgacccggac tgctgggagc atctgtgctg 2040
ggactggacg atattcaccg ggcttggaga gcatttgtcc tgagggtgcg cgcacaggac 2100
cctcccccag aactgtactt cgtgaaagtc gccgtgaccg gggcttatga cacaatccct 2160
caggatcggc tgactgaagt gatcgcctcc atcattaagc cacagaatac ctactgcgtg 2220
cggagatatg ctgtggtcag gcgcgctgca cacggccatg tgaggaagag cttcaagcgc 2280
cacgtcagca cactgactga tctgcagccc tacatgagac agttcgtggc tcatctgcag 2340
gagaccagcc ctctgaggga cgcagtggtc atcgaacagt cctctagtct gaacgaggca 2400
tcaagcgggc tgttcgatgt ctttctgcgg ttcgtgtgcc accatgccgt cagaattgga 2460
ggcaaatctt acgtgcagtg tcagggcatc ccccagggca gcattctgtc taccctgctg 2520
tgcagcctgt gctatggcga catggaaaat aagctgtttg ccggaatccg acgggatggc 2580
ctgctgctga gactggtggc cgcttttctg ctggtcactc cacacctgac ccatgccaaa 2640
gctttcctgc gcacactggt ccgaggggtg ccagagtacg gatgcgtggt caacctgagg 2700
aagaccgtgg tcaatttccc agtggaagac gaggccctgg gcggcacagc atttgtccag 2760
ctgccagcac acggactgtt cccatggtgt ggactgctgc tggacacccg cacactggag 2820
gtgcagtccg attactcctc ttatgcccgg acaagcatca gagcttccct gacttttaac 2880
agaggcttca aggccgggag gaatatgaga aggaaactgt ttggcgtgct gcgcctgaag 2940
tgccattccc tgttcctgta tctgcaggtg aactctctgc agactgtctg taccaacgtg 3000
tacaaaattt ttctgctgca ggcctatcgg ttccacgctt gcgtgctgca gctgccattc 3060
catcagcagg tcaggaagaa ccccaccttc tttctgcgcg tgatctctga tacagctagt 3120
ctgtgctact caattctgaa ggccaaaaat gctggcatga gcctgggagc aaaaggagca 3180
gcaggaccat ttccttccga ggctgcacag tggctgtgcc accaggcatt cctgctgaag 3240
ctggcccgac atcgggtgac atataggtgc ctgctgggcg cactgcgaac agcacagact 3300
cagctgtgca gaaagctgcc cggggccact ctggctgccc tggaagccgc tgccgaccct 3360
gccctgacct ccgatttcaa gactattctg gactgataa 3399
<210> 20
<211> 1131
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 20
Pro Arg Ala Pro Arg Cys Arg Ala Val Arg Ser Leu Leu Arg Ser Arg
1 5 10 15
Tyr Arg Glu Val Leu Pro Leu Ala Thr Phe Val Arg Arg Leu Gly Pro
20 25 30
Gln Gly Arg Arg Leu Val Gln Arg Gly Asp Pro Ala Ala Phe Arg Ala
35 40 45
Leu Val Ala Gln Cys Leu Val Cys Val Pro Trp Asp Ala Arg Pro Pro
50 55 60
Pro Ala Ala Pro Ser Phe Arg Gln Val Ser Cys Leu Lys Glu Leu Val
65 70 75 80
Ala Arg Val Val Gln Arg Leu Cys Glu Arg Gly Ala Arg Asn Val Leu
85 90 95
Ala Phe Gly Phe Ala Leu Leu Asp Gly Ala Arg Gly Gly Pro Pro Glu
100 105 110
Ala Phe Thr Thr Ser Val Arg Ser Tyr Leu Pro Asn Thr Val Thr Asp
115 120 125
Thr Leu Arg Gly Ser Gly Ala Trp Gly Leu Leu Leu Arg Arg Val Gly
130 135 140
Asp Asp Val Leu Val His Leu Leu Ala Arg Cys Ala Leu Tyr Val Leu
145 150 155 160
Val Ala Pro Ser Cys Ala Tyr Gln Val Cys Gly Pro Pro Leu Tyr Asp
165 170 175
Leu Gly Ala Ala Thr Gln Ala Arg Pro Pro Pro His Ala Ser Gly Thr
180 185 190
Arg Arg Gly Leu Gly Thr Glu Gln Ala Trp Asn His Ser Val Arg Glu
195 200 205
Ala Gly Val Pro Leu Gly Leu Pro Ala Pro Gly Ala Arg Arg Arg Arg
210 215 220
Gly Ser Ala Gly Arg Ser Leu Pro Leu Ala Lys Arg Pro Arg Arg Gly
225 230 235 240
Ala Ala Pro Glu Pro Glu Arg Thr Pro Val Gly Gln Gly Ser Trp Ala
245 250 255
His Pro Gly Arg Thr Arg Gly Pro Ser Asp Arg Gly Phe Cys Val Val
260 265 270
Ser Pro Ala Arg Pro Ala Glu Glu Ala Thr Ser Leu Glu Gly Ala Leu
275 280 285
Ser Gly Thr Arg His Ser His Pro Ser Val Gly Arg Gln His His Ala
290 295 300
Gly Pro Pro Ser Thr Ser Arg Pro Pro Arg Pro Trp Asp Thr Pro Cys
305 310 315 320
Pro Pro Val Tyr Ala Glu Thr Lys His Phe Leu Tyr Ser Ser Gly Asp
325 330 335
Lys Glu Gln Leu Arg Pro Ser Phe Leu Leu Ser Ser Leu Arg Pro Ser
340 345 350
Leu Thr Gly Ala Arg Arg Leu Val Glu Thr Ile Phe Leu Gly Ser Arg
355 360 365
Pro Trp Met Pro Gly Thr Pro Arg Arg Thr Pro Arg Leu Pro Gln Arg
370 375 380
