CN109069604A - 新抗原组合物及其在免疫肿瘤治疗中的使用方法 - Google Patents
新抗原组合物及其在免疫肿瘤治疗中的使用方法 Download PDFInfo
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Abstract
本发明,尤其是,提供了组合物,其包括含有癌抗原性肽和成熟MHC II类肽的融合蛋白、编码所述蛋白的核酸、其药物制剂、表达所述蛋白的抗原呈递细胞。本发明还提供了利用这些组合物治疗癌症的方法。
Description
相关申请的交叉参考
本申请要求2016年2月22日提交的美国临时专利申请62/298,275的优先权和权益,该专利内容全部并入本发明作参考及用于所有目的。
对以ASCII文件递交的“序列表”、表或者计算机程序列表附录的参考
在此并入在2017年2月22日创建的29,951字节的机器格式IBM-PC、MS-Windows操作系统的文件49906-503001WO_ST25.TXT中编写的序列表作为参考。
发明背景
在过去几十年中,绝大多数的研究显著地帮助理解导致癌症的分子机制。然而,分子肿瘤学领域的这种科学进步与癌症治疗方面的相应进展未并行。在大多数患者中,手术和/或放射疗法仍然是局部治疗癌症的主要方式。然而,这些治疗仅在疾病的初始阶段、特别是对于某些实体瘤有效,而其对疾病的远处复发无效。在一些肿瘤类别中,已经开发了化学治疗方法,其通常依赖于药物、激素和抗体,靶向癌症生长和扩散所使用的特定生物过程。然而,迄今为止,由于副作用的严重性和全身毒性导致许多癌症疗法的疗效有限。因此,迫切需要新的治疗方法以推进癌症的治疗。本发明提供了本领域中的这些和其它问题的解决方案。
发明概述
本发明提供了治疗癌症的组合物和治疗方法。
一方面,本发明提供了蛋白质,其包括共价附着于成熟的MHC II类肽的癌症抗原性肽,所述癌症抗原性肽能直接非共价结合MHC II类肽。
一方面,本发明提供了抗原呈递细胞。所述抗原呈递细胞包括一或多种本发明所述蛋白质。
一方面,本发明提供了编码本发明所述任一蛋白质的核酸。
一方面,本发明提供了药物制剂,其包含本发明揭示的核酸及药学可接受的赋形剂。
另一方面,本发明提供了包含本发明所述任何核酸的树突细胞或B细胞。
一方面,本发明提供了治疗有需要的患者中癌症的方法。所述方法包括将本发明所述抗原呈递细胞与CD4+T细胞在体外接触,从而激活CD4+T细胞,其中所述CD4+T细胞和抗原呈递细胞来自患者;使活化的CD4+T细胞扩展,从而形成多个扩展的CD4+T细胞;及给患者施用有效量的多个扩展的CD4+T细胞。
一方面,本发明提供了治疗有需要的患者中癌症的方法。所述方法包括给患者施用有效量的本发明所述的核酸。
附图简述
图1:示出用于治疗肿瘤的自体T细胞转移的图示。
图2A-2B:图2A是本发明揭示的融合蛋白的示意图。图2B是融合蛋白的预测3D结构。
图3示出利用本发明平台的治疗工作流程。
发明详述
I.定义
虽然在本文示出和描述了本发明的各种实施方案和方面,但是本领域技术人员显而易见的是这些实施方案和方面仅作为示例提供。在不偏离本发明的情况下,本领域技术人员可以对本发明进行各种变化、改变和替换。应理解本发明所述实施方案的各种替代方案可用于实施本发明。
这里使用的章节标题仅用于文章结构之目的,不应解释为限制所描述的主题。本申请中引用的所有文件或文件的一部分,包括但不限于专利、专利申请、文章、书籍、手册和论文,以其全部内容并入本文作参考并用于任何目的。
除非另外定义,否则本发明使用的所有技术和科学术语均具有本发明所属领域的技术人员通常理解的含义。以下参考文献为本领域技术人员提供了本发明中使用的许多术语的一般定义:Singleton et al.,Dictionary of Microbiology and MolecularBiology(2nd ed.1994);The Cambridge Dictionary of Science and Technology(Walker ed.,1988);The Glossary of Genetics,5th Ed.,R.Rieger et al.(eds.),Springer Verlag(1991)和Hale&Marham,The Harper Collins Dictionary of Biology(1991)。如本文所用,除非另有说明,否则以下术语具有其认可的含义。
在本公开和以下权利要求中使用的单数不定冠词或定冠词(例如“一个”、“所述”等)根据专利中的传统应用是指“至少一个”,除非在特定情况中从上下文中可以清楚示出该术语在该特定情况中是指明确的一个且仅一个。同样地,术语“包含”是开放式的,不排除其它项目、特征、成分等。除非另有说明,否则本发明中使用的参考文献以其全部内容并入本文作参考。
术语“包含”、“包括”和“具有”及其衍生词作为综合的开放式术语在本发明中可互换使用。例如,使用“包含”、“包括”或“具有”意味着包含、具有或包括的任何元素不是含有该动词的条款主题涵盖的唯一元素。
术语“氨基酸”是指天然存在的和合成的氨基酸,以及以与天然存在的氨基酸相似的方式起作用的氨基酸类似物和氨基酸模拟物。天然存在的氨基酸是由遗传密码编码的那些氨基酸,以及后来被修饰的那些氨基酸,例如羟脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。氨基酸类似物是指与天然存在的氨基酸具有相同基本化学结构的化合物,即与氢、羧基、氨基和R基团结合的α碳,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。这种类似物具有修饰的R基团(例如正亮氨酸)或修饰的肽主链,但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的一般化学结构不同的结构但是以与天然存在的氨基酸相似的方式起作用的化学化合物。术语“非天然存在的氨基酸”和“非天然氨基酸”是指在自然界中未发现的氨基酸类似物、合成氨基酸和氨基酸模拟物。
氨基酸在本发明中可以由IUPAC-IUB生物化学命名委员会推荐的其通常已知的三字母符号或一字母符号表示。同样,核苷酸可以由其通常公认的一字母代码指代。
术语“多肽”、“肽”和“蛋白质”在本发明中可互换使用,是指氨基酸残基的聚合物,其中在实施方案中所述聚合物可以与不由氨基酸组成的部分缀合。该术语适用于其中一或多个氨基酸残基是相应天然存在的氨基酸的人工化学模拟物的氨基酸聚合物,以及天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。“融合蛋白”是指编码作为一个部分重组表达的两或更多个单独蛋白质序列的嵌合蛋白。
如本发明可使用的,术语“核酸”、“核酸分子”、“核酸寡聚物”、“寡核苷酸”、“核酸序列”、“核酸片段”和“多核苷酸”可互换使用,是指包括但不限于共价连接在一起的各种长度的核苷酸(脱氧核糖核苷酸或核糖核苷酸,或者其类似物、衍生物或修饰物)的聚合形式。不同的多核苷酸可以具有不同的三维结构,并且可以执行已知或未知的各种功能。多核苷酸的非限制性实例包括基因、基因片段、外显子、内含子、基因间DNA(包括但不限于异染色质DNA)、信使RNA(mRNA)、转移RNA、核糖体RNA、核酶、cDNA、重组多核苷酸、支链多核苷酸、质粒、载体、分离的DNA序列、分离的RNA序列、核酸探针和引物。可用于本发明方法的多核苷酸可包含天然核酸序列及其变体、人工核酸序列或这些序列的组合。
多核苷酸通常由四个核苷酸碱基的特定序列组成:腺嘌呤(A),胞嘧啶(C),鸟嘌呤(G)和胸腺嘧啶(T)(当多核苷酸是RNA时,尿嘧啶(U)替代胸腺嘧啶(T))。因此,术语“多核苷酸序列”是多核苷酸分子的字母表示;或者,该术语可以应用于多核苷酸分子自身。这种字母表示可以输入具有中央处理单元的计算机的数据库中并用于生物信息学应用,例如功能基因组学和同源性检索。多核苷酸可任选地包括一或多个非标准核苷酸、核苷酸类似物和/或修饰的核苷酸。
“保守修饰的变体”适用于氨基酸和核酸序列。关于特定的核酸序列,“保守修饰的变体”是指编码相同或基本相同的氨基酸序列的那些核酸。由于遗传密码的简并性,许多核酸序列将编码任何给定蛋白质。例如,密码子GCA、GCC、GCG和GCU均编码氨基酸丙氨酸。因此,在丙氨酸由密码子指定的每个位置,所述密码子可以改变为所述的任何相应密码子而不改变编码的多肽。这种核酸变化是“沉默变异”,其是保守修饰变异的一种。本发明中编码多肽的每个核酸序列也描述了核酸的每种可能的沉默变异。技术人员将认识到核酸中的每个密码子(除了AUG,其通常是甲硫氨酸的唯一密码子;及TGG,其通常是色氨酸的唯一密码子)均可以被修饰以产生功能相同的分子。因此,编码多肽的核酸的每个沉默变异隐含在每个所述序列中。
关于氨基酸序列,技术人员将识别在编码序列中改变、添加或缺失单个氨基酸或少量氨基酸的核酸、肽、多肽或蛋白质序列的各个取代、缺失或添加是“保守修饰的变体”,其中所述改变导致氨基酸由化学相似的氨基酸取代。提供功能相似的氨基酸的保守取代表为本领域熟知。这种保守修饰的变体在本发明的多态变体、种间同源物和等位基因之外而不排除本发明的多态变体、种间同源物和等位基因。
如下八组每组均含有彼此是保守取代的氨基酸:
1)丙氨酸(A),甘氨酸(G);
2)天冬氨酸(D),谷氨酸(E);
3)天冬酰胺(N),谷氨酰胺(Q);
4)精氨酸(R),赖氨酸(K);
5)异亮氨酸(I),亮氨酸(L),甲硫氨酸(M),缬氨酸(V);
6)苯丙氨酸(F),酪氨酸(Y),色氨酸(W);
7)丝氨酸(S),苏氨酸(T);及
8)半胱氨酸(C),甲硫氨酸(M)
(见例如Creighton,Proteins(1984))。
“序列相同性百分比”是通过在对比窗比较两个最佳比对的序列而确定,其中对比窗中的部分多核苷酸或多肽序列可以包含与参考序列(其不包含添加或缺失)相比的添加或缺失(即缺口)以最佳比对两个序列。所述百分比如下计算:通过确定在两个序列中出现相同核酸碱基或氨基酸残基的位置数以产生匹配位置的数量,将匹配位置的数量除以对比窗中的位置总数,并将结果乘以100以得到序列相同性百分比。
在关于两或多个核酸或多肽序列的描述中,术语“相同”或“相同性”百分比是指与在对比窗或者指定区域使用如下序列对比算法之一或者通过人工比对和目测测量测量的最大相应性对比和比对时,相同的或具有指定百分比的相同氨基酸残基或核苷酸(即在例如在本发明的完整多肽序列的特定区域或者本发明多肽的各个结构域中60%相同性,任选65%、70%、75%、80%、85%、90%、95%、98%或99%相同性)的两或多个序列或子序列。然后,这些序列被称为“基本相同的”。这个定义还指测试序列的互补序列。任选地,所述相同性存在于长度为至少大约50个核苷酸的区域,或者更优选地长度为100-500或1000或更多个核苷酸的区域。本发明包括与SEQ ID NO:1-62任一序列基本相同的核酸序列和多肽。
术语“MHC II类肽”在其常规意义上是指具有在两端均开放的功能性抗原结合沟及最低限度含有衍生自HLA基因(例如HLA-DRAα链肽)的功能性α亚基(包括天然α亚基的功能片段)的蛋白质。抗原结合沟通常结合长度为15-24个氨基酸的肽序列。成熟的MHC II类肽不包括全长信号肽。
如本发明所用,“信号肽”是指指导蛋白质转运至内质网(ER)以进行翻译后修饰的氨基酸序列,必要地包括蛋白酶识别序列。信号肽通常位于蛋白质的N-末端,蛋白酶识别序列通常位于信号肽的C-末端。“蛋白酶识别序列”是由通常起到切割信号肽的作用的信号肽酶识别的氨基酸序列。在实施方案中,蛋白酶识别序列是4氨基酸序列,如EHVI(SEQ ID NO:1)。在实施方案中,成熟的MHC II类肽包括蛋白酶识别序列,但不包括信号肽的任何其它部分。蛋白酶识别序列可以在MHC II类肽的N-末端。
在实施方案中,MHC II类分子包括α链(亚基)而不包括β链(亚基)。在其它实施方案中,MHC II类分子是包含α和β链的异二聚体。下表总结了MHC II类分子及其α和β链编码基因的实施方案。
术语“癌症抗原性肽”、“肿瘤抗原”或“新抗原”可互换使用,是指源自癌症细胞或肿瘤的抗原(在宿主对象如人体中能诱导免疫应答的分子)。源自肿瘤细胞的抗原在此称为肿瘤特异性抗原(TSA)。在实施方案中,TSA得自肿瘤特异性突变。
例如,在肿瘤细胞是乳腺癌细胞时,抗原可以是EpCAM(上皮细胞粘附分子)、Her2/neu(人表皮生长因子受体2)、MUC-1、EGFR(表皮生长因子受体)、TAG-12(肿瘤相关糖蛋白12)、IGF1R(胰岛素样生长因子1受体)、TACSTD2(肿瘤相关钙信号转导蛋白2)、CD318、CD340、CD104或N-钙粘蛋白之一。
例如,在肿瘤细胞是前列腺癌细胞时,抗原可以是EpCAM、MUC-1、EGFR、PSMA(前列腺特异性膜抗原)、PSA(前列腺特异性抗原)、TACSTD2、PSCA(前列腺干细胞抗原)、PCSA(前列腺细胞表面抗原)、CD318、CD104或N-钙粘蛋白之一。
例如,当肿瘤细胞是结肠直肠癌细胞时,抗原可以是EpCAM、CD66c、CD66e、CEA(癌胚抗原)、TACSTD2、CK20(细胞角蛋白20)、CD104、MUC-1、CD318或N-钙粘蛋白之一。
例如,在肿瘤细胞是肺癌细胞时,抗原可以是CK18、CK19、CEA、EGFR、TACSTD2、CD318、CD104或EpCAM之一。
例如,在肿瘤细胞是胰腺癌细胞时,抗原可以是HSP70、mHSP70、MUC-1、TACSTD2、CEA、CD104、CD318、N-钙粘蛋白或EpCAM1之一。
例如,在肿瘤细胞是卵巢癌细胞时,抗原可以是MUC-1、TACSTD2、CD318、CD104、N-钙粘蛋白或EpCAM之一。
例如,在肿瘤细胞是膀胱癌细胞时,抗原可以是CD34、CD146、CD62、CD105、CD106、VEGF受体(血管内皮生长因子受体)、MUC-1、TACSTD2、EpCAM、CD318、EGFR、6B5或叶酸结合受体之一。
例如,在肿瘤细胞是癌症干细胞时,抗原可以是CD133、CD135、CD117或CD34之一。
例如,在肿瘤细胞是黑色素瘤癌症细胞时,抗原可以是黑素细胞分化抗原、癌胚抗原、肿瘤特异性抗原、SEREX抗原或其组合之一。黑素细胞分化抗原例如包括但不限于酪氨酸酶、gp75、gp100、MART1或TRP-2。癌胚抗原例如包括MAGE家族抗原(MAGE-A1,MAGE-A4)、BAGE家族抗原、GAGE家族抗原或NY-ESO1。肿瘤特异性抗原例如包括CDK4和13-连环蛋白。SEREX抗原例如包括D-1和SSX-2。
示例的新抗原还包括但不限于下表中列出的那些抗原。
本领域技术人员可易于认识到上述新抗原以“[蛋白质名称]-[野生型残基][残基数][残基突变]”的形式表示。技术人员也可以根据本领域可获得的序列数据库容易地确定上面列出的每个新抗原的序列。选择的新抗原的示例序列包括但不限于:
IDH1-R132H(短)
ataatcggtcatcatgcttatggggaccag(SEQ ID NO:2)
I I G H H A Y G D Q(SEQ ID NO:3)
IDH1-R132H
agcggatgggtaaaacctattataatcggtcatcatgcttatggggaccagtacagagcaacg(SEQID NO:4)
S G W V K P I I I G H H A Y G D Q Y R A T(SEQ ID NO:5)
IDH2-R140Q
tggaagtctccgaacggcaccattcagaatattctcggcggcactgtgttccgggag(SEQ ID NO:6)
W K S P N G T I Q N I L G G T V F R E(SEQ ID NO:7)
IDH2-R172K
ggttggacgaaaccaatcactattggcaagcatgctcatggagaccagtacaag(SEQ ID NO:8)
G W T K P I T I G K H A H G D Q Y K(SEQ ID NO:9)
KNRAS-61R
ttggatattctcgacacagcaggtcgagaggagtacagtgcaatgagggac(SEQ ID NO:10)
L D I L D T A G R E E Y S A M R D(SEQ ID NO:11)
KNRAS-61H
ttggatattctcgacacagcaggtcatgaggagtacagtgcaatgagggac(SEQ ID NO:12)