Tyr Trp Gln Met Arg Pro Leu Phe Leu Glu Leu Leu Gly Asn His Ala
385 390 395 400
Gln Cys Pro Tyr Gly Ala Leu Leu Arg Thr His Cys Pro Leu Arg Ala
405 410 415
Ala Val Thr Pro Ala Ala Gly Val Cys Ala Arg Glu Lys Pro Gln Gly
420 425 430
Ser Val Ala Ala Pro Glu Glu Glu Asp Thr Asp Pro Arg Arg Leu Val
435 440 445
Gln Leu Leu Arg Gln His Ser Ser Pro Trp Gln Val Tyr Gly Phe Leu
450 455 460
Arg Ala Cys Leu Arg Arg Leu Val Pro Pro Gly Leu Trp Gly Ser Arg
465 470 475 480
His Asn Glu Arg Arg Phe Leu Arg Asn Thr Lys Lys Phe Ile Ser Leu
485 490 495
Gly Lys His Ala Lys Leu Ser Leu Gln Glu Leu Thr Trp Lys Met Ser
500 505 510
Val Arg Asp Cys Ala Trp Leu Arg Arg Ser Pro Gly Val Gly Cys Val
515 520 525
Pro Ala Ala Glu His Arg Leu Arg Glu Glu Ile Leu Ala Lys Phe Leu
530 535 540
His Trp Leu Met Ser Val Tyr Val Val Glu Leu Leu Arg Ser Phe Phe
545 550 555 560
Tyr Val Thr Glu Thr Thr Phe Gln Lys Asn Tyr Leu Phe Phe Tyr Arg
565 570 575
Lys Ser Val Trp Ser Lys Leu Gln Ser Ile Gly Ile Arg Gln His Leu
580 585 590
Lys Arg Val Gln Leu Arg Glu Leu Ser Glu Ala Glu Val Arg Gln His
595 600 605
Arg Glu Ala Arg Pro Ala Leu Leu Thr Ser Arg Leu Arg Phe Leu Pro
610 615 620
Lys Pro Asp Gly Leu Arg Pro Ile Val Asn Met Asp Tyr Val Val Gly
625 630 635 640
Ala Arg Thr Phe Arg Arg Glu Lys Arg Ala Glu Arg Leu Thr Ser Arg
645 650 655
Val Lys Thr Leu Phe Ser Val Leu Asn Tyr Glu Arg Ala Arg Arg Pro
660 665 670
Gly Leu Leu Gly Ala Ser Val Leu Gly Leu Asp Asp Ile His Arg Ala
675 680 685
Trp Arg Ala Phe Val Leu Arg Val Arg Ala Gln Asp Pro Pro Pro Glu
690 695 700
Leu Tyr Phe Val Lys Val Ala Val Thr Gly Ala Tyr Asp Thr Ile Pro
705 710 715 720
Gln Asp Arg Leu Thr Glu Val Ile Ala Ser Ile Ile Lys Pro Gln Asn
725 730 735
Thr Tyr Cys Val Arg Arg Tyr Ala Val Val Arg Arg Ala Ala His Gly
740 745 750
His Val Arg Lys Ser Phe Lys Arg His Val Ser Thr Leu Thr Asp Leu
755 760 765
Gln Pro Tyr Met Arg Gln Phe Val Ala His Leu Gln Glu Thr Ser Pro
770 775 780
Leu Arg Asp Ala Val Val Ile Glu Gln Ser Ser Ser Leu Asn Glu Ala
785 790 795 800
Ser Ser Gly Leu Phe Asp Val Phe Leu Arg Phe Val Cys His His Ala
805 810 815
Val Arg Ile Gly Gly Lys Ser Tyr Val Gln Cys Gln Gly Ile Pro Gln
820 825 830
Gly Ser Ile Leu Ser Thr Leu Leu Cys Ser Leu Cys Tyr Gly Asp Met
835 840 845
Glu Asn Lys Leu Phe Ala Gly Ile Arg Arg Asp Gly Leu Leu Leu Arg
850 855 860
Leu Val Ala Ala Phe Leu Leu Val Thr Pro His Leu Thr His Ala Lys
865 870 875 880
Ala Phe Leu Arg Thr Leu Val Arg Gly Val Pro Glu Tyr Gly Cys Val
885 890 895
Val Asn Leu Arg Lys Thr Val Val Asn Phe Pro Val Glu Asp Glu Ala
900 905 910
Leu Gly Gly Thr Ala Phe Val Gln Leu Pro Ala His Gly Leu Phe Pro
915 920 925
Trp Cys Gly Leu Leu Leu Asp Thr Arg Thr Leu Glu Val Gln Ser Asp
930 935 940
Tyr Ser Ser Tyr Ala Arg Thr Ser Ile Arg Ala Ser Leu Thr Phe Asn
945 950 955 960
Arg Gly Phe Lys Ala Gly Arg Asn Met Arg Arg Lys Leu Phe Gly Val
965 970 975
Leu Arg Leu Lys Cys His Ser Leu Phe Leu Tyr Leu Gln Val Asn Ser
980 985 990
Leu Gln Thr Val Cys Thr Asn Val Tyr Lys Ile Phe Leu Leu Gln Ala
995 1000 1005
Tyr Arg Phe His Ala Cys Val Leu Gln Leu Pro Phe His Gln Gln
1010 1015 1020
Val Arg Lys Asn Pro Thr Phe Phe Leu Arg Val Ile Ser Asp Thr
1025 1030 1035
Ala Ser Leu Cys Tyr Ser Ile Leu Lys Ala Lys Asn Ala Gly Met
1040 1045 1050
Ser Leu Gly Ala Lys Gly Ala Ala Gly Pro Phe Pro Ser Glu Ala
1055 1060 1065
Ala Gln Trp Leu Cys His Gln Ala Phe Leu Leu Lys Leu Ala Arg
1070 1075 1080
His Arg Val Thr Tyr Arg Cys Leu Leu Gly Ala Leu Arg Thr Ala
1085 1090 1095
Gln Thr Gln Leu Cys Arg Lys Leu Pro Gly Ala Thr Leu Ala Ala
1100 1105 1110
Leu Glu Ala Ala Ala Asp Pro Ala Leu Thr Ser Asp Phe Lys Thr
1115 1120 1125
Ile Leu Asp
1130
<210> 21
<211> 2307
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 21
atggactgga catggattct gttcctggtc gccgccgcaa ctcgcgtgca ttcctggaac 60
gcactgcatg agactgattc tgctgtcgca ctgggacgga gaccccggtg gctgtgcgct 120
ggagcactgg tgctggccgg cgggggattc ctgctgggat tcctgtttgg ctggtttatc 180
aaaagctcca gcgaggctac caatattacc cctaagcaca ataagaaagc attcctggat 240
gaactgaaag ccgagaacat caagaaattc ctgtacaact tcacaagaat tccacatctg 300
gctggcactg agcagaactt ccagctggca aaacagatcc agagtcagtg gaaggaattt 360
gggctggact cagtggagct gacccactac gatgtcctgc tgtcctatcc aaataagact 420
catcccaact acatctctat cattaacgaa gacggaaatg agattttcaa cacctctctg 480
tttgaacccc ctccacccgg ctatgagaat gtcagtgacg tggtccctcc attctcagcc 540
ttcagccccc aggggatgcc tgagggagat ctggtgtacg tcaattatgc tagaacagaa 600
gacttcttta agctggagag ggatatgaaa atcaactgtt ccggcaagat cgtgattgcc 660
cggtacggga aggtgttcag aggaaataag gtcaaaaacg ctcagctggc cggagctacc 720
ggcgtgatcc tgtacagcga ccccgctgat tattttgcac ctggcgtgaa gtcctatcca 780
gacggatgga atctgcccgg cgggggagtg cagaggggaa acatcctgaa cctgaatgga 840
gccggcgatc ctctgactcc aggatacccc gccaacgaat acgcttatcg ccggggaatt 900
gcagaggccg tgggcctgcc tagcatccca gtccatccca ttggctatta cgatgcccag 960
aagctgctgg agaaaatggg cgggagcgct ccccctgact ctagttggaa gggctccctg 1020
aaagtgcctt acaatgtcgg gccaggattc actgggaact tttctaccca gaaggtgaaa 1080
atgcacatcc atagtaccag cgaggtgaca cgaatctaca acgtcattgg caccctgaga 1140
ggcgccgtgg agcctgatcg ctatgtcatt ctgggaggcc acagagactc atgggtgttc 1200
gggggaatcg atccacagag cggagcagct gtggtccatg aaattgtgcg cagctttggg 1260
accctgaaga aagagggatg gcgacccagg cgcacaatcc tgttcgcatc ctgggacgcc 1320
gaggaatttg ggctgctggg cagcacagaa tgggccgagg aaaattctcg cctgctgcag 1380
gagcgagggg tggcttacat caatgcagac tcaagcattg aaggaaacta taccctgcgg 1440
gtggattgca cacccctgat gtacagtctg gtctataacc tgacaaagga gctgaaatca 1500
cctgacgagg gcttcgaagg gaaaagcctg tacgaatcct ggactgagaa gagcccatcc 1560
cccgaattca gcggcatgcc taggatctct aagctgggca gtgggaacga ttttgaggtg 1620
ttctttcagc gcctgggaat tgcctctggc cgagctcggt acacaaaaaa ttgggagact 1680
aacaagttct cctcttaccc actgtatcac agcgtgtacg agacttatga actggtcgag 1740
aaattctacg accccacttt taagtatcat ctgaccgtgg cacaggtcag gggcgggatg 1800
gtgttcgaac tggccaatag catcgtcctg ccatttgact gtcgagatta cgctgtggtc 1860
ctgcggaagt acgcagacaa gatctataac atctccatga agcaccccca ggagatgaag 1920
gcctattctg tgagtttcga ttccctgttt tctgccgtca aaaatttcac cgaaatcgct 1980
agtaagtttt cagagcgcct gcaggacctg gataagtcca atcccatcct gctgcggatt 2040
atgaacgatc agctgatgtt cctggaaaga gcctttatcg accctctggg cctgcctgat 2100
agaccattct acaggcacgt gatctacgca cctagttcac ataacaagta cgccggcgag 2160
tctttcccag ggatctatga cgctctgttt gatattgaat caaaggtgga ccccagcaaa 2220
gcatggggcg aggtcaagag acagatcagc attgcagcct ttacagtgca ggccgccgcc 2280
gaaaccctgt ccgaagtcgc ttgataa 2307
<210> 22
<211> 660
<212> DNA
<213> 智人（Homo sapiens）
<400> 22
atgtgtccag cgcgcagcct cctccttgtg gctaccctgg tcctcctgga ccacctcagt 60
ttggccagaa acctccccgt ggccactcca gacccaggaa tgttcccatg ccttcaccac 120
tcccaaaacc tgctgagggc cgtcagcaac atgctccaga aggccagaca aactctagaa 180
ttttaccctt gcacttctga agagattgat catgaagata tcacaaaaga taaaaccagc 240
acagtggagg cctgtttacc attggaatta accaagaatg agagttgcct aaattccaga 300
gagacctctt tcataactaa tgggagttgc ctggcctcca gaaagacctc ttttatgatg 360
gccctgtgcc ttagtagtat ttatgaagac ttgaagatgt accaggtgga gttcaagacc 420
atgaatgcaa agcttctgat ggatcctaag aggcagatct ttctagatca aaacatgctg 480
gcagttattg atgagctgat gcaggccctg aatttcaaca gtgagactgt gccacaaaaa 540