L D I L D T A G H E E Y S A M R D(SEQ ID NO:13)
KNRAS-61K
ttggatattctcgacacagcaggtaaagaggagtacagtgcaatgagggac(SEQ ID NO:14)
L D I L D T A G K E E Y S A M R D(SEQ ID NO:15)
KNRAS-61L
ttggatattctcgacacagcaggtctagaggagtacagtgcaatgagggac(SEQ ID NO:16)
L D I L D T A G L E E Y S A M R D(SEQ ID NO:17)
BRAF–V600E
ataggtgattttggtctagctacagAgaaatctcgatggagtgggtcccat(SEQ ID NO:18)
I G D F G L A T E K S R W S G S H(SEQ ID NO:19)
PIK3CA-E545 WT
cgagatcctctctctgaaatcactgagcaggagaaagattttctatggagt(SEQ ID NO:20)
R D P L S E I T E Q E K D F L W S(SEQ ID NO:21)
PIK3CA-E545Q
cgagatcctctctctgaaatcactCagcaggagaaagattttctatggagt(SEQ ID NO:22)
R D P L S E I T Q Q E K D F L W S(SEQ ID NO:23)
PIK3CA-E545K
cgagatcctctctctgaaatcactaagcaggagaaagattttctatggagt(SEQ ID NO:24)
R D P L S E I T K Q E K D F L W S(SEQ ID NO:25)
PIK3CA-E545A
cgagatcctctctctgaaatcactgcgcaggagaaagattttctatggagt(SEQ ID NO:26)
R D P L S E I T A Q E K D F L W S(SEQ ID NO:27)
PIK3CA-E545G
cgagatcctctctctgaaatcactgggcaggagaaagattttctatggagt(SEQ ID NO:28)
R D P L S E I T G Q E K D F L W S(SEQ ID NO:29)
PIK3CA-E545V
cgagatcctctctctgaaatcactgtgcaggagaaagattttctatggagt(SEQ ID NO:30)
R D P L S E I T V Q E K D F L W S(SEQ ID NO:31)
PIK3CA-Q546P
cgagatcctctctctgaaatcactgagccggagaaagattttctatggagt(SEQ ID NO:32)
R D P L S E I T E P E K D F L W S(SEQ ID NO:33)
PIK3CA-Q546K
cgagatcctctctctgaaatcactgagaaggagaaagattttctatggagt(SEQ ID NO:34)
R D P L S E I T E K E K D F L W S(SEQ ID NO:35)
PIK3CA-Q546E
cgagatcctctctctgaaatcactgaggaggagaaagattttctatggagt(SEQ ID NO:36)
R D P L S E I T E E E K D F L W S(SEQ ID NO:37)
PIK3CA-Q546R
cgagatcctctctctgaaatcactgagcgggagaaagattttctatggagt(SEQ ID NO:38)
R D P L S E I T E R E K D F L W S(SEQ ID NO:39)
PIK3CA-Q546L
cgagatcctctctctgaaatcactgagctggagaaagattttctatggagt(SEQ ID NO:40)
R D P L S E I T E L E K D F L W S(SEQ ID NO:41)
PIK3CA-H1047R
ttcatgaaacaaatgaatgatgcacgtcatggtggctggacaacaaaaatg(SEQ ID NO:42)
F M K Q M N D A R H G G W T T K M(SEQ ID NO:43)
PIK3CA-H1047L
ttcatgaaacaaatgaatgatgcacttcatggtggctggacaacaaaaatg(SEQ ID NO:44)
F M K Q M N D A L H G G W T T K M(SEQ ID NO:45)
用于发现新肿瘤抗原的最流行的方法基于全基因组转录谱或者肿瘤的总蛋白含量分析。这些研究通常可以鉴别在肿瘤中差异表达的mRNA组和蛋白质组。然后进行验证实验,最终在数百种已鉴定的RNA/蛋白质中挑出极少数有可能成为有用标记物的RNA/蛋白质。或者,深度测序技术可鉴别基因组蛋白质编码部分(外显子组)内的突变并预测潜在的新抗原(Science 348:69–74,2015)。在各个示例实施方案中,鉴别新抗原的方法包括如下步骤:从患者获得肿瘤样品;鉴别表达的基因内一或多个肿瘤特异性突变;鉴别含有这些突变中每一种的相应肽;任选通过使用预测算法或者通过质谱分析过滤含有一或多个肿瘤特异性突变的肽;及评估任选过滤的肽的T细胞识别。用于鉴别和测定新抗原的其它组合物和方法在美国专利9,115,402中描述,其内容并入本文作参考。
可以纯化本发明描述的组合物。纯化的组合物为目标化合物的至少大约60%重量(干重)。优选地,所述制备物是目标化合物重量的至少大约75%,更优选至少大约90%,最优选至少大约99%或更高。通过任何适当的标准方法测量纯度,例如通过高效液相层析、聚丙烯酰胺凝胶电泳。
如本文所用“细胞”是指进行足以保存或复制其基因组DNA的代谢或其它功能的细胞。细胞可以通过本领域熟知的方法鉴别,包括例如完整细胞膜的存在,特定染料的染色,产生子代的能力,或者在配子的情况中与第二配子结合产生存活后代的能力。细胞可包括原核细胞和真核细胞。原核细胞包括但不限于细菌。真核细胞包括但不限于酵母细胞和源自植物和动物例如哺乳动物、昆虫(例如夜蛾)的细胞和人体细胞。
术语“抗原呈递细胞”(APC)包括组成型表达MHC II类分子的“专职抗原呈递细胞”(例如人体中的B淋巴细胞,单核细胞,树突细胞,朗罕氏细胞和活化的T细胞)以及能将抗原呈递给T细胞的其它抗原呈递细胞。APC可以表达MHC分子与本领域已知足以将抗原呈递给T细胞或者可以被诱导或工程化以表达这种分子的共刺激和/或粘附分子的适当组合。
如本文所用,术语“载体”是指能转运与其连接的另一核酸的核酸分子。一种类型的载体是“质粒”,其是指线性或环状双链DNA环,其中可以连接另外的DNA区段。另一种类型的载体是病毒载体,其中另外的DNA节段可以连接至病毒基因组。某些载体在其被导入的宿主细胞中能自主复制(例如具有细菌复制起点的细菌载体和附加型哺乳动物载体)。其它载体(例如非附加型哺乳动物载体)在导入宿主细胞后整合到宿主细胞的基因组中,从而与宿主基因组一起复制。此外,某些载体能指导其可操纵地连接的基因的表达。这种载体在本文中称为“表达载体”。通常,用于重组DNA技术的表达载体通常是质粒形式。在本说明书中,“质粒”和“载体”可互换使用,因为质粒是最常用的载体形式。然而,本发明旨在包括其它形式的表达载体,如病毒载体(例如复制缺陷型逆转录病毒、腺病毒和腺相关病毒),其具有等价功能。此外,一些病毒载体能特异性或非特异性靶向特定细胞类型。无复制能力的病毒载体或复制缺陷型病毒载体是指能感染其靶细胞并递送其病毒荷载的病毒载体,但随后不能继续导致细胞裂解和死亡的典型裂解途径。
“药物组合物”是适合施用给对象的形式的含有本发明所述核酸的制剂。在实施方案中,所述药物组合物是大量或者单位剂型。单位剂型是任何各种形式,包括例如胶囊、IV袋、片剂、气雾吸入器或小瓶上的单个泵。单位剂量组合物中活性成分(例如揭示的核酸制剂)的数量是有效量并且根据所涉及的具体治疗而变化。本领域技术人员将意识到有时需要根据患者的年龄和状况对剂量进行常规变化。剂量还取决于施用途径。考虑了多种途径,包括口服、经肺、直肠、肠胃外、透皮、皮下、静脉内、肌肉内、腹膜内、吸入、口腔、舌下、胸膜内、鞘内、鼻内等。用于局部或透皮施用本发明化合物的剂型包括粉末、喷雾剂、软膏、糊剂、乳膏、洗剂、凝胶、溶液、贴剂和吸入剂。在实施方案中,活性核酸在无菌条件下与药学可接受的载体以及所需任何防腐剂、缓冲剂或推进剂混合。
如本文所用,短语“药学可接受的”是指那些适用于与人体和动物组织接触而没有过多的毒性、刺激、过敏反应或其它问题或并发症的在可靠医学判断范围内与合理的利益/风险比相称的那些化合物、阴离子、阳离子、材料、组合物、载体和/或剂型。
“药学可接受的赋形剂”是指可用于制备药物组合物的赋形剂,其通常是安全的、无毒的以及既不是生物学上也不是其它方面不合需要的,包括兽医用途以及人类药物用途可接受的赋形剂。如说明书和权利要求中所用“药学可接受的赋形剂”包括一和多于一种这样的赋形剂。关于药学可接受的赋形剂的详尽讨论可见于REMINGTON'S PHARMACEUTICALSCIENCES(Mack Pub.Co.,N.J.1991)。治疗组合物中的药学可接受的赋形剂可含有液体如水、盐水、甘油和乙醇。另外,在这种载体中可以存在辅助物质如润湿剂或乳化剂、pH缓冲物质等。
本发明的药物组合物配制与预期施用途径相容。施用途径例如包括肠胃外施用,例如静脉内、皮内、皮下、口服(例如吸入)、透皮(局部)和经粘膜施用。
适于口服施用的制剂的组成可以是:(a)液体溶液,例如有效量的悬浮在稀释剂如水、盐水或PEG 400中的包装核酸;(b)胶囊、小袋或片剂,其均含有预定量的活性成分,如液体、固体、颗粒或明胶;(c)于适当液体中的悬浮液;(d)合适的乳液。片剂形式可包括乳糖、蔗糖、甘露醇、山梨糖醇、磷酸钙、玉米淀粉、马铃薯淀粉、微晶纤维素、明胶、胶状二氧化硅、滑石、硬脂酸镁、硬脂酸的一或多种,及其它赋形剂、着色剂、填充剂、粘合剂、稀释剂、缓冲剂、润湿剂、防腐剂、调味剂、染料、崩解剂以及药学相容的载体。锭剂(lozenge)形式可包含在调味剂如蔗糖中的活性成分,以及在惰性基质例如明胶和甘油或蔗糖及阿拉伯胶乳剂、凝胶等中包含活性成分和除了活性成分之外包含本领域已知的载体等的锭剂(pastille)。
药物组合物还可以包括大的、缓慢代谢的大分子,如蛋白质、多糖例如壳聚糖、聚乳酸、聚乙醇酸及共聚物(例如乳胶功能化的琼脂糖(TM)、琼脂糖、纤维素等)、聚氨基酸、氨基酸共聚物和脂质聚集体(如油滴或脂质体)。另外,这些载体可以起免疫刺激剂(即佐剂)的作用。
对于直肠施用的合适制剂包括例如栓剂,其由包装的核酸和栓剂基质组成。合适的栓剂基质包括天然或合成的甘油三酯或链烷烃。此外,也可以使用明胶直肠胶囊,其由所选化合物与基质的组合组成,所述基质包括例如液体甘油三酯、聚乙二醇和链烷烃。
适于肠胃外施用例如通过关节内(在关节内)、静脉内、肌肉内、瘤内、皮内、腹膜内和皮下途径的制剂,包括水相和非水相等渗无菌注射液,其可含有使得所述制剂与指定接受者的血液等渗的抗氧化剂、缓冲剂、抑菌剂和溶质,及包括水相和非水相无菌悬浮液,其可包含悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂。在本发明的实践中,组合物可以例如通过静脉内输注、口服、局部、腹膜内、膀胱内或鞘内施用。肠胃外施用、口服施用和静脉内施用是优选的施用方法。所述化合物制剂可存在于单位剂量或多剂量密封容器中,例如在安瓿和小瓶中。
用于肠胃外、皮内或皮下应用的溶液或悬浮液可包括以下成分:无菌稀释液如注射用水、盐水溶液、不挥发油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗菌剂如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二胺四乙酸;缓冲剂如乙酸盐、柠檬酸盐或磷酸盐,以及调节渗透压的物质如氯化钠或葡萄糖。可以用酸或碱调节pH,例如盐酸或氢氧化钠。肠胃外制备物可以封装在安瓿、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。
本发明的药物组合物可以目前用于化学治疗的许多熟知方法给对象施用。例如,对于癌症的治疗,本发明的组合物可以直接注射进肿瘤中、注射至血流或体腔中,或者口服或通过皮肤贴剂应用。选择的剂量应足以建立有效的治疗,但不能高到引起不可接受的副作用。优选在治疗期间和治疗后的合理时间内密切监测患者的疾病状况(例如癌症、癌前病变等)和健康状况。
如本文所用,“单一治疗”是指给有需要的对象施用单一的活性或治疗性化合物。优选地,单一治疗包括施用治疗有效量的活性组合物(例如核酸)。例如,本发明描述的可以是将本发明的核酸之一给予需要治疗癌症的对象的癌症单一治疗。单一治疗可与组合治疗对比,在组合治疗中施用多种活性组合物(例如多种核酸)的组合,优选所述组合的每种成分以治疗有效量存在。使用本发明组合物的单一治疗在诱导所需生物学效应方面可能比组合治疗更有效。
如本文所用,“组合治疗”或“联合治疗”包括施用本发明的组合物和至少第二种物质作为特定治疗方案的一部分,旨在通过这些治疗剂的共同作用提供有益效果。组合的有益效果可包括但不限于得自治疗剂组合的药代动力学或药效学共同作用。组合施用这些治疗剂通常在限定的时间段内进行(根据选择是组合通常是几分钟、数小时、数天或数周)。“组合治疗”可以是(但通常不是)旨在包括施用两或更多种这些作为单独的单一治疗方案的一部分的治疗剂,这样偶然地和任意地获得本发明的组合。
“组合治疗”是指包括以顺序方式施用这些治疗剂,其中每种治疗剂在不同时间施用,以及以基本上同时的方式施用这些治疗剂或至少两种治疗剂。基本上同时施用可以通过例如给对象施用具有固定比例的每种治疗剂的单个胶囊或者多个每种治疗剂的单一胶囊进行。顺序施用或基本上同时施用每种治疗剂可以通过任何合适的途径实现,包括但不限于口服途径、静脉内途径、肌肉内途径和通过粘膜组织的直接吸收。治疗剂可以通过相同途径或不同途径施用。例如,所选组合的第一治疗剂可以通过静脉内注射施用,而该组合的其它治疗剂可以口服施用。或者,例如,所有治疗剂均可以口服施用,或者所有治疗剂可以通过静脉内注射施用。治疗剂的施用顺序并不是非常关键的。
“组合治疗”还包括施用上述治疗剂与其它生物活性成分和非药物疗法(例如手术或放射治疗)的进一步组合。在组合治疗进一步包括非药物治疗的情况中,非药物治疗可以在任何合适时间进行,只要达到所述治疗剂与非药物治疗组合的共同作用的有益效果即可。例如,在适当的情况中,当非药物治疗暂时从施用治疗剂中去除时,仍获得所述有益效果,可能持续数天或甚至数周。
本发明的组合物可以与第二化疗剂组合施用。第二化疗剂(也称为抗肿瘤剂或抗增生剂)可以是烷化剂;抗生素;抗代谢物;解毒剂;干扰素;多克隆或单克隆抗体;EGFR抑制剂;HER2抑制剂;组蛋白脱乙酰酶抑制剂;激素;有丝分裂抑制剂;MTOR抑制剂;多激酶抑制剂;丝氨酸/苏氨酸激酶抑制剂;酪氨酸激酶抑制剂;VEGF/VEGFR抑制剂;紫杉烷或紫杉烷衍生物,芳香酶抑制剂,蒽环霉素,微管靶向药,拓扑异构酶毒性药物,分子靶或酶(如激酶或蛋白质甲基转移酶)的抑制剂,胞苷类似物药物或者任何www.cancer.org/docroot/cdg/cdg_0.asp中列出的化疗剂、抗肿瘤剂或者抗增生剂。
如本文所用,“有需要的对象”或“患者”是患有癌症的对象。有需要的对象可具有癌前状况。通常,有需要的对象患有癌症。“对象”或“患者”包括哺乳动物。哺乳动物可以是例如人或适当的非人哺乳动物,例如灵长类动物、小鼠、大鼠、狗、猫、牛、马、山羊、骆驼、绵羊或猪。对象也可以是鸟或禽。在实施方案中,所述哺乳动物是人。因此,所述方法适用于人体治疗和兽医应用。