tcctcccttg aagaaccgga tttttataaa actaaaatca agctctgcat acttcttcat 600
gctttcagaa ttcgggcagt gactattgat agagtgatga gctatctgaa tgcttcctaa 660
<210> 23
<211> 219
<212> PRT
<213> 智人（Homo sapiens）
<400> 23
Met Cys Pro Ala Arg Ser Leu Leu Leu Val Ala Thr Leu Val Leu Leu
1 5 10 15
Asp His Leu Ser Leu Ala Arg Asn Leu Pro Val Ala Thr Pro Asp Pro
20 25 30
Gly Met Phe Pro Cys Leu His His Ser Gln Asn Leu Leu Arg Ala Val
35 40 45
Ser Asn Met Leu Gln Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys
50 55 60
Thr Ser Glu Glu Ile Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser
65 70 75 80
Thr Val Glu Ala Cys Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys
85 90 95
Leu Asn Ser Arg Glu Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala
100 105 110
Ser Arg Lys Thr Ser Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr
115 120 125
Glu Asp Leu Lys Met Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys
130 135 140
Leu Leu Met Asp Pro Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu
145 150 155 160
Ala Val Ile Asp Glu Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr
165 170 175
Val Pro Gln Lys Ser Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys
180 185 190
Ile Lys Leu Cys Ile Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr
195 200 205
Ile Asp Arg Val Met Ser Tyr Leu Asn Ala Ser
210 215
<210> 24
<211> 987
<212> DNA
<213> 智人（Homo sapiens）
<400> 24
atgtgtcacc agcagttggt catctcttgg ttttccctgg tttttctggc atctcccctc 60
gtggccatat gggaactgaa gaaagatgtt tatgtcgtag aattggattg gtatccggat 120
gcccctggag aaatggtggt cctcacctgt gacacccctg aagaagatgg tatcacctgg 180
accttggacc agagcagtga ggtcttaggc tctggcaaaa ccctgaccat ccaagtcaaa 240
gagtttggag atgctggcca gtacacctgt cacaaaggag gcgaggttct aagccattcg 300
ctcctgctgc ttcacaaaaa ggaagatgga atttggtcca ctgatatttt aaaggaccag 360
aaagaaccca aaaataagac ctttctaaga tgcgaggcca agaattattc tggacgtttc 420
acctgctggt ggctgacgac aatcagtact gatttgacat tcagtgtcaa aagcagcaga 480
ggctcttctg acccccaagg ggtgacgtgc ggagctgcta cactctctgc agagagagtc 540
agaggggaca acaaggagta tgagtactca gtggagtgcc aggaggacag tgcctgccca 600
gctgctgagg agagtctgcc cattgaggtc atggtggatg ccgttcacaa gctcaagtat 660
gaaaactaca ccagcagctt cttcatcagg gacatcatca aacctgaccc acccaagaac 720
ttgcagctga agccattaaa gaattctcgg caggtggagg tcagctggga gtaccctgac 780
acctggagta ctccacattc ctacttctcc ctgacattct gcgttcaggt ccagggcaag 840
agcaagagag aaaagaaaga tagagtcttc acggacaaga cctcagccac ggtcatctgc 900
cgcaaaaatg ccagcattag cgtgcgggcc caggaccgct actatagctc atcttggagc 960
gaatgggcat ctgtgccctg cagttag 987
<210> 25
<211> 328
<212> PRT
<213> 智人（Homo sapiens）
<400> 25
Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu
1 5 10 15
Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser
325
<210> 26
<211> 418
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 26
Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu Pro Ala Val Pro Ser
1 5 10 15
Leu Pro Gly Gly Gly Gly Cys Ala Leu Pro Val Ser Gly Ala Ala Gln
20 25 30
Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Ala Ala Pro Tyr Gly Ser
35 40 45
Leu Gly Gly Pro His Ser Phe Ile Lys Gln Glu Pro Ser Trp Gly Gly
50 55 60
Ala Asp Pro His Glu Glu Gln Cys Leu Ser Ala Phe Thr Val His Phe
65 70 75 80
Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg Tyr Gly Pro Phe
85 90 95
Gly Ala Pro Pro Pro Ser Gln Ala Pro Ser Gly Gln Ala Arg Met Phe
100 105 110
Pro Asn Ala Pro Tyr Leu Pro Asn Cys Leu Glu Ser Gln Pro Ala Ile
115 120 125
Arg Asn Gln Gly Tyr Ser Thr Val Ala Phe Asp Gly Thr Pro Ser Tyr
130 135 140
Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro Asn His Ser Phe
145 150 155 160
Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu Gly Glu Gln Gln
165 170 175
Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr Pro Thr Asp Ser
180 185 190
Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro Tyr Asn Ser Asp
195 200 205
Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met Thr Trp Asn Gln
210 215 220
Met Asn Leu Gly Ser Thr Leu Lys Gly His Ala Thr Gly Tyr Glu Ser
225 230 235 240
Asp Asn His Thr Thr Pro Met Leu Tyr Ser Cys Gly Ala Gln Tyr Arg
245 250 255
Ile His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg Arg Val
260 265 270
Pro Gly Val Ala Pro Thr Ile Val Arg Ser Ala Ser Glu Thr Asn Glu
275 280 285
Lys Arg Pro Phe Met Gly Ala Tyr Pro Gly Gly Asn Lys Arg Tyr Phe
290 295 300
Lys Leu Ser His Leu Gln Met Gly Ser Arg Lys Gly Thr Gly Glu Lys
305 310 315 320
Pro Tyr Gln Gly Asp Phe Lys Asp Gly Glu Arg Arg Phe Ser Arg Ser
325 330 335
Asp Gln Leu Lys Arg Gly Gln Arg Arg Gly Thr Gly Val Lys Pro Phe
340 345 350
Gln Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His Leu Lys
355 360 365
Thr His Thr Arg Thr His Thr Gly Lys Thr Ser Glu Lys Pro Phe Ser
370 375 380
Cys Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu
385 390 395 400
Val Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu
405 410 415
Ala Leu
<210> 27
<211> 1260
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 27
gggagtgatg tgagagacct gaacgccctg ctgccagcag tgccatccct gcctggcggg 60
ggaggctgcg ctctgccagt ctctggagca gctcagtggg ctcccgtgct ggactttgca 120
ccccctgcag ccccttacgg aagtctgggc ggcccacact cattcatcaa acaggagcca 180
agctggggcg gggcagatcc tcatgaggaa cagtgcctgt cagccttcac agtccacttt 240
agcgggcagt tcactggaac cgcaggagct tgtagatacg gaccctttgg agcaccaccc 300
ccttcccagg caccttctgg acaggcacgc atgttcccaa acgctcccta tctgcctaat 360
tgtctggaaa gccagcccgc tattaggaac cagggctact ccacagtggc atttgacggg 420
actcctagct atggacatac cccatcccac catgctgcac agtttcctaa tcactccttc 480
aagcatgagg accccatggg acagcagggg tccctgggag aacagcagta ctctgtgccc 540
cctcccgtgt acggatgcca cacaccaact gacagttgta caggctcaca ggccctgctg 600
ctgcgaactc catacaacag tgataatctg tatcagatga cctcacagct ggagtgcatg 660
acatggaacc agatgaatct gggcagcaca ctgaaaggcc atgccactgg gtacgaatct 720
gacaaccaca ccacacctat gctgtacagt tgtggagccc agtatagaat ccacactcat 780
ggagtcttca gaggcattca ggatgtgcgg agagtcccag gagtggcacc aactatcgtg 840
cggagcgcct ccgagaccaa cgaaaagcgc ccctttatgg gcgcctaccc tggaggcaat 900
aagcggtatt tcaaactgtc tcacctgcag atggggagta gaaaggggac cggagagaaa 960
ccttatcagg gcgactttaa agatggggaa aggcgcttct ctcgcagtga ccagctgaag 1020
cgaggacagc gacgaggaac cggggtgaag ccatttcagt gcaaaacatg tcagagaaag 1080
ttctcaagga gcgatcacct gaagacccat acaagaactc acaccggcaa gaccagcgag 1140
aaaccatttt cctgccgatg gccctcttgt cagaagaaat tcgcccgctc cgacgaactg 1200
gtccgacacc acaatatgca tcagagaaat atgacaaaac tgcagctggc tctgtgataa 1260
<210> 28
<211> 749
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多肽
<400> 28
Trp Asn Ala Leu His Glu Thr Asp Ser Ala Val Ala Leu Gly Arg Arg
1 5 10 15
Pro Arg Trp Leu Cys Ala Gly Ala Leu Val Leu Ala Gly Gly Gly Phe
20 25 30
Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile Lys Ser Ser Ser Glu Ala
35 40 45
Thr Asn Ile Thr Pro Lys His Asn Lys Lys Ala Phe Leu Asp Glu Leu
50 55 60
Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr Asn Phe Thr Arg Ile Pro
65 70 75 80
His Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile Gln
85 90 95
Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser Val Glu Leu Thr His Tyr
100 105 110
Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile Ser
115 120 125
Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe Glu
130 135 140
Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser Asp Val Val Pro Pro Phe
145 150 155 160
Ser Ala Phe Ser Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr Val
165 170 175
Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met Lys
180 185 190
Ile Asn Cys Ser Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val Phe
195 200 205
Arg Gly Asn Lys Val Lys Asn Ala Gln Leu Ala Gly Ala Thr Gly Val
210 215 220
Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys Ser
225 230 235 240
Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly Asn
245 250 255
Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr Pro
260 265 270
Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly Leu
275 280 285
Pro Ser Ile Pro Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys Leu
290 295 300
Leu Glu Lys Met Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Lys Gly
305 310 315 320
Ser Leu Lys Val Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn Phe
325 330 335
Ser Thr Gln Lys Val Lys Met His Ile His Ser Thr Ser Glu Val Thr
340 345 350
Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro Asp
355 360 365
Arg Tyr Val Ile Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly Gly
370 375 380
Ile Asp Pro Gln Ser Gly Ala Ala Val Val His Glu Ile Val Arg Ser
385 390 395 400
Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile Leu
405 410 415
Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr Glu
420 425 430
Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala Tyr
435 440 445
Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val Asp
450 455 460
Cys Thr Pro Leu Met Tyr Ser Leu Val Tyr Asn Leu Thr Lys Glu Leu
465 470 475 480
Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser Trp
485 490 495
Thr Glu Lys Ser Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile Ser
500 505 510
Lys Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu Gly
515 520 525
Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn Lys
530 535 540
Phe Ser Ser Tyr Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu Leu
545 550 555 560
Val Glu Lys Phe Tyr Asp Pro Thr Phe Lys Tyr His Leu Thr Val Ala
565 570 575
Gln Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val Leu
580 585 590
Pro Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala Asp
595 600 605
Lys Ile Tyr Asn Ile Ser Met Lys His Pro Gln Glu Met Lys Ala Tyr
610 615 620
Ser Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr Glu
625 630 635 640
Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln Asp Leu Asp Lys Ser Asn
645 650 655
Pro Ile Leu Leu Arg Ile Met Asn Asp Gln Leu Met Phe Leu Glu Arg
660 665 670
Ala Phe Ile Asp Pro Leu Gly Leu Pro Asp Arg Pro Phe Tyr Arg His
675 680 685
Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu Ser Phe
690 695 700
Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys Val Asp Pro
705 710 715 720
Ser Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Ser Ile Ala Ala Phe
725 730 735
Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val Ala
740 745
<210> 29
<211> 2253
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述：合成的
多核苷酸
<400> 29
tggaacgcac tgcatgagac tgattctgct gtcgcactgg gacggagacc ccggtggctg 60
tgcgctggag cactggtgct ggccggcggg ggattcctgc tgggattcct gtttggctgg 120
tttatcaaaa gctccagcga ggctaccaat attaccccta agcacaataa gaaagcattc 180
ctggatgaac tgaaagccga gaacatcaag aaattcctgt acaacttcac aagaattcca 240
catctggctg gcactgagca gaacttccag ctggcaaaac agatccagag tcagtggaag 300