如本文所用,术语“癌症”是指在哺乳动物中发现的所有类型的癌症、新生物或恶性肿瘤,包括白血病、淋巴瘤、黑色素瘤、神经内分泌肿瘤、癌(carcinoma)和肉瘤。可用本发明提供的组合物、药物组合物或方法治疗的癌症例如包括淋巴瘤、肉瘤、膀胱癌、骨癌、脑癌、宫颈癌、结肠癌、食管癌、胃癌、头颈癌、肾癌、骨髓瘤、甲状腺癌、白血病、前列腺癌、乳腺癌(例如三阴性,ER阳性,ER阴性,化疗抗性,赫赛汀抗性,HER2阳性,多柔比星抗性,他莫昔芬抗性,导管癌,小叶癌,原发癌,转移癌)、卵巢癌、胰腺癌、肝癌(如肝细胞癌)、肺癌(如非小细胞肺癌,鳞状细胞肺癌,腺癌,大细胞肺癌,小细胞肺癌,类癌,肉瘤)、多形性胶质母细胞瘤、胶质瘤、黑色素瘤、前列腺癌、去势抗性前列腺癌、乳腺癌、三阴性乳腺癌、胶质母细胞瘤、卵巢癌、肺癌、鳞状细胞癌(例如头部,颈部或食道)、结肠直肠癌、白血病、急性髓性白血病、淋巴瘤、B细胞淋巴瘤或多发性骨髓瘤。其它实例包括甲状腺癌、内分泌系统癌、脑癌、乳腺癌、子宫颈癌、结肠癌、头颈癌、食管癌、肝癌、肾癌、肺癌、非小细胞肺癌、黑色素瘤、间皮瘤、卵巢癌、肉瘤、胃癌、子宫癌或成神经管细胞瘤、霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤、神经母细胞瘤、胶质瘤、多形性胶质母细胞瘤、卵巢癌、横纹肌肉瘤、原发性血小板增多症、原发性巨球蛋白血症、原发性脑肿瘤、癌症、恶性胰腺胰岛素瘤、恶性类癌、膀胱癌、癌前皮肤病变、睾丸癌、淋巴瘤、甲状腺癌、神经母细胞瘤、食管癌、泌尿生殖道癌、恶性高钙血症、子宫内膜癌、肾上腺皮质癌、胰腺内分泌或外分泌肿瘤、甲状腺髓样癌、甲状腺髓样癌瘤、黑色素瘤、结直肠癌、乳头状甲状腺癌、肝细胞癌、佩吉特乳头病、叶状肿瘤、小叶癌、导管癌、胰腺星形细胞癌、肝星形细胞癌或前列腺癌。
术语“白血病”泛指造血器官的进行性恶性疾病,其特征通常在于血液和骨髓中白细胞及其前体的变形增殖和发育。白血病通常基于如下情况进行临床分类:(1)疾病的持续时间和特征-分为急性或慢性;(2)涉及的细胞类型,分为髓样(髓性)、淋巴样(淋巴性)或单核细胞性;(3)血液中异常细胞数量的增加或不增加,分为白细胞性或白细胞缺乏性白血病(亚白血病性)。可用本发明提供的组合物、药物组合物或方法治疗的示例性白血病包括例如急性非淋巴细胞白血病、慢性淋巴细胞白血病、急性粒细胞白血病、慢性粒细胞白血病、急性早幼粒细胞白血病、成人T细胞白血病、白细胞缺乏性白血病、白细胞性白血病、嗜碱性白血病(basophylic leukemia)、干细胞性白血病(blast cell leukemia)、牛白血病、慢性中幼粒细胞白血病、皮肤白血病、干细胞性白血病(embryonal leukemia)、嗜酸性白血病、格罗斯白血病、毛细胞白血病、成血细胞性白血病(hemoblastic leukemia)、成血细胞性白血病(hemocytoblastic leukemia)、组织细胞性白血病、干细胞白血病、急性单核细胞白血病、白细胞减少性白血病、淋巴性白血病、成淋巴细胞性白血病、淋巴细胞白血病、淋巴原白血病、淋巴样白血病、淋巴肉瘤细胞性白血病、肥大细胞白血病、巨核细胞白血病、小原粒型白血病、单核细胞性白血病、成髓细胞白血病、粒细胞性白血病、骨髓性粒细胞性白血病、粒单核细胞白血病、Naegeli型白血病、浆细胞白血病、多发性骨髓瘤、浆细胞性白血病、前髓细胞性白血病、里德尔细胞性白血病、希林白血病、干细胞白血病、亚白血病性白血病和未分化细胞白血病。
术语“肉瘤”通常是指由如胚胎结缔组织等物质组成的肿瘤,通常由嵌入纤维状或均质物质中的紧密堆积的细胞组成。可用本发明提供的组合物、药物组合物或方法治疗的肉瘤包括软骨肉瘤、纤维肉瘤、淋巴肉瘤、黑素肉瘤、粘液肉瘤、骨肉瘤、Abemethy肉瘤、脂肪肉瘤、脂肉瘤、肺泡软组织肉瘤、成釉细胞肉瘤、葡萄状肉瘤、绿色肉瘤、绒毛膜癌、胚胎肉瘤、Wilms瘤肉瘤、子宫内膜肉瘤、间质肉瘤,Ewing肉瘤,筋膜肉瘤,成纤维细胞肉瘤、巨细胞肉瘤、粒细胞肉瘤、霍奇金肉瘤、特发性多发性色素性出血性肉瘤、B细胞免疫母细胞肉瘤、淋巴瘤、T细胞免疫母细胞肉瘤、Jensen's肉瘤、Kaposi肉瘤、Kupffer细胞肉瘤、血管肉瘤、白血病性肉瘤、恶性间叶瘤肉瘤、骨膜外肉瘤、网状细胞肉瘤、Rous肉瘤、浆液囊性肉瘤、滑膜肉瘤或毛细血管扩张性肉瘤。
术语“黑色素瘤”是指由皮肤和其它器官的黑素细胞系统产生的肿瘤。可用本发明提供的组合物、药物组合物或方法治疗的黑色素瘤包括例如肢端黑色素瘤、无色素性黑色素瘤、良性幼年型黑色素瘤、Cloudman黑色素瘤、S91黑色素瘤、Harding-Passey黑色素瘤、幼年型黑色素瘤、恶性雀斑样黑色素瘤、恶性黑色素瘤、结节性黑色素瘤、指甲下黑色素瘤或浅表扩散性黑色素瘤。
术语“癌(carcinoma)”是指由上皮细胞构成的恶性新生长,其倾向于渗入周围组织并引起转移。可用本发明提供的组合物、药物组合物或方法治疗的示例性癌包括例如甲状腺髓样癌、家族性甲状腺髓样癌、腺泡癌、腺泡状癌、腺样囊性癌、腺囊癌、腺癌(carcinoma adenomatosum)、肾上腺皮质癌、肺泡癌、肺泡细胞癌、基底细胞癌(basal cellcarcinoma)、基底细胞癌(carcinoma basocellulare)、基底细胞样癌、基底鳞状细胞癌、细支气管肺泡癌、细支气管癌、支气管原癌、髓样癌(cerebriform carcinoma)、胆管细胞癌、绒毛膜癌、胶体癌、粉刺状癌、子宫体癌、筛状癌、胸廓癌、皮肤癌,柱状细胞癌(cylindricalcarcinoma)、柱状细胞癌(cylindrical cell carcinoma)、导管癌(duct carcinoma)、导管癌(ductal carcinoma)、硬癌(carcinoma durum)、胚胎性癌、髓样癌、表皮样癌、腺样基底细胞癌、外植癌、溃疡性癌、纤维癌(carcinoma fibrosum)、gelatiniforni癌、胶样癌、巨细胞癌(giant cell carcinoma)、巨细胞癌(carcinoma gigantocellulare)、腺癌、颗粒细胞癌、发基质癌、多血癌、肝细胞癌、Hurthle细胞癌、粘液癌(hyaline carcinoma)、肾上腺样癌、幼稚型胚胎性癌、原位癌、表皮内癌、上皮内癌、克罗姆佩柯赫尔肿瘤、库尔契茨基细胞癌、大细胞癌、豆状癌(lenticular carcinoma)、豆状癌(carcinoma lenticulare)、脂瘤样癌、小叶癌、淋巴上皮癌、髓样癌(carcinoma medullare)、髓样癌(medullary carcinoma)、黑色素癌、软癌、粘液癌(mucinous carcinoma)、胶样癌(carcinoma muciparum)、粘液细胞癌(carcinoma mucocellulare)、粘液表皮样癌、粘液癌(carcinoma mucosum)、粘液癌(mucous carcinoma)、粘液瘤样癌、鼻咽癌、燕麦细胞癌、骨化性癌、骨质癌、乳头状癌、门脉周癌、浸润前癌、棘细胞癌、粉刺癌、肾细胞癌、贮备细胞癌、肉瘤样癌、schneiderian癌、硬癌(scirrhous carcinoma)、阴囊癌、印戒细胞癌、单纯癌、小细胞癌、马铃薯状癌(solanoidcarinoma)、球状细胞癌、梭形细胞癌、髓样癌(carcinoma spongiosum)、鳞癌、鳞状细胞癌、绳捆癌、血管扩张性癌(carcinoma telangiectaticum)、血管扩张性癌(carcinomatelangiectodes)、移行细胞癌、结节性皮癌(carcinoma tuberosum)、小管癌、结节性皮癌(tuberous carcinoma)、疣状癌或者绒毛状癌。
如本文所用,术语“转移”、“转移的”和“转移癌症”可互换使用,是指增殖性疾病或病症例如癌症从一个器官扩散至另一个非相邻器官或机体部分。癌症在原始部位例如乳腺发生,该部位被称为原发性肿瘤,例如原发性乳腺癌。原发肿瘤或原始部位的一些癌症细胞获得穿透和侵润局部区域周围正常组织的能力和/或穿透淋巴系统或脉管系统的管壁通过该系统循环至机体的其它部位和组织的能力。由原发肿瘤的癌症细胞形成的另一个临床可检测的肿瘤称为转移性或继发性肿瘤。当癌症细胞转移时,假定转移性肿瘤及其细胞与原始肿瘤的相似。因此,如果肺癌转移到乳腺,则乳腺部位的继发性肿瘤由异常的肺细胞而非异常的乳腺细胞组成。乳腺中的继发性肿瘤被称为转移性肺癌。因此,短语转移性癌症是指其中对象患有或曾患有原发性肿瘤并且具有一或多个继发性肿瘤的疾病。短语非转移性癌症或其癌症不是转移性的对象是指其中对象具有原发性肿瘤但不具有一或多个继发性肿瘤的疾病。例如,转移性肺癌是指对象具有原发性肺肿瘤或具有原发性肺肿瘤病史且在另一位置或多个位置例如在乳腺中具有一或多个继发性肿瘤的疾病。
待治疗的癌症可以根据American Joint Committee on Cancer(AJCC)TNM分类系统分期,其中肿瘤(T)被指定为TX、T1、T1mic、T1a、T1b、T1c、T2、T3、T4、T4a、T4b、T4c或T4d阶段;其中局部淋巴结(N)被指定为NX、N0、N1、N2、N2a、N2b、N3、N3a、N3b或N3c阶段;及远处转移(M)可被指定为MX、M0或M1阶段。根据American Joint Committee on Cancer(AJCC)分类法,可以将待治疗的癌症分为I期、IIA期、IIB期、IIIA期、IIIB期、IIIC期或者IV期。根据AJCC分类,可以将待治疗的癌症分为等级GX(例如不能评定等级)、1级、2级、3级或4级。待治疗的癌症根据AJCC病理分类(pN)可以分为pNX、pN0、PN0(I-)、PN0(I+)、PN0(mol-)、PN0(mol+)、PN1、PN1(mi)、PN1a、PN1b、PN1c、pN2、pN2a、pN2b、pN3、pN3a、pN3b或pN3c。
待治疗的癌症可包括已确定直径小于或等于约2厘米的肿瘤。待治疗的癌症可包括已确定直径为约2厘米至约5厘米的肿瘤。待治疗的癌症可包括已确定直径大于或等于约3厘米的肿瘤。待治疗的癌症可包括已确定直径大于5厘米的肿瘤。待治疗的癌症可以通过显微外观分类为分化良好、中分化、低分化或未分化。待治疗的癌症可以通过有丝分裂计数(例如细胞分裂的量)或核多形性(例如细胞的变化)的显微外观分类。待治疗的癌症可通过显微外观分类为与坏死区域(例如死亡或退化细胞的区域)相关。待治疗的癌症可以被分类为具有异常核型、具有异常数量的染色体、或具有一或多个外观异常的染色体。待治疗的癌症可以分类为非整倍体、三倍体、四倍体或具有改变的倍性。待治疗的癌症可以被分类为具有染色体易位,或者整个染色体的缺失或复制,或者一部分染色体的缺失、复制或扩增区域。
可以通过DNA细胞计数法、流式细胞术或成像细胞计数法评估待治疗的癌症。待治疗的癌症可以分型为具有约10%、20%、30%、40%、50%、60%、70%、80%或90%的细胞在细胞分裂的合成阶段(例如在细胞分裂的S期)。待治疗的癌症可以被分类为具有低S期分数或高S期分数。
本发明提供的“有效量”或“治疗有效量”是指有效实现其预期目的的量。对于特定应用,有效的实际量尤其取决于所治疗的病症。当在治疗疾病的方法中施用时,本发明所述的药物组合物将含有有效实现期望结果的量的活性核酸或扩展的CD4+T细胞,所述期望结果例如是引发针对肿瘤的免疫应答,和/或减少、消除或减缓疾病症状(例如癌症)的进展,或表现出可检测的治疗或抑制作用。所述作用可以通过本领域已知的任何测定方法检测。对于对象的精确有效量取决于对象的体重、体格和健康状况;病症的性质和程度;以及选择用于施用的治疗剂或治疗剂组合。对于指定情况的治疗有效量可以通过常规实验确定,这在临床医生的技术和判断能力内。在优选的方面,待治疗的疾病或病症是癌症。
如本文所用,“治疗”描述出于对抗疾病、病症或失调而对患者的管理和护理,包括施用本发明的组合物以减轻疾病、病症失调的症状或并发症,或者消除疾病、病症或失调。术语“治疗”还可包括体外细胞或动物模型的治疗。
如本文所用,术语“减轻”是描述减少病症的迹象或症状的严重性的过程。重要地,迹象或症状可以缓解而未消除。施用本发明的组合物或药物组合物也许或可以导致迹象或症状的消除,但是不必需消除。有效剂量被期望应可以降低迹象或症状的严重性。例如,对于可以在多个位置发生的病症例如癌症,如果癌症的严重性在多个位置中的至少一个位置降低,则称所述病症的迹象或症状减轻。
如本文所用,术语“严重性”是描述癌症从癌前期或良性状态转变为恶性状态的可能性。或者或另外,严重性旨在描述癌症分期,例如根据TNM系统(由International UnionAgainst Cancer(UICC)和American Joint Committee on Cancer(AJCC)认可)或者其它公认的方法分期。癌症分期是指基于诸如原发肿瘤的位置、肿瘤大小、肿瘤数量和淋巴结受累(癌症扩散到淋巴结)等因素的癌症的程度或严重性。或者或另外,严重性是指通过本领域公认的方法描述肿瘤等级(参见National Cancer Institute,www.cancer.gov)。肿瘤等级是用于根据癌症细胞在显微镜下看起来如何异常以及肿瘤可能如何快速生长和扩散来对癌症细胞进行分类的系统。在确定肿瘤等级时考虑许多因素,包括细胞的结构和生长模式。用于确定肿瘤等级的具体因素随每种类型的癌症而变化。严重性还描述了组织学分级,也称为分化,其指肿瘤细胞与相同组织类型的正常细胞相似的程度(见National CancerInstitute,website at www.cancer.gov)。此外,严重性描述了核分级,指肿瘤细胞中核的大小和形状以及分裂的肿瘤细胞的百分比(见National Cancer Institute,www.cancer.gov)。
严重性还可以描述肿瘤分泌生长因子、降解细胞外基质、血管化、丧失并列组织粘附或转移的程度。此外,严重性可以描述原发性肿瘤转移的位置的数量。最后,严重性可包括治疗不同类型和位置的肿瘤的难度。例如,不能手术的肿瘤、更多侵润多个机体系统的那些癌症(血液学和免疫性肿瘤)以及对传统治疗最具抗性的那些癌症被认为是最严重的。在这些情况中,延长对象的预期寿命和/或减少疼痛、降低癌细胞比例或将细胞限制于一个系统以及改善癌症分期/肿瘤等级/组织学等级/核等级被认为是缓解了癌症的迹象或症状。
如本文所用,术语“症状”被定义为疾病、病症、损伤或机体内一些不正常的现象的指征。出现症状的个体会感觉到或注意到症状,但其它人可能不容易注意到这些症状。其它人被定义为非医疗保健专业人员。
如本文所用,术语“迹象”也被定义为机体内一些不正常的现象的指征。但是,迹象被定义为是医生、护士或其它医疗保健专业人员可见的现象。
癌症是可能引起几乎任何迹象或症状的一组疾病。迹象和症状将取决于癌症的位置、癌症的大小,以及其对附近器官或结构的影响程度。如果癌症扩散(转移),则症状可能出现在机体的不同部分。例如,癌症也可能引起诸如发烧、疲劳或体重减轻等症状。疼痛可能是某些癌症的早期症状,如骨癌或睾丸癌。但大多数情况中,疼痛是晚期疾病的症状。随着皮肤癌一起,一些内部癌症可以导致可见的皮肤迹象。这些变化包括皮肤看起来更暗(色素沉着过度)、黄色(黄疸)或红色(红斑)、痒或者过度的毛发生长。
或者或另外,癌症亚型呈现特定的迹象或症状。排便习惯或膀胱功能的改变可能提示癌症。长期便秘、腹泻或粪便大小的改变可能是结肠癌的迹象。排尿疼痛、尿液中的血液或膀胱功能的改变(例如更频繁或更不频繁的排尿)可能与膀胱癌或前列腺癌有关。
皮肤状况的改变或者出现新的皮肤状况可提示癌症。皮肤癌可以出血及看起来像是不愈合的疮疡。口腔中持久的疼痛可以是口腔癌,尤其是在吸烟、咀嚼烟草或经常饮酒的患者中。阴茎或阴道上的疮疡可能是感染或早期癌症的迹象。
不正常的出血或排血可以提示癌症。不正常的出血可能发生在早期或晚期癌症中。痰(痰液)中的血液可能是肺癌的迹象。粪便中的血液(或暗色或黑色粪便)可以是结肠癌或直肠癌的迹象。子宫颈癌或子宫内膜(子宫的内膜)癌可引起阴道流血。尿液中的血液可能是膀胱癌或肾癌的迹象。乳头泌血可能是乳腺癌的迹象。
乳房或机体其它部位的增厚或肿块可以提示存在癌症。许多癌症可以通过皮肤感觉到,主要是在乳房、睾丸、淋巴结(腺体)和机体的软组织。肿块或增厚可能是癌症的早期或晚期迹象。任何肿块或增厚都可能提示癌症,特别是如果是新形成的或增大的情况。
消化不良或吞咽困难可提示癌症。虽然这些症状通常有其它原因,但消化不良或吞咽问题可以是食道、胃或咽喉(喉咙)的癌症的迹象。
疣或痣的新近变化可提示癌症。任何颜色、大小或形状发生变化或者失去其明确边界的疣、痣或雀斑都提示癌症的潜在发展。例如,皮肤病变可以是黑色素瘤。
持续的咳嗽或声音嘶哑可以提示癌症。不会消失的咳嗽可能是肺癌的迹象。声音嘶哑可能是喉(喉头)癌或甲状腺癌的迹象。
虽然上面列出的迹象和症状是癌症中较常见的,但还有许多其它不常见且未在此列出的症状和迹象。
治疗癌症也许导致或者可导致肿瘤大小减小。肿瘤大小的减小也可称为“肿瘤消退”。优选地,在治疗之后,相对于治疗前的大小,肿瘤大小将减少大约5%或更多;更优选肿瘤大小减少大约10%或更多;更优选减少大约20%或更多;更优选减少大约30%或更多;更优选减少大约40%或更多;甚至更优选减少大约50%或更多;最优选减少大于大约75%或更多。肿瘤的大小可以通过任何可重复的测量方法测量。肿瘤的大小可以肿瘤的直径测量。
治疗癌症也许导致或者可导致肿瘤体积缩小。优选地,在治疗之后,相对于治疗前的大小,肿瘤体积将缩小大约5%或更多;更优选肿瘤体积缩小大约10%或更多;更优选地缩小大约20%或更多;更优选缩小大约30%或更多;更优选缩小大约40%或更多;甚至更优选缩小大约50%或更多;最优选缩小大于大约75%或更多。可以通过任何可重复的测量方法测量肿瘤体积。
治疗癌症也许导致或者可导致肿瘤数量的减少。优选地,在治疗后,相对于治疗前的数量,肿瘤数量将减少大约5%或更多;更优选肿瘤数减少大约10%或更多;更优选减少大约20%或更多;更优选减少大约30%或更多;更优选减少大约40%或更多;甚至更优选减少大约50%或更多;最优选减少大于大约75%。可以通过任何可重复的测量方法测量肿瘤的数量。可以通过计数肉眼或以指定的放大倍数可见的肿瘤来测量肿瘤的数量。优选地,指定的放大倍数是2X、3X、4X、5X、10X或50X。
治疗癌症也许导致或者可导致远离原发肿瘤部位的其它组织或器官中的转移性病变数量减少。优选地,在治疗之后,相对于治疗前的数量,转移性病变的数量将减少大约5%或更多;更优选转移性病变的数量减少大约10%或更多;更优选减少大约20%或更多;更优选减少大约30%或更多;更优选减少大约40%或更多;甚至更优选减少大约50%或更多;最优选减少大于大约75%。可通过任何可重复的测量方法测量转移性病变的数量。可以通过计数肉眼或在指定的放大倍数下可见的转移性病变而测量转移性病变的数量。优选地,指定的放大倍数是2X、3X、4X、5X、10X或50X。
与仅接受载体的群体相比,治疗癌症也许导致或者可导致治疗对象群体的平均存活时间增加。优选地,平均存活时间将增加超过30天;更优选超过60天;更优选超过90天;最优选超过120天。可以通过任何可重复的方法测量群体的平均存活时间的增加。例如,可以通过计算在开始用活性组合物治疗后的群体平均存活长度来测量群体的平均存活时间的增加。群体的平均存活时间的增加也可以例如通过计算在用活性组合物完成第一轮治疗后的群体平均存活长度而测量。
与未治疗的对象群体相比,治疗癌症也许导致或者可导致治疗对象群体的平均存活时间的增加。优选地,平均存活时间将增加超过30天;更优选超过60天;更优选超过90天;最优选超过120天。可以通过任何可重复的方法测量群体的平均存活时间的增加。例如,可以通过计算在开始用活性组合物治疗后的群体平均存活长度来测量群体的平均存活时间的增加。群体的平均存活时间的增加还可以例如通过计算在用活性组合物完成第一轮治疗后群体的平均存活长度而测量。
与接受不是本发明组合物的药物的单一治疗的群体相比,治疗癌症也许导致或者可导致治疗对象群体的平均存活时间的增加。优选地,平均存活时间将增加超过30天;更优选超过60天;更优选超过90天;最优选超过120天。可以通过任何可重复的方法测量群体的平均存活时间的增加。例如,可以通过计算在开始用活性组合物治疗后的群体平均存活长度来测量群体的平均存活时间的增加。群体的平均存活时间的增加也可以例如通过计算在用活性组合物完成第一轮治疗后群体的平均存活长度而测量。
与仅接受载体的群体相比,治疗癌症也许导致或者可导致治疗对象群体的死亡率降低。与未治疗的群体相比,治疗癌症也许导致或者可导致治疗对象群体的死亡率降低。与接受不是本发明组合物的药物或其药学可接受的盐、前药、代谢物、类似物或衍生物的单一治疗的群体相比,治疗癌症也许导致或者可导致治疗对象群体的死亡率降低。优选地,死亡率将降低超过2%;更优选降低超过5%;更优选降低超过10%;最优选降低超过25%。可以通过任何可重复的方法测量治疗对象群体的死亡率的降低。例如,可以通过计算开始用活性组合物治疗后群体每单位时间疾病相关死亡的平均数量,测量群体死亡率的降低。群体死亡率的降低也可以例如通过计算在完成用活性组合物的第一轮治疗后群体每单位时间的疾病相关死亡的平均数量而测量。
治疗癌症也许导致或者可导致肿瘤生长速率降低。优选地,在治疗后,相对于治疗前的数目,肿瘤生长速率将降低至少5%;更优选肿瘤生长速率降低至少10%;更优选降低至少20%;更优选降低至少30%;更优选降低至少40%;更优选降低至少50%;甚至更优选降低至少50%;最优选降低至少75%。可以通过任何可重复的测量方法测量肿瘤生长速率。肿瘤生长速率可以根据每单位时间肿瘤直径的变化来测量。
治疗癌症也许导致或者可导致肿瘤再生长的降低。优选地,在治疗后,肿瘤再生长小于5%;更优选肿瘤再生长小于10%;更优选小于20%;更优选小于30%;更优选小于40%;更优选小于50%;甚至更优选小于50%;最优选小于75%。可以通过任何可重复的测量方法测量肿瘤再生长。肿瘤再生长例如通过测量在治疗后之前肿瘤缩小之后的肿瘤直径的增加来测量。在治疗停止后肿瘤不再重新出现表明肿瘤再生长的降低。
II.组合物
本发明提供了一种新型免疫疗法,其增强内源性T细胞破坏癌症细胞的能力。免疫疗法的基本原理是癌症细胞充满潜在的抗原,所述抗原当由抗原呈递细胞呈递给辅助和细胞毒性T细胞时变成免疫原性的。与现有的癌症免疫疗法相比,本发明所述的免疫疗法平台(例如组合物和方法)提供了许多益处和优势。例如,本发明所述的平台(例如组合物和方法)导致效率高得多(例如比其它免疫疗法高10倍或更多)地刺激抗原特异性CD4+T细胞群。本发明提供的平台还使得可以快速开发已知和未知的新抗原。本发明描述的平台适于多路复用,例如患者可接受多于1种的蛋白质/核酸(例如2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或更多种本文描述的蛋白质/核酸)以进行治疗。本发明描述的平台也易于扩展,例如本发明所述的蛋白质/核酸/载体/药物组合物可以大量制备并且可以随时使用。本发明描述的平台容易便捷实施,因此为每个个体患者提供了极好的个性化治疗。图3中示出了利用本发明的平台进行这种个性化治疗的示例治疗工作流程。本发明描述的平台还避免了其它免疫疗法面临的许多潜在缺点和挑战。例如,所述平台不会触发基因组整合,因为本发明的核酸通常用脂质体包装施用。所述平台也没有脱靶效应,因为仅插入构建体/载体中的特异性新抗原肽序列被呈递。所述平台还示出自身免疫风险没有增加。所述平台利用优化的翻译,从而减少了可变开始读取的机会。
因此,一方面,本发明提供了蛋白质(或融合蛋白),其包括与成熟的MHC II类肽共价连接的癌症抗原性肽(即新抗原),所述癌症抗原性肽能非共价地直接结合MHC II类肽。包含一或多种本发明所述融合蛋白的构建体称为CD4see构建体。
在实施方案中,所述癌症抗原性肽在成熟的MHC II类肽的N-末端。
在实施方案中,所述蛋白质还包括共价连接癌症抗原性肽与成熟的MHC II类肽的肽接头。通常,肽接头具有一或多个(例如1、2、3、4、5或更多个)甘氨酸、一或多个(例如1、2、3、4、5或更多个)丝氨酸,或者一或多个(例如1、2、3、4、5或更多个)甘氨酸与一或多个(例如1、2、3、4、5或更多个)丝氨酸的组合。例如,接头肽包括GGGSGGG(SEQ ID NO:46),GGGSGGGG(SEQ ID NO:47)、GGGGSGGGG(SEQ ID NO:48)、GGGGSGGG(SEQ ID NO:49)或IIGGGSGGGGSGGGGS(SEQ ID NO:50)所示序列。
在实施方案中,本发明接头的核酸序列与SEQ ID No:46-50之一具有一定程度的序列相同性,即至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性。
在实施方案中,所述蛋白质还包括共价附着于癌症抗原性肽的N-末端的信号肽。通常,信号肽的长度为10-30个氨基酸。在实施方案中,信号肽包括MAISGVPVLGFFIIAVLMSAQESWAIKE(SEQ ID NO:51)所示序列。在实施方案中,信号肽包括MAISGVPVLGFFIIAVLMSAQESWA IKEEHVI(SEQ ID NO:62)所示序列。
在实施方案中,本发明信号肽的氨基酸序列与SEQ ID No:51或62序列具有一定程度的序列相同性,即至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同性。
在实施方案中,所述信号肽包括在信号肽的C末端的蛋白酶识别序列。例如,这个蛋白酶识别序列的氨基酸序列包含SEQ ID NO:1。在实施方案中,本发明的这个蛋白酶识别序列的氨基酸序列与SEQ ID No:1具有一定程度的序列相同性,即至少95%、96%、97%、98%、99%或100%相同性。
在实施方案中,成熟的MHC II类肽是成熟的HLA-DRAα链肽。在实施方案中,成熟的HLA-DRAα链肽包含跨膜结构域和/或胞质结构域。
HLA-DRAα链大约为33-35kDa,其基因含有5个外显子。外显子1编码前导肽,外显子2和3编码两个胞外结构域,外显子4编码跨膜结构域和胞质尾区。HLA-DRA*01:01是人群中的主要等位基因,两个次要变体是HLA-DRA*01:02:01和HLA-DRA*01:02:01。这三个等位基因在肽结合部分中不具有多态性,作为β链DRB1、DRB3、DRB4和DRB5的唯一α链。HLA-DRA序列可公开获得。例如核苷酸序列可见于:NC_000006.12、NC_018917.2、NT_007592.16、NT_113891.3、NT_167245.2、NT_167246.2、NT_167247.2、NT_167248.2、NT_167249.2、NT_187692.1。例如,氨基酸序列可见于:NP_061984.2。
在实施方案中,成熟的HLA-DRAα链包括如下氨基酸序列(NCBI登记号CAG33294.1):
下划线:信号肽
在实施方案中,成熟的HLA-DRA α链包括如下核苷酸序列:
atggccataagtggagtccctgtgctaggatttttcatcatagctgtgctgatgagcgctcaggaatcatgggctat caaagaagaacatgtgatcatacaggccgagttctatctgaatcctgaccaatcaggcgagtttatgtttgactttgatggtgatgagattttccatgtggatatggcaaagaaggagacggtctggcggcttgaagaatttggacgatttgccagctttgaggctcaaggtgcattggccaacatagctgtggacaaagccaacttggaaatcatgacaaagcgctccaactatactccgatcaccaatgacaagttcaccccaccagtggtcaatgtcacgtggcttcgaaatggaaaacctgtcaccacaggagtgtcagagacagtcttcctgcccagggaagaccaccttttccgcaagttccactatctccccttcctgccctcaactgaggacgtttacgactgcagggtggagcactggggcttggatgagcctcttctcaagcactgggagtttgatgctccaagccctctcccagagactacagagaacgtggtgtgtgccctgggcctgactgtgggtctggtgggcatcattattgggaccatcttcatcatcaagggattgcgcaaaagcaatgcagcagaacgcagggggcctctgtaa(SEQ ID NO:53)
下划线:编码信号肽的核苷酸
本领域技术人员将理解HLA-DRA核酸和蛋白质分子可以与公众可获得的那些不同,例如导致一或多个取代、缺失、插入或者其组合、同时仍保留HLA-D A生物活性的多态性。因此,在各个实施方案中,本发明蛋白质的HLA-DRA成分的氨基酸序列与可公开获得的HLA-DRA序列或者与SEQ ID NO:52或其片段可以是大约95%、大约96%、大约97%、大约98%、大约99%相同。片段长度可以是3-10个氨基酸、10-20个氨基酸、20-40个氨基酸、40-56个氨基酸或者甚至更长。与本发明所述片段具有大约95%、大约96%、大约97%、大约98%、大约99%相同性的氨基酸序列也包括在本发明的范围内。
在多个实施方案中,编码本发明蛋白质的HLA-DRA成分的核酸序列与可公开获得的HLA-DRA序列或者与SEQ ID NO:53或其片段可以是大约95%、大约96%、大约97%、大约98%、大约99%相同的。片段长度可以是3-10个核苷酸、10-20个核苷酸、20-40个核苷酸、40-56个核苷酸或甚至更长。与本发明所述片段具有大约95%、大约96%、大约97%、大约98%、大约99%相同性的核酸序列也包括在本发明的范围内。
在实施方案中,癌症抗原性肽的长度为8-30个氨基酸。例如,癌症抗原性肽长度为8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个氨基酸。例如,癌症抗原性肽的长度为8-15、10-20、15-24或者20-30个氨基酸。通常,癌症抗原性肽的长度为15-24个氨基酸。
在实施方案中,癌症抗原性肽包含具有SEQ ID No:3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43和45任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的氨基酸序列,或由具有SEQ ID No:3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43和45任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的氨基酸序列组成。
在实施方案中,癌症抗原性肽由包含具有SEQ ID No:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42和44任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的核酸序列的核酸序列编码,或由由具有SEQ ID No:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42和44任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的核酸序列组成的核酸序列编码。
在实施方案中,一个示例融合蛋白(例如IDH1-R132Hshort构建体)包括如下氨基酸序列:
粗体下划线:HLA-DRA信号肽
双下划线:4个氨基酸(信号肽的蛋白酶识别序列)
波浪形下划线:新抗原IDH1-R132H
点状下划线:接头
下划线:HLA-DRA
在实施方案中,所述融合蛋白包含具有SEQ ID NO:54的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或者由具有SEQ ID NO:54的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成。
IDH1-R132Hshort构建体的相应DNA序列包括:
5’-
atggccataagtggagtccctgtgctaggatttttcatcatagctgtgctgatgagcgctcaggaatcatgggctatcaaagaagaacatgtgatcataatcggtcatcatgcttatggggaccagatcatcggaggaggaagtggcggcggcggcagcggtggtggtggttcgatcatccaggccgagttctatctgaatcctgaccaatcaggcgagtttatgtttgactttgatggtgatgagattttccatgtggatatggcaaagaaggagacggtctggcggcttgaagaatttggacgatttgccagctttgaggctcaaggtgcattggccaacatagctgtggacaaagccaacttggaaatcatgacaaagcgctccaactatactccgatcaccaatgacaagttcaccccaccagtggtcaatgtcacgtggcttcgaaatggaaaacctgtcaccacaggagtgtcagagacagtcttcctgcccagggaagaccaccttttccgcaagttccactatctccccttcctgccctcaactgaggacgtttacgactgcagggtggagcactggggcttggatgagcctcttctcaagcactgggagtttgatgctccaagccctctcccagagactacagagaacgtggtgtgtgccctgggcctgactgtgggtctggtgggcatcattattgggaccatcttcatcatcaagggattgcgcaaaagcaatgcagcagaacgcagggggcctctgtaa(SEQ ID NO:55)