gaatttgggc tggactcagt ggagctgacc cactacgatg tcctgctgtc ctatccaaat 360
aagactcatc ccaactacat ctctatcatt aacgaagacg gaaatgagat tttcaacacc 420
tctctgtttg aaccccctcc acccggctat gagaatgtca gtgacgtggt ccctccattc 480
tcagccttca gcccccaggg gatgcctgag ggagatctgg tgtacgtcaa ttatgctaga 540
acagaagact tctttaagct ggagagggat atgaaaatca actgttccgg caagatcgtg 600
attgcccggt acgggaaggt gttcagagga aataaggtca aaaacgctca gctggccgga 660
gctaccggcg tgatcctgta cagcgacccc gctgattatt ttgcacctgg cgtgaagtcc 720
tatccagacg gatggaatct gcccggcggg ggagtgcaga ggggaaacat cctgaacctg 780
aatggagccg gcgatcctct gactccagga taccccgcca acgaatacgc ttatcgccgg 840
ggaattgcag aggccgtggg cctgcctagc atcccagtcc atcccattgg ctattacgat 900
gcccagaagc tgctggagaa aatgggcggg agcgctcccc ctgactctag ttggaagggc 960
tccctgaaag tgccttacaa tgtcgggcca ggattcactg ggaacttttc tacccagaag 1020
gtgaaaatgc acatccatag taccagcgag gtgacacgaa tctacaacgt cattggcacc 1080
ctgagaggcg ccgtggagcc tgatcgctat gtcattctgg gaggccacag agactcatgg 1140
gtgttcgggg gaatcgatcc acagagcgga gcagctgtgg tccatgaaat tgtgcgcagc 1200
tttgggaccc tgaagaaaga gggatggcga cccaggcgca caatcctgtt cgcatcctgg 1260
gacgccgagg aatttgggct gctgggcagc acagaatggg ccgaggaaaa ttctcgcctg 1320
ctgcaggagc gaggggtggc ttacatcaat gcagactcaa gcattgaagg aaactatacc 1380
ctgcgggtgg attgcacacc cctgatgtac agtctggtct ataacctgac aaaggagctg 1440
aaatcacctg acgagggctt cgaagggaaa agcctgtacg aatcctggac tgagaagagc 1500
ccatcccccg aattcagcgg catgcctagg atctctaagc tgggcagtgg gaacgatttt 1560
gaggtgttct ttcagcgcct gggaattgcc tctggccgag ctcggtacac aaaaaattgg 1620
gagactaaca agttctcctc ttacccactg tatcacagcg tgtacgagac ttatgaactg 1680
gtcgagaaat tctacgaccc cacttttaag tatcatctga ccgtggcaca ggtcaggggc 1740
gggatggtgt tcgaactggc caatagcatc gtcctgccat ttgactgtcg agattacgct 1800
gtggtcctgc ggaagtacgc agacaagatc tataacatct ccatgaagca cccccaggag 1860
atgaaggcct attctgtgag tttcgattcc ctgttttctg ccgtcaaaaa tttcaccgaa 1920
atcgctagta agttttcaga gcgcctgcag gacctggata agtccaatcc catcctgctg 1980
cggattatga acgatcagct gatgttcctg gaaagagcct ttatcgaccc tctgggcctg 2040
cctgatagac cattctacag gcacgtgatc tacgcaccta gttcacataa caagtacgcc 2100
ggcgagtctt tcccagggat ctatgacgct ctgtttgata ttgaatcaaa ggtggacccc 2160
agcaaagcat ggggcgaggt caagagacag atcagcattg cagcctttac agtgcaggcc 2220
gccgccgaaa ccctgtccga agtcgcttga taa 2253
Claims (40)
1.一种免疫原性合成物，包含人端粒酶逆转录酶(hTERT)、Wilms肿瘤-1(WT-1)和前列腺特异性膜抗原(PSMA)。
2.根据权利要求1所述的免疫原性合成物，其中，hTERT由DNA质粒编码，WT-1由DNA质粒编码和/或PSMA由DNA质粒编码。
3.根据权利要求2所述的免疫原性合成物，其中，hTERT、WT-1和PSMA由相同的DNA质粒编码；其中，hTERT、WT-1和PSMA中的两个由相同的DNA质粒编码；或其中，hTERT、WT-1和PSMA由不同的DNA质粒编码。
4.根据前述权利要求中任一项所述的免疫原性合成物，其中：
所述hTERT包含氨基酸序列SEQ ID NO:20或由核酸序列SEQ ID NO:19编码；
所述WT-1包含氨基酸序列SEQ ID NO:26或由核酸序列SEQ ID NO:27编码；和/或
所述PSMA包含氨基酸序列SEQ ID NO:28或由核酸序列SEQ ID NO:29编码。
5.一种疫苗，包含：
前述权利要求中任一项所述的免疫原性合成物；
IL12；以及
抗程序性细胞死亡受体1(PD-1)抗体。
6.根据权利要求5所述的疫苗，其中，所述抗PD-1抗体：
包含重链可变区(HCVR)(包含氨基酸序列SEQ ID NO:1)的重链互补决定区(HCDR1、HCDR2和HCDR3)以及轻链可变区(LCVR)(氨基酸序列SEQ ID NO:2)的三个轻链互补决定区(LCDR1、LCDR2和LCDR3)；
包含三个HCDR(HCDR1、HCDR2和HCDR3)和三个LCDR(LCDR1、LCDR2和LCDR3)，其中，HCDR1包含氨基酸序列SEQ ID NO:3；HCDR2包含氨基酸序列SEQ ID NO:4；HCDR3包含氨基酸序列SEQ ID NO:5；LCDR1包含氨基酸序列SEQ ID NO:6；LCDR2包含氨基酸序列SEQ ID NO:7；以及LCDR3包含氨基酸序列SEQ ID NO:8；
包含与SEQ ID NO:1具有90％序列一致性的HCVR；
包含与SEQ ID NO:2具有90％序列一致性的LCVR；
包含与SEQ ID NO:1具有90％序列一致性的HCVR以及与SEQ ID NO:2具有90％序列一致性的LCVR；
包含含有氨基酸序列SEQ ID NO:1的HCVR以及含有氨基酸序列SEQ ID NO:2的LCVR；
包含含有氨基酸序列SEQ ID NO:9的重链以及含有氨基酸序列SEQ ID NO:10的轻链；
为IgG4抗体；或
为REGN2810或其生物仿制药或生物等效物。
7.根据权利要求5或权利要求6所述的疫苗，其中，所述IL-12由DNA质粒编码。
8.根据权利要求5、权利要求6或权利要求7所述的疫苗，其中，
所述IL12 p35亚基包含氨基酸序列SEQ ID NO:23；