在实施方案中,所述融合蛋白由包含具有SEQ ID NO:55的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列的核酸序列编码,或者由由具有SEQ ID NO:55的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列组成的核酸序列编码。
在实施方案中,一个示例融合蛋白(例如IDH1-R132H构建体)包括如下氨基酸序列:
粗体下划线:HLA-DRA信号肽
双下划线:4个氨基酸(信号肽的蛋白酶识别序列)
波浪下划线:新抗原IDH1-R132H
点状下划线:接头
下划线:HLA-DRA
在实施方案中,所述融合蛋白包含具有SEQ ID NO:56的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或者由具有SEQ ID NO:56的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成。
IDH1-R132H构建体的相应DNA序列包括:
5’-
atggccataagtggagtccctgtgctaggatttttcatcatagctgtgctgatgagcgctcaggaatcatgggctatcaaagaagaacatgtgatcagcggatgggtaaaacctattataatcggtcatcatgcttatggggaccagtacagagcaacgatcatcggaggaggaagtggcggcggcggcagcggtggtggtggttcgatcatccaggccgagttctatctgaatcctgaccaatcaggcgagtttatgtttgactttgatggtgatgagattttccatgtggatatggcaaagaaggagacggtctggcggcttgaagaatttggacgatttgccagctttgaggctcaaggtgcattggccaacatagctgtggacaaagccaacttggaaatcatgacaaagcgctccaactatactccgatcaccaatgacaagttcaccccaccagtggtcaatgtcacgtggcttcgaaatggaaaacctgtcaccacaggagtgtcagagacagtcttcctgcccagggaagaccaccttttccgcaagttccactatctccccttcctgccctcaactgaggacgtttacgactgcagggtggagcactggggcttggatgagcctcttctcaagcactgggagtttgatgctccaagccctctcccagagactacagagaacgtggtgtgtgccctgggcctgactgtgggtctggtgggcatcattattgggaccatcttcatcatcaagggattgcgcaaaagcaatgcagcagaacgcagggggcctctgtaa(SEQ ID NO:57)
在实施方案中,所述融合蛋白由包含具有SEQ ID NO:57的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列的核酸序列编码,或者由由具有SEQ ID NO:57的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列组成的核酸序列编码。
在实施方案中,一个示例融合蛋白(例如IDH2-R140Q构建体)包括如下氨基酸序列:
粗体下划线:HLA-DRA信号肽
双下划线:4个氨基酸(信号肽的蛋白酶识别序列)
波浪下划线:新抗原IDH2-R140Q
点状下划线:接头
下划线:HLA-DRA
在实施方案中,所述融合蛋白包含具有SEQ ID NO:58的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或者由具有SEQ ID NO:58的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成。
IDH2-R140Q构建体的相应DNA序列包括:
5’-
atggccataagtggagtccctgtgctaggatttttcatcatagctgtgctgatgagcgctcaggaatcatgggctatcaaagaagaacatgtgatctggaagtctccgaacggcaccattcagaatattctcggcggcactgtgttccgggagatcatcggaggaggaagtggcggcggcggcagcggtggtggtggttcgatcatccaggccgagttctatctgaatcctgaccaatcaggcgagtttatgtttgactttgatggtgatgagattttccatgtggatatggcaaagaaggagacggtctggcggcttgaagaatttggacgatttgccagctttgaggctcaaggtgcattggccaacatagctgtggacaaagccaacttggaaatcatgacaaagcgctccaactatactccgatcaccaatgacaagttcaccccaccagtggtcaatgtcacgtggcttcgaaatggaaaacctgtcaccacaggagtgtcagagacagtcttcctgcccagggaagaccaccttttccgcaagttccactatctccccttcctgccctcaactgaggacgtttacgactgcagggtggagcactggggcttggatgagcctcttctcaagcactgggagtttgatgctccaagccctctcccagagactacagagaacgtggtgtgtgccctgggcctgactgtgggtctggtgggcatcattattgggaccatcttcatcatcaagggattgcgcaaaagcaatgcagcagaacgcagggggcctctgtaa(SEQ ID NO:59)
在实施方案中,所述融合蛋白由包含具有SEQ ID NO:59的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列的核酸序列编码,或者由由具有SEQ ID NO:59的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列组成的核酸序列编码。
在实施方案中,一个示例融合蛋白(例如IDH2-R172K构建体)包括如下氨基酸序列:
粗体下划线:HLA-DRA信号肽
双下划线:4个氨基酸(信号肽的蛋白酶识别序列)
波浪下划线:新抗原IDH2-R172K
点状下划线:接头
下划线:HLA-DRA
在实施方案中,所述融合蛋白包含具有SEQ ID NO:60的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或者由具有SEQ ID NO:60的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成。
IDH2-R172K构建体的相应DNA序列包括:
5’-
atggccataagtggagtccctgtgctaggatttttcatcatagctgtgctgatgagcgctcaggaatcatgggctatcaaagaagaacatgtgatcggttggacgaaaccaatcactattggcaagcatgctcatggagaccagtacaagatcatcggaggaggaagtggcggcggcggcagcggtggtggtggttcgatcatccaggccgagttctatctgaatcctgaccaatcaggcgagtttatgtttgactttgatggtgatgagattttccatgtggatatggcaaagaaggagacggtctggcggcttgaagaatttggacgatttgccagctttgaggctcaaggtgcattggccaacatagctgtggacaaagccaacttggaaatcatgacaaagcgctccaactatactccgatcaccaatgacaagttcaccccaccagtggtcaatgtcacgtggcttcgaaatggaaaacctgtcaccacaggagtgtcagagacagtcttcctgcccagggaagaccaccttttccgcaagttccactatctccccttcctgccctcaactgaggacgtttacgactgcagggtggagcactggggcttggatgagcctcttctcaagcactgggagtttgatgctccaagccctctcccagagactacagagaacgtggtgtgtgccctgggcctgactgtgggtctggtgggcatcattattgggaccatcttcatcatcaagggattgcgcaaaagcaatgcagcagaacgcagggggcctctgtaa(SEQ ID NO:61)
在实施方案中,所述融合蛋白由包含具有SEQ ID NO:61的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列的核酸序列编码,或者由由具有SEQ ID NO:61的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的核酸序列组成的核酸序列编码。
在实施方案中,本发明的融合蛋白包括:
a.信号肽,其包含具有SEQ ID NO:62的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的氨基酸序列,或者由具有SEQ ID NO:62的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的氨基酸序列组成;
b.癌症抗原性肽,其包含具有SEQ ID No:3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43和45任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或由具有SEQ ID No:3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43和45任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成;及
c.接头,其包含具有SEQ ID No:46-50任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或者由具有SEQ ID No:46-50任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成。
在实施方案中,本发明融合蛋白由包含如下序列的核酸序列部分编码:
a.编码信号肽的核酸序列,所述信号肽包含具有SEQ ID NO:62的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的氨基酸序列,或者由具有SEQ ID NO:62的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或者100%的氨基酸序列组成;
b.编码癌症抗原性肽的核酸序列,所述癌症抗原性肽包含具有SEQ ID No:3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43和45任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或者由具有SEQ ID No:3、5、7、9、11、13、15、17、19、21、23、25、27、29、31、33、35、37、39、41、43和45任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成;及
c.编码接头的核酸序列,所述接头包含具有SEQ ID No:46-50任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列,或者由具有SEQ ID No:46-50任一序列的至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%的氨基酸序列组成。
本发明提供的另一方面涉及表达一或多种本文所述蛋白质的抗原呈递细胞。通常,所述蛋白质在抗原呈递细胞的细胞表面表达。在实施方案中,所述抗原呈递细胞是树突细胞或B细胞。典型地,所述抗原呈递细胞是树突细胞。所述抗原呈递细胞可以源自一个对象或多个对象。典型地,所述抗原呈递细胞得自将接受治疗的相同对象。因此,所述抗原呈递细胞可以是接受者自体的。
可以根据本领域可用的任何方法例如通过常规转化、转导、感染或转染技术,在抗原呈递细胞中表达所述一或多种蛋白质。如本文所用,术语“转化”、“转导”、“感染”和“转染”是指将外来核酸(例如DNA)导入宿主细胞的各种本领域公认技术,包括磷酸钙或氯化钙共沉淀、DEAE葡聚糖介导的转染、脂染或者电穿孔。此外,转染可以通过转染剂介导。“转染剂”是指包括介导DNA掺入宿主细胞中的任何化合物,例如脂质体。转化或转染宿主细胞的合适方法可见于Sambrook,et al.(MOLECULAR CLONING:A LABORATORY MANUAL.2nd ed.,Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,N.Y.,1989)以及其它实验室手册。
另一方面,本发明提供了包含如本发明所述任何核酸的树突细胞或B细胞。
本发明还提供了编码本发明所述一或多种蛋白质的核酸(多核苷酸序列)。“多核苷酸”是核糖核酸(RNA)、脱氧核糖核酸(DNA)、修饰的RNA或DNA、或者RNA或DNA模拟物(例如PNA)及其衍生物及其同源物的核酸聚合物。因此,多核苷酸包括由天然存在的核碱基、糖和共价核苷间(主链)键组成的聚合物,以及具有相似功能的非天然存在部分的聚合物。这种修饰或取代的核酸聚合物为本领域熟知,且出于本发明的目的被称为“类似物”。典型地,核酸是mRNA。或者,核酸是dsDNA。
在实施方案中,本发明描述的核酸组成载体核酸的一部分。通常,载体是无复制能力的病毒载体。例如,无复制能力的病毒载体是无复制能力的DNA病毒载体(包括但不限于腺病毒,腺相关病毒)。例如,无复制能力的病毒载体是无复制能力的RNA病毒载体(包括但不限于复制缺陷型逆转录病毒和慢病毒)。
在实施方案中,分离或纯化本发明的多肽和其它组合物。如本文所用,“分离的”或“纯化的”核苷酸或多肽基本上不含其它核苷酸和多肽。当通过化学合成时,纯化的核苷酸和多肽也不含细胞材料或其它化学物。纯化的化合物是至少大约60重量(干重)%的目标化合物。优选地,所述制备物是至少大约75重量%,更优选至少大约90重量%,最优选至少大约99重量%的目标化合物。例如,纯化的核苷酸和多肽重量上是至少大约90%、大约91%、大约92%、大约93%、大约94%、大约95%、大约98%、大约99%或大约100%(w/w)的希望的核苷酸和多肽。通过任何适当的标准方法测量纯度,例如通过柱层析、薄层层析或者高效液相层析(HPLC)分析。核苷酸和多肽被纯化并用于许多产品中供人和动物消费,例如伴侣(狗,猫)以及家畜(牛,马,绵羊,山羊或猪,以及家禽)。“纯化的”还定义了对于施用给人对象是安全的无菌程度,例如没有感染性或毒性物质。
相似地,“基本上纯的”是指已经与其天然伴随的成分分离的核苷酸或多肽。典型地,当核苷酸和多肽重量上至少大约60%、大约70%、大约80%、大约90%、大约95%或者甚至大约99%没有与其天然相关的蛋白质和天然存在的有机分子时,称其是基本上纯的。
在实施方案中,本发明描述的任何核酸可以在药学可接受的脂质体构建体或者药学可接受的聚合物构建体内。
脂质体,也称为囊泡,通常由磷脂和其它脂质组分如胆固醇组成。其可以作为载体起作用,其基本结构特征是包裹水性核心体积的双极脂质膜,在水性核心体积中药物制剂溶解于其中及因此包囊。本领域已经描述了各种脂质制剂及其制备方法,用于将药物活性剂输送至宿主。例如,Geho和Lau在美国专利4,603,044中描述了一种靶向脂质体输送系统,用于将药物输送至肝脏的肝胆受体。所述系统由包囊在囊泡或脂质体形式的脂质膜结构中或者与囊泡或脂质体形式的脂质膜结构结合的药物或诊断剂和附着于囊泡壁的具有脂肪取代基的分子以及是胆汁吸引化合物的靶取代基如取代的亚氨基二乙酸盐/酯复合物组成。所述系统特别用于在I型和II型糖尿病的治疗中分别输送胰岛素和5-羟色胺。
本领域已经描述了各种生物活性剂的聚合物制剂及其制备方法。美国专利3,773,919、3,991,776、4,076,779、4,093,709、4,118,470、4,131,648、4,138,344、4,293,539和4,675,189例如揭示了用于药物和药剂包囊的生物相容的、可生物降解的聚合物的制备和应用,例如聚(乳酸)、聚(乙醇酸)、乙醇酸和乳酸的共聚物、poly(o-hydroxycarboxy lieacid)、聚内酯、聚缩醛、聚原酸酯和聚原碳酸酯。这些聚合物机械地包囊活性成分,然后通过聚合物溶解或降解提供活性成分的控制释放。由二乙烯基醚和多元醇形成的某些缩聚物在Polymer Letters,18,293(1980)中描述。已经证明聚合物是成功的控释药物输送装置。
关于可用于本发明的脂质体构建体或聚合物构建体的更多信息可见于Schwendener RA et al.,Ther Adv Vaccines.2014Nov;2(6):159–182;Li Y et al.,JGene 2011,Med 13:60–72;Pichon C et al.,Methods Mol Biol 2013 969:247–274;McNamara MA et al.,J Immunol Res.2015;2015:794528;Sayour E.J.et al.,Journalfor Immunotherapy of Cancer.2015;3,article 13;Bettinger T.et al,CurrentOpinion in Molecular Therapeutics.2001;3(2):116–124;Lu D.et al.,Cancer GeneTherapy.1994;1(4):245–252;Wasungu L.et al.,Journal of ControlledRelease.2006;116(2):255–264;Little S.et al.,Proceedings of the NationalAcademy of Sciences of the United States of America.2004;101(26):9534–9539;Phua K.et al.,Journal of Controlled Release.2013;166(3):227–233;Su X et al.,Molecular Pharmaceutics.2011;8(3):774–787;Phua K.K.L.et al.,Nanoscale.2014;6(14):7715–7729;Phua K.K.L.et al.,Scientific Reports.2014;4,article 5128。
本发明还提供药物组合物/制剂,其包括本发明揭示的核酸组合至少一种药学可接受的赋形剂或载体。
可接受的载体、赋形剂或稳定剂在所用剂量和浓度下对接受者是无毒性的,包括缓冲剂,如磷酸盐、柠檬酸盐或乙酸盐,pH通常为5.0-8.0、最通常为6.0-7.0;盐,如氯化钠、氯化钾等,使得等渗;抗氧化剂,防腐剂,低分子量多肽,蛋白质,亲水聚合物如聚山梨醇酯80,氨基酸如甘氨酸,碳水化合物,螯合剂,糖和本领域技术人员已知的其它标准成分(Remington’s Pharmaceutical Science 16th edition,Osol,A.Ed.1980)。
包含本发明所述核酸的药物制剂可通过本领域已知的多种方法施用。施用途径和/或方式根据所需结果而变化。在实施方案中,通过静脉内、肌肉内、腹膜内或皮下施用,或者在靶标部位的近端施用。药学可接受的赋形剂可适用于静脉内、肌肉内、皮下、肠胃外、脊髓或表皮施用(例如通过注射或输注)。
本发明所述核酸的药物制剂可以根据本领域熟知和常用的方法制备。见例如Remington:The Science and Practice of Pharmacy,Mack Publishing Co.,20th ed.,2000;和Sustained and Controlled Release Drug Delivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。药物组合物优选在GMP条件下制备。
可改变本发明药物组合物中活性成分(即本发明所述核酸)的实际剂量水平以获得有效实现特定患者所需治疗反应的活性成分的量、组合物和施用方式,同时对患者无毒性。选择的剂量水平取决于多种药代动力学因素,包括所用的本发明特定组合物的活性,施用途径,施用时间,使用的特定组合物(例如本发明所述核酸)的排泄速率,治疗的持续时间,与所用特定组合物组合使用的其它药物、化合物和/或材料,所治疗患者的年龄、性别、体重、状况、一般健康状况和既往病史等因素。
医生或兽医可以以低于实现期望治疗效果所需水平的水平开始所述药物制剂中使用的本发明核酸的剂量,并逐渐增加剂量直至达到所需效果。通常,本发明组合物的有效剂量根据许多不同因素而变化,包括待治疗的具体疾病或病症,施用方式,靶部位,患者的生理状态(无论患者是人还是动物),施用的其它药物以及治疗是预防性还是治疗性的。治疗剂量需要滴定以优化安全性和功效。对于施用本发明的药物制剂,剂量范围为大约0.0001-100mg/kg宿主体重,更通常为0.01-5mg/kg宿主体重。例如,剂量可以是1mg/kg体重或者10mg/kg体重,或者在1-10mg/kg范围内。示例的治疗方案需要每两周施用一次或者每月一次或者每3-6个月一次。
本发明提供的组合物可以多次施用。单剂量间隔可以是每周、每月或每年一次。间隔也可以是不规则的,根据测量对新抗原的免疫应答而指示。或者,组合物可以作为持续释放制剂施用,在这种情况中需要较低频率的施用。剂量和频率根据所述组合物在患者中的半衰期而变化。施用的剂量和频率可以根据治疗是预防性还是治疗性的而变化。在预防性应用中,在较长时间内以相对不频繁的间隔施用相对较低的剂量。一些患者在余生中持续接受治疗。在治疗应用中,有时需要以相对短的间隔给予相对高的剂量直至疾病进展被降低或终止,优选直至患者示出疾病症状的部分或完全改善。此后,可以给患者施用预防性方案。
III.方法
一方面,本发明提供了治疗有需要的患者中癌症的方法。所述方法包括使本发明所述的抗原呈递细胞与CD4+T细胞在体外接触,从而激活CD4+T细胞,其中CD4+T细胞和抗原呈递细胞来源于患者;使活化的CD4+T细胞扩展,从而形成多个扩展的CD4+T细胞;及给患者施用有效量的多个扩展的CD4+T细胞。在实施方案中,癌症是转移的多形性胶质母细胞瘤(GBM)。
一方面,本发明提供了治疗有需要的患者中癌症的方法。所述方法包括给患者施用有效量的本发明所述的核酸。在实施方案中,所述核酸是mRNA。在实施方案中,所述核酸组成核酸-脂质体复合物的一部分。在实施方案中,所述有效量有效激活患者中的CD4+T细胞。在实施方案中,所述核酸组成无复制能力的病毒载体的一部分。
CD4+T细胞的分离和活化可以根据本领域已知的任何方法测定。例如,从对象抽取全血(约20ml)置于含EDTA的血液试管中。在无菌条件下,用PBS将血液样品稀释至1:1,在30ml Ficoll-hypaque上部分层并在400g旋转30分钟。收集外周血淋巴细胞层并用PBS稀释(1:7),随后以300g离心10分钟。通过在PBS中重悬将细胞再冲洗两次。通过台盼蓝排阻计数存活细胞。用无菌尼龙棉柱去除贴壁细胞以富集T细胞。简言之,将尼龙棉柱用T细胞培养基(1640RPMI,含10%FBS)洗涤并在37℃保温1小时。将外周血淋巴细胞(107/ml)加入预热的柱中并在37℃保温1小时,之后通过打开柱的活塞收集非贴壁细胞。将柱用5ml的T细胞培养基洗涤两次,收集全部流出物。将富含T细胞的级分与羧基荧光素二乙酸琥珀酰亚胺酯(CFSE)溶液(在PBS中4μM)在37℃水浴中保温8分钟。温育后,将溶液用10倍体积的T细胞培养基稀释,离心沉淀(300g,10分钟)并用含有0.1%牛血清白蛋白的PBS洗涤两次。重悬CFSE标记的细胞,计数并使用其一部分通过流式细胞术(Accuri division of BDBiosciences,San Jose,CA,USA)评估CFSE荧光。在进行流式细胞术之前,用Alexa647-缀合的抗-CD4抗体(BD Biosciences)对细胞进行免疫染色,以允许分析CD4+细胞群中的CFSE荧光。使用FCS express 4流式细胞术软件(De Novo Software,Los Angeles,CA,USA)进行进一步的流式细胞术数据和直方图分析。
实施方案
本发明涵盖的实施方案包括如下实施方案P1-PX28。
实施方案P1。包含共价附着于成熟的MHC II类肽的癌症抗原性肽的蛋白质,所述癌症抗原性肽能非共价直接结合所述MHC II类肽。
实施方案P2。实施方案P1的蛋白质,其中所述癌症抗原性肽在所述成熟的MHC II类肽的N-末端。
实施方案P3。实施方案P1或P2之一的蛋白质,进一步包含将所述癌症抗原性肽和所述成熟的MHC II类肽共价连接的肽接头。
实施方案P4。实施方案P3的蛋白质,其中所述肽接头由一或多个甘氨酸、一或多个丝氨酸或者一或多个甘氨酸与一或多个丝氨酸的组合组成。
实施方案P5。实施方案P1-P4之一的蛋白质,进一步包含共价附着于所述癌症抗原性肽N-末端的信号肽。
实施方案P6。实施方案P1-P5之一的蛋白质,其中所述成熟的MHC II类肽是成熟的HLA-DRAα链肽。
实施方案P7。实施方案P1-P6之一的蛋白质,其中所述癌症抗原性肽的长度是8-30个氨基酸。
实施方案P8。实施方案P1-P6之一的蛋白质,其中所述癌症抗原性肽的长度是15-24个氨基酸。
实施方案P9。一种抗原呈递细胞,其包含实施方案P1-P8之一的蛋白质。
实施方案P10。实施方案P9的抗原呈递细胞,其中所述蛋白质位于所述抗原呈递细胞的细胞表面。
实施方案P11。实施方案P9或P10的抗原呈递细胞,其中所述抗原呈递细胞是树突细胞或B细胞。
实施方案P12。实施方案P9或P10的抗原呈递细胞,其中所述抗原呈递细胞是树突细胞。
实施方案P13。编码实施方案P1-P8之一的蛋白质的核酸。
实施方案P14。实施方案P13的核酸,其中所述核酸是mRNA。
实施方案P15。实施方案P13的核酸,其中所述核酸是dsDNA。
实施方案P16。实施方案P13的核酸,其中所述核酸形成无复制能力的病毒载体核酸的一部分。
实施方案P17。实施方案P16的核酸,其中所述无复制能力的病毒载体核酸是无复制能力的慢病毒载体。
实施方案P18。实施方案P16的核酸,其中所述无复制能力的病毒载体核酸是无复制能力的DNA病毒载体或无复制能力的RNA病毒载体。
实施方案P19。实施方案P13-P18之一的核酸,其中所述核酸在药学可接受的脂质体构建体或药学可接受的聚合构建体内。
实施方案P20。包含实施方案P13-P19之一的核酸和药学可接受的赋形剂的药物制剂。
实施方案P21。包含实施方案P13-P19之一的核酸的树突细胞或B细胞。
实施方案P22。一种治疗有需要的患者中癌症的方法,所述方法包括:(i)将实施方案P9-P12之一的抗原呈递细胞与CD4+T细胞在体外接触,从而激活所述CD4+T细胞,其中CD4+T细胞和抗原呈递细胞来自所述患者;(ii)使所述CD4+T细胞扩展,从而形成多个扩展的CD4+T细胞;(iii)给所述患者施用有效量的所述多个扩展的CD4+T细胞。
实施方案P23。实施方案P22的方法,其中所述癌症是转移的多形性胶质母细胞瘤(GBM)。
实施方案P24。一种治疗有需要的患者中癌症的方法,所述方法包括给所述患者施用有效量的实施方案P13-P19之一的核酸。
实施方案P25。实施方案P24的方法,其中所述核酸是mRNA。
实施方案P26。实施方案P24或P25的方法,其中所述核酸形成核酸-脂质体复合物的一部分。
实施方案P27。实施方案P24-P26之一的方法,其中所述有效量有效激活所述患者中的CD4+T细胞。
实施方案P28。实施方案P24的方法,其中所述核酸形成无复制能力的病毒载体的一部分。
实施例
实施例1:CD4see构建体设计与产生
从NCBI核苷酸数据库下载HLA-DRA1序列(SEQ ID NO:52或53)。设计寡核苷酸编码引物用于使用聚合酶链式反应(PCR)扩增HLA-DRA的编码序列(cDNA)。使用来自发明人血液的逆转录的RNA模板通过PCR产生HLA-DRA1cDNA。将cDNA克隆到质粒载体中。
设计甘氨酸/丝氨酸接头序列并使用定点诱变立即掺入在HLA-DRA1cDNA的信号肽切割位点后。所有构建体均是这个基础载体的衍生物,每个构建体在接头序列之后立即掺入不同的靶肽。CD4see靶肽的DNA和RNA序列来自经鉴定为驱动突变(driver mutations)或乘客突变(passenger mutations)的蛋白质。
设计并产生CD4see构建体,其靶向转移的多形性胶质母细胞瘤(GBM)中的新抗原驱动突变。70%以上的复发GBM细胞在异柠檬酸脱氢酶(IDH)-1或IDH2中携带突变。在IDH2的172位氨基酸精氨酸的突变可以改变蛋白质的酶活性。在晚期GBM中发现的最常见的IDH1突变是在IDH1的132位精氨酸132(R132)的单个氨基酸错义突变,其改变IDH1蛋白的氨基酸序列。设计并产生包括这些突变区域的CD4see构建体。
编码IDH1新抗原肽的互补寡核苷酸从商业供应商订购,加热、退火并连接至制备的CD4see构建体中。具体地,设计并构建CD4see构建体以在接头和HLA-DRA1的非信号肽区域之间具有Bcl1限制性内切核酸酶位点。退火的IDH1寡核苷酸包括相容末端以连接至Bcl1切割位点中。在准备连接时,通过用Bcl1酶消化含有CD4see的质粒制备CD4see构建体。使用定点诱变,通过连接反应产生的CD4see构建体将IDH1新抗原肽的编码序列符合读框地导入CD4see主链内信号肽与接头肽之间。
实施例2:体外人体测试
使用从健康志愿者抽取的白细胞测试CD4see构建体在正常健康成人中刺激抗原特异性CD4+T细胞增殖的能力。将含有CD4see构建体的表达质粒在细菌中生长,使用去除内毒素污染物的商业质粒纯化试剂盒纯化。从志愿者抽取的全血被分级分离以纯化单核细胞。用含有CD4see构建体的质粒DNA瞬时转染单核细胞,将所述细胞用脂多糖和肿瘤坏死因子-α(TNF-α)刺激1-3天。分离自相同血液样品(组织相容性匹配)的T细胞用荧光探针如CFSE(Begum et al.,2014)标记。刺激3天后,将处理过的单核细胞与荧光标记的T细胞再共培养7天。用荧光标记的抗CD4抗体对细胞混合物进行免疫染色,并通过流式细胞术测定。设置流式细胞分析仪门控,以使用前向散射(FSC)和侧向散射(SSC)图鉴别存活细胞,然后对那些细胞针对抗CD4荧光团进行门控以选择CD4+细胞。在直方图上绘制CD4+细胞群的CFSE荧光强度,以揭示在共培养期间经历5-8或更多次细胞分裂的CD4+T细胞的比例。在含有IL-2而不含CD4see构建体的伴随共培养物中通过CFSE荧光计算细胞分裂。进一步研发在一些人对象中刺激强CD4+T细胞增殖的CD4see构建体
实施例3:CD4see治疗癌症的应用
将患有转移性结直肠癌的患者用CD4see技术如下治疗。首先,取患者1-3个肿瘤进行活组织检查,使用几种可商购的RNA纯化试剂盒之一例如Qiagen’s RNeasy分离RNA。使用可得自Illumina、Roche或其它供应商的任何几种技术处理RNA以用于下一代RNA测序(RNAseq)。RNAseq运行产生一千万-三千万个读数,充分覆盖了由肿瘤表达的mRNA。分析该序列以鉴别产生导致新抗原的符合读框的氨基酸突变的单核苷酸多态性(Polyakova etal.,2015)。这些新抗原包括促进肿瘤生长的驱动突变或者似乎不促进肿瘤生长的乘客突变。已知的驱动突变的例子可包括但不限于IDH1-R132H、IDH2-R140Q、IDH2-R172K、BRAF-V600E、KRAS-G12D、NRAS-Q61K、PIK3CA-E545K。RNAseq还检测经常伴随肿瘤生长的癌症-睾丸(CT)抗原例如NY-ESO-1和MAGE-A3的较高表达。