所述IL12 p40亚基包含氨基酸序列SEQ ID NO:25；
所述IL12 p35亚基包含氨基酸序列SEQ ID NO:23以及所述IL12 p40亚基包含氨基酸序列SEQ ID NO:25；
所述IL12 p35亚基由核酸序列SEQ ID NO:22编码；
所述IL12 p40亚基由核酸序列SEQ ID NO:24编码；或者
所述IL12 p35亚基由核酸序列SEQ ID NO:22编码以及所述IL12 p40亚基由核酸序列SEQ ID NO:24编码。
所述IL12 p35亚基包含氨基酸序列SEQ ID NO:23，所述IL12 p40亚基包含氨基酸序列SEQ ID NO:25，或两者兼有。
9.一种治疗受试者脑癌的方法，包括向受试者施用：
白介素-12(IL-12)；
一种免疫原性合成物，包含人端粒酶逆转录酶(hTERT)、Wilms肿瘤-1(WT-1)和前列腺特异性膜抗原(PSMA)；以及
一种抗程序性细胞死亡受体1(PD-1)抗体。
10.一种用于治疗受试者脑癌的疫苗，其中，所述疫苗包含：
一种免疫原性合成物，包含人端粒酶逆转录酶(hTERT)、Wilms肿瘤-1(WT-1)和前列腺特异性膜抗原(PSMA)；以及一种抗程序性细胞死亡受体1(PD-1)抗体。
11.根据权利要求9所述的方法或权利要求10所述的疫苗，其中，所述受试者具有未甲基化O6-甲基鸟嘌呤甲基转移酶(MGMT)基因启动子。
12.根据权利要求9所述的方法或权利要求10所述的疫苗，其中，所述受试者具有甲基化O6-甲基鸟嘌呤甲基转移酶(MGMT)基因启动子。
13.根据权利要求9-12中任一项所述的方法或疫苗，其中，IL-12由DNA质粒编码。
14.根据权利要求9-13中任一项所述的方法或疫苗，其中，hTERT由DNA质粒编码，WT-1由DNA质粒编码和/或PSMA由DNA质粒编码。
15.根据权利要求14所述的方法或疫苗，其中，hTERT、WT-1和PSMA由相同的DNA质粒编码；hTERT、WT-1和PSMA中的两个由相同的DNA质粒编码；或者其中，hTERT、WT-1和PSMA由不同的DNA质粒编码。
16.根据权利要求9-15中任一项所述的方法或疫苗，其中，所述抗PD-1抗体：
包含重链可变区(HCVR)(包含氨基酸序列SEQ ID NO:1)的重链互补决定区(HCDR1、HCDR2和HCDR3)以及轻链可变区(LCVR)(包含氨基酸序列SEQ ID NO:2)的三个轻链互补决定区(LCDR1、LCDR2和LCDR3)；
包含三个HCDR(HCDR1、HCDR2和HCDR3)和三个LCDR(LCDR1、LCDR2和LCDR3)，其中，HCDR1包含氨基酸序列SEQ ID NO:3；HCDR2包含氨基酸序列SEQ ID NO:4；HCDR3包含氨基酸序列SEQ ID NO:5；LCDR1包含氨基酸序列SEQ ID NO:6；LCDR2包含氨基酸序列SEQ ID NO:7；以及LCDR3包含氨基酸序列SEQ ID NO:8；
包含与SEQ ID NO:1具有90％序列一致性的HCVR；
包含与SEQ ID NO:2具有90％序列一致性的LCVR；
包含与SEQ ID NO:1具有90％序列一致性的HCVR以及与SEQ ID NO:2具有90％序列一致性的LCVR；
包含含有氨基酸序列SEQ ID NO:1的HCVR以及含有氨基酸序列SEQ ID NO:2的LCVR；
包含含有氨基酸序列SEQ ID NO:9的重链以及含有氨基酸序列SEQ ID NO:10的轻链；
为IgG4抗体；或
为REGN2810或其生物仿制药或生物等效物。
17.根据权利要求9-16中任一项所述的方法或疫苗，其中，所述抗PD-1抗体经静脉或皮下给药。
18.根据权利要求9-17中任一项所述的方法或疫苗，其中，每三周施用350mg抗PD-1抗体。
19.根据权利要求9-18中任一项所述的方法或疫苗，其中，
所述IL12 p35亚基包含氨基酸序列SEQ ID NO:23；
所述IL12 p40亚基包含氨基酸序列SEQ ID NO:25；
所述IL12 p35亚基包含氨基酸序列SEQ ID NO:23以及所述IL12 p40亚基包含氨基酸序列SEQ ID NO:25；
所述IL12 p35亚基由核酸序列SEQ ID NO:22编码；
所述IL12 p40亚基由核酸序列SEQ ID NO:24编码；或者
所述IL12 p35亚基由核酸序列SEQ ID NO:22编码以及所述IL12 p40亚基由核酸序列SEQ ID NO:24编码。
20.根据权利要求9-19中任一项所述的方法或疫苗，其中，
所述hTERT包含氨基酸序列SEQ ID NO:20或由核酸序列SEQ ID NO:19编码；
所述WT-1包含氨基酸序列SEQ ID NO:26或由核酸序列SEQ ID NO:27编码；和/或
所述PSMA包含氨基酸序列SEQ ID NO:28或由核酸序列SEQ ID NO:29编码。
21.根据权利要求20所述的方法或疫苗，其中，所述方法包括向受试者施用所述疫苗，或者其中，所述疫苗包含3mg DNA质粒编码hTERT、3mg DNA质粒编码PSMA、3mg DNA质粒编码WT-1以及1mg质粒编码IL-12。
22.根据权利要求9-21中任一项所述的方法或疫苗，其中，所述IL-12和免疫原性合成物通过肌肉注射，每三周施用一次，共四剂，然后每九周施用一次。
23.根据权利要求22所述的方法或疫苗，进一步包括在每次肌肉注射后进行电穿孔。
24.根据权利要求9-23中任一项所述的方法或疫苗，进一步包括向受试者施用一剂或多剂放疗。
25.根据权利要求24所述的方法或疫苗，其中，每剂量的放疗包括20-50Gy。
26.根据权利要求25所述的方法或疫苗，其中，所述放疗为分割放疗。
27.根据权利要求26所述的方法或疫苗，其中，所述分割放疗包括2-20次分割。
28.根据权利要求27所述的方法或疫苗，其中，所述分割放疗在15次分割中包括40Gy。
29.根据权利要求28所述的方法或疫苗，其中，所述分割放疗连续进行21天。
30.根据权利要求9-29中任一项所述的方法或疫苗，进一步包括向受试者施用一剂或多剂化疗剂；可选地，其中，所述化疗剂为替莫唑胺。
31.根据权利要求30所述的方法或疫苗，包括在连续21天的分割放疗中向受试者施用75mg/m2替莫唑胺。
32.根据权利要求30或权利要求31所述的方法或疫苗，进一步包括如果受试者的肿瘤具有甲基化MGMT启动子，则向受试者施用替莫唑胺维持治疗。
33.根据权利要求9-32中任一项所述的方法或疫苗，其中，所述脑癌为胶质母细胞瘤。
34.根据权利要求33所述的方法或疫苗，其中，所述脑癌为MGMT-甲基化胶质母细胞瘤。
35.根据权利要求33所述的方法或疫苗，其中，所述脑癌为MGMT-未甲基化胶质母细胞瘤。
36.根据权利要求9-35中任一项所述的方法或疫苗，其中，所述方法临床证明安全、临床证明有效或两种兼有。
37.根据权利要求1-4中任一项所述的免疫原性合成物，所述免疫原性合成物用于生产治疗脑癌的药物。
38.根据权利要求37所述的免疫原性合成物，其中，所述脑癌为胶质母细胞瘤。
39.根据权利要求38所述的免疫原性合成物，其中，所述脑癌为MGMT-甲基化胶质母细胞瘤。
40.根据权利要求38所述的免疫原性合成物，其中，所述脑癌为MGMT-未甲基化胶质母细胞瘤。
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| MX2022005345A (es) | 2022-08-11 |
| AU2024202791A1 (en) | 2024-05-23 |
| BR112022008164A2 (pt) | 2022-07-12 |
| EP4055033A1 (en) | 2022-09-14 |
| WO2021092019A1 (en) | 2021-05-14 |
| IL292462A (en) | 2022-06-01 |
| KR20220097928A (ko) | 2022-07-08 |
| AU2020380288B2 (en) | 2024-02-01 |
| CA3156227A1 (en) | 2021-05-14 |
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