对驱动突变和乘客突变的新抗原以及升高的CT抗原进行分析,以鉴别CD4see介导的应答的最合适的靶标。产生靶肽,其包括选择的突变和受影响的蛋白质序列中该位点的8-10个侧翼残基氨基和羧基。产生编码这些序列的寡核苷酸,杂交并剪接进CD4see载体,由此新抗原序列与CD4see蛋白质复合读框地翻译。如有必要,将完整的CD4see构建体移至其它表达载体中。使用相同程序为患者产生8-20或更多的新抗原CD4see构建体。在需要共同的驱动突变的情况中,可以使用先前开发的构建体。
递送CD4see构建体以刺激新抗原特异性CD4+T细胞
在一个重复中,编码CD4see-新抗原肽构建体的mRNA在体外转录。CD4see-新抗原构建体可以单独转录或批次转录。将产生的mRNA从DNA和其它杂质纯化。将纯化的mRNA包装进脂质体中并用于转染源自患者或合适供体的抗原呈递细胞(APC)。或者,通过电穿孔将含有CD4see-新抗原构建体的mRNA或表达质粒导入APC。例如,将从患者自身的血液单核细胞制备的2百万个APC置于具有适量mRNA或表达质粒的样品池中,经受足够强度和持续时间的电子脉冲以将mRNA转染到细胞中。含有荧光报道蛋白如DS-RED或M-CHERRY的第二表达质粒可用于确立转染效率。将经处理的APC与从患者血液分离的T细胞共培养,产生适量的新抗原特异性CD4+T细胞。纯化新抗原特异性CD4+T细胞并通过静脉滴注回输患者。
另一个重复可包括通过静脉内滴注或注射进淋巴结而将mRNA转导的APC施用给患者。APC的体内施用补充有掺入靶向的新抗原序列的肽疫苗,以促进由CD4see应答性Th2细胞刺激的B细胞/抗体应答。
另一重复可涉及将CD4see-新抗原构建体整合进慢病毒载体中,用于在APC中表达蛋白质以进行如上述的体外或体内治疗。
另一重复可使用体外研究以筛选用于患者的最大应答组合的所有可能构建体。
另一重复可使用肿瘤浸润淋巴细胞(TIL)在APC介导的增殖中作为T细胞来源。
序列表
<110> 欧申赛德生物技术公司
<120> 新抗原组合物及其在免疫肿瘤治疗中的使用方法
<130> 49906-503001WO
<150> US 62/298,275
<151> 2016-02-22
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<223> Synthetic polynucleotide
<400> 20
cgagatcctc tctctgaaat cactgagcag gagaaagatt ttctatggag t 51
<210> 21
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 21
Arg Asp Pro Leu Ser Glu Ile Thr Glu Gln Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 22
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 22
cgagatcctc tctctgaaat cactcagcag gagaaagatt ttctatggag t 51
<210> 23
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 23
Arg Asp Pro Leu Ser Glu Ile Thr Gln Gln Glu Lys Asp Phe Leu Trp
1 5 10 15
<210> 24
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 24
cgagatcctc tctctgaaat cactaagcag gagaaagatt ttctatggag t 51
<210> 25
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 25
Arg Asp Pro Leu Ser Glu Ile Thr Lys Gln Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 26
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 26
cgagatcctc tctctgaaat cactgcgcag gagaaagatt ttctatggag t 51
<210> 27
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 27
Arg Asp Pro Leu Ser Glu Ile Thr Ala Gln Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 28
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 28
cgagatcctc tctctgaaat cactgggcag gagaaagatt ttctatggag t 51
<210> 29
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 29
Arg Asp Pro Leu Ser Glu Ile Thr Gly Gln Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 30
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 30
cgagatcctc tctctgaaat cactgtgcag gagaaagatt ttctatggag t 51
<210> 31
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 31
Arg Asp Pro Leu Ser Glu Ile Thr Val Gln Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 32
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 32
cgagatcctc tctctgaaat cactgagccg gagaaagatt ttctatggag t 51
<210> 33
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 33
Arg Asp Pro Leu Ser Glu Ile Thr Glu Pro Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 34
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 34
cgagatcctc tctctgaaat cactgagaag gagaaagatt ttctatggag t 51
<210> 35
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 35
Arg Asp Pro Leu Ser Glu Ile Thr Glu Lys Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 36
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 36
cgagatcctc tctctgaaat cactgaggag gagaaagatt ttctatggag t 51
<210> 37
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 37
Arg Asp Pro Leu Ser Glu Ile Thr Glu Glu Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 38
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 38
cgagatcctc tctctgaaat cactgagcgg gagaaagatt ttctatggag t 51
<210> 39
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 39
Arg Asp Pro Leu Ser Glu Ile Thr Glu Arg Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 40
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 40
cgagatcctc tctctgaaat cactgagctg gagaaagatt ttctatggag t 51
<210> 41
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 41
Arg Asp Pro Leu Ser Glu Ile Thr Glu Leu Glu Lys Asp Phe Leu Trp
1 5 10 15
Ser
<210> 42
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 42
ttcatgaaac aaatgaatga tgcacgtcat ggtggctgga caacaaaaat g 51
<210> 43
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 43
Phe Met Lys Gln Met Asn Asp Ala Arg His Gly Gly Trp Thr Thr Lys
1 5 10 15
Met
<210> 44
<211> 51
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 44
ttcatgaaac aaatgaatga tgcacttcat ggtggctgga caacaaaaat g 51
<210> 45
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 45
Phe Met Lys Gln Met Asn Asp Ala Leu His Gly Gly Trp Thr Thr Lys
1 5 10 15
Met
<210> 46
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 46
Gly Gly Gly Ser Gly Gly Gly
1 5
<210> 47
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 47
Gly Gly Gly Ser Gly Gly Gly Gly
1 5
<210> 48
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 48
Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5
<210> 49
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 49
Gly Gly Gly Gly Ser Gly Gly Gly
1 5
<210> 50
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 50
Ile Ile Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 51
<211> 28
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 51
Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val
1 5 10 15
Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu
20 25
<210> 52
<211> 254
<212> PRT
<213> Homo sapiens
<400> 52
Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val
1 5 10 15
Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile
20 25 30
Ile Gln Ala Glu Phe Tyr Leu Asn Pro Asp Gln Ser Gly Glu Phe Met
35 40 45
Phe Asp Phe Asp Gly Asp Glu Ile Phe His Val Asp Met Ala Lys Lys
50 55 60
Glu Thr Val Trp Arg Leu Glu Glu Phe Gly Arg Phe Ala Ser Phe Glu
65 70 75 80
Ala Gln Gly Ala Leu Ala Asn Ile Ala Val Asp Lys Ala Asn Leu Glu
85 90 95
Ile Met Thr Lys Arg Ser Asn Tyr Thr Pro Ile Thr Asn Val Pro Pro
100 105 110
Glu Val Thr Val Leu Thr Asn Ser Pro Val Glu Leu Arg Glu Pro Asn
115 120 125
Val Leu Ile Cys Phe Ile Asp Lys Phe Thr Pro Pro Val Val Asn Val
130 135 140
Thr Trp Leu Arg Asn Gly Lys Pro Val Thr Thr Gly Val Ser Glu Thr
145 150 155 160
Val Phe Leu Pro Arg Glu Asp His Leu Phe Arg Lys Phe His Tyr Leu
165 170 175
Pro Phe Leu Pro Ser Thr Glu Asp Val Tyr Asp Cys Arg Val Glu His
180 185 190
Trp Gly Leu Asp Glu Pro Leu Leu Lys His Trp Glu Phe Asp Ala Pro
195 200 205
Ser Pro Leu Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu Gly Leu
210 215 220
Thr Val Gly Leu Val Gly Ile Ile Ile Gly Thr Ile Phe Ile Ile Lys
225 230 235 240
Gly Val Arg Lys Ser Asn Ala Ala Glu Arg Arg Gly Pro Leu
245 250
<210> 53
<211> 690
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 53
atggccataa gtggagtccc tgtgctagga tttttcatca tagctgtgct gatgagcgct 60
caggaatcat gggctatcaa agaagaacat gtgatcatac aggccgagtt ctatctgaat 120
cctgaccaat caggcgagtt tatgtttgac tttgatggtg atgagatttt ccatgtggat 180
atggcaaaga aggagacggt ctggcggctt gaagaatttg gacgatttgc cagctttgag 240
gctcaaggtg cattggccaa catagctgtg gacaaagcca acttggaaat catgacaaag 300
cgctccaact atactccgat caccaatgac aagttcaccc caccagtggt caatgtcacg 360
tggcttcgaa atggaaaacc tgtcaccaca ggagtgtcag agacagtctt cctgcccagg 420
gaagaccacc ttttccgcaa gttccactat ctccccttcc tgccctcaac tgaggacgtt 480
tacgactgca gggtggagca ctggggcttg gatgagcctc ttctcaagca ctgggagttt 540
gatgctccaa gccctctccc agagactaca gagaacgtgg tgtgtgccct gggcctgact 600
gtgggtctgg tgggcatcat tattgggacc atcttcatca tcaagggatt gcgcaaaagc 660
aatgcagcag aacgcagggg gcctctgtaa 690
<210> 54
<211> 256
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 54
Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val
1 5 10 15
Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile
20 25 30
Ile Ile Gly His His Ala Tyr Gly Asp Gln Ile Ile Gly Gly Gly Ser
35 40 45
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Ile Gln Ala Glu Phe
50 55 60
Tyr Leu Asn Pro Asp Gln Ser Gly Glu Phe Met Phe Asp Phe Asp Gly
65 70 75 80
Asp Glu Ile Phe His Val Asp Met Ala Lys Lys Glu Thr Val Trp Arg
85 90 95
Leu Glu Glu Phe Gly Arg Phe Ala Ser Phe Glu Ala Gln Gly Ala Leu
100 105 110
Ala Asn Ile Ala Val Asp Lys Ala Asn Leu Glu Ile Met Thr Lys Arg
115 120 125
Ser Asn Tyr Thr Pro Ile Thr Asn Asp Lys Phe Thr Pro Pro Val Val
130 135 140
Asn Val Thr Trp Leu Arg Asn Gly Lys Pro Val Thr Thr Gly Val Ser
145 150 155 160
Glu Thr Val Phe Leu Pro Arg Glu Asp His Leu Phe Arg Lys Phe His
165 170 175
Tyr Leu Pro Phe Leu Pro Ser Thr Glu Asp Val Tyr Asp Cys Arg Val
180 185 190
Glu His Trp Gly Leu Asp Glu Pro Leu Leu Lys His Trp Glu Phe Asp
195 200 205
Ala Pro Ser Pro Leu Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu
210 215 220
Gly Leu Thr Val Gly Leu Val Gly Ile Ile Ile Gly Thr Ile Phe Ile
225 230 235 240
Ile Lys Gly Leu Arg Lys Ser Asn Ala Ala Glu Arg Arg Gly Pro Leu
245 250 255
<210> 55
<211> 771
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 55
atggccataa gtggagtccc tgtgctagga tttttcatca tagctgtgct gatgagcgct 60
caggaatcat gggctatcaa agaagaacat gtgatcataa tcggtcatca tgcttatggg 120
gaccagatca tcggaggagg aagtggcggc ggcggcagcg gtggtggtgg ttcgatcatc 180
caggccgagt tctatctgaa tcctgaccaa tcaggcgagt ttatgtttga ctttgatggt 240
gatgagattt tccatgtgga tatggcaaag aaggagacgg tctggcggct tgaagaattt 300
ggacgatttg ccagctttga ggctcaaggt gcattggcca acatagctgt ggacaaagcc 360
aacttggaaa tcatgacaaa gcgctccaac tatactccga tcaccaatga caagttcacc 420
ccaccagtgg tcaatgtcac gtggcttcga aatggaaaac ctgtcaccac aggagtgtca 480
gagacagtct tcctgcccag ggaagaccac cttttccgca agttccacta tctccccttc 540
ctgccctcaa ctgaggacgt ttacgactgc agggtggagc actggggctt ggatgagcct 600
cttctcaagc actgggagtt tgatgctcca agccctctcc cagagactac agagaacgtg 660
gtgtgtgccc tgggcctgac tgtgggtctg gtgggcatca ttattgggac catcttcatc 720
atcaagggat tgcgcaaaag caatgcagca gaacgcaggg ggcctctgta a 771
<210> 56
<211> 266
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 56
Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val
1 5 10 15
Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile
20 25 30
Ser Gly Trp Val Lys Pro Ile Ile Ile Gly His His Ala Tyr Gly Asp
35 40 45
Gln Tyr Arg Ala Thr Ile Ile Gly Gly Gly Ser Gly Gly Gly Gly Ser
50 55 60
Gly Gly Gly Gly Ser Ile Ile Gln Ala Glu Phe Tyr Leu Asn Pro Asp
65 70 75 80
Gln Ser Gly Glu Phe Met Phe Asp Phe Asp Gly Asp Glu Ile Phe His
85 90 95
Val Asp Met Ala Lys Lys Glu Thr Val Trp Arg Leu Glu Glu Phe Gly
100 105 110
Arg Phe Ala Ser Phe Glu Ala Gln Gly Ala Leu Ala Asn Ile Ala Val
115 120 125
Asp Lys Ala Asn Leu Glu Ile Met Thr Lys Arg Ser Asn Tyr Thr Pro
130 135 140
Ile Thr Asn Asp Lys Phe Thr Pro Pro Val Val Asn Val Thr Trp Leu
145 150 155 160
Arg Asn Gly Lys Pro Val Thr Thr Gly Val Ser Glu Thr Val Phe Leu
165 170 175
Pro Arg Glu Asp His Leu Phe Arg Lys Phe His Tyr Leu Pro Phe Leu
180 185 190
Pro Ser Thr Glu Asp Val Tyr Asp Cys Arg Val Glu His Trp Gly Leu
195 200 205
Asp Glu Pro Leu Leu Lys His Trp Glu Phe Asp Ala Pro Ser Pro Leu
210 215 220
Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu Gly Leu Thr Val Gly
225 230 235 240
Leu Val Gly Ile Ile Ile Gly Thr Ile Phe Ile Ile Lys Gly Leu Arg
245 250 255
Lys Ser Asn Ala Ala Glu Arg Arg Gly Pro
260 265
<210> 57
<211> 804
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 57
atggccataa gtggagtccc tgtgctagga tttttcatca tagctgtgct gatgagcgct 60
caggaatcat gggctatcaa agaagaacat gtgatcagcg gatgggtaaa acctattata 120
atcggtcatc atgcttatgg ggaccagtac agagcaacga tcatcggagg aggaagtggc 180
ggcggcggca gcggtggtgg tggttcgatc atccaggccg agttctatct gaatcctgac 240
caatcaggcg agtttatgtt tgactttgat ggtgatgaga ttttccatgt ggatatggca 300
aagaaggaga cggtctggcg gcttgaagaa tttggacgat ttgccagctt tgaggctcaa 360
ggtgcattgg ccaacatagc tgtggacaaa gccaacttgg aaatcatgac aaagcgctcc 420
aactatactc cgatcaccaa tgacaagttc accccaccag tggtcaatgt cacgtggctt 480
cgaaatggaa aacctgtcac cacaggagtg tcagagacag tcttcctgcc cagggaagac 540
caccttttcc gcaagttcca ctatctcccc ttcctgccct caactgagga cgtttacgac 600
tgcagggtgg agcactgggg cttggatgag cctcttctca agcactggga gtttgatgct 660
ccaagccctc tcccagagac tacagagaac gtggtgtgtg ccctgggcct gactgtgggt 720
ctggtgggca tcattattgg gaccatcttc atcatcaagg gattgcgcaa aagcaatgca 780
gcagaacgca gggggcctct gtaa 804
<210> 58
<211> 265
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 58
Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val
1 5 10 15
Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile
20 25 30
Trp Lys Ser Pro Asn Gly Thr Ile Gln Asn Ile Leu Gly Gly Thr Val
35 40 45
Phe Arg Glu Ile Ile Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
50 55 60
Gly Gly Ser Ile Ile Gln Ala Glu Phe Tyr Leu Asn Pro Asp Gln Ser
65 70 75 80
Gly Glu Phe Met Phe Asp Phe Asp Gly Asp Glu Ile Phe His Val Asp
85 90 95
Met Ala Lys Lys Glu Thr Val Trp Arg Leu Glu Glu Phe Gly Arg Phe
100 105 110
Ala Ser Phe Glu Ala Gln Gly Ala Leu Ala Asn Ile Ala Val Asp Lys
115 120 125
Ala Asn Leu Glu Ile Met Thr Lys Arg Ser Asn Tyr Thr Pro Ile Thr
130 135 140
Asn Asp Lys Phe Thr Pro Pro Val Val Asn Val Thr Trp Leu Arg Asn
145 150 155 160
Gly Lys Pro Val Thr Thr Gly Val Ser Glu Thr Val Phe Leu Pro Arg
165 170 175
Glu Asp His Leu Phe Arg Lys Phe His Tyr Leu Pro Phe Leu Pro Ser
180 185 190
Thr Glu Asp Val Tyr Asp Cys Arg Val Glu His Trp Gly Leu Asp Glu
195 200 205
Pro Leu Leu Lys His Trp Glu Phe Asp Ala Pro Ser Pro Leu Pro Glu
210 215 220
Thr Thr Glu Asn Val Val Cys Ala Leu Gly Leu Thr Val Gly Leu Val
225 230 235 240
Gly Ile Ile Ile Gly Thr Ile Phe Ile Ile Lys Gly Leu Arg Lys Ser
245 250 255
Asn Ala Ala Glu Arg Arg Gly Pro Leu
260 265
<210> 59
<211> 798
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 59
atggccataa gtggagtccc tgtgctagga tttttcatca tagctgtgct gatgagcgct 60
caggaatcat gggctatcaa agaagaacat gtgatctgga agtctccgaa cggcaccatt 120
cagaatattc tcggcggcac tgtgttccgg gagatcatcg gaggaggaag tggcggcggc 180
ggcagcggtg gtggtggttc gatcatccag gccgagttct atctgaatcc tgaccaatca 240
ggcgagttta tgtttgactt tgatggtgat gagattttcc atgtggatat ggcaaagaag 300
gagacggtct ggcggcttga agaatttgga cgatttgcca gctttgaggc tcaaggtgca 360
ttggccaaca tagctgtgga caaagccaac ttggaaatca tgacaaagcg ctccaactat 420
actccgatca ccaatgacaa gttcacccca ccagtggtca atgtcacgtg gcttcgaaat 480
ggaaaacctg tcaccacagg agtgtcagag acagtcttcc tgcccaggga agaccacctt 540
ttccgcaagt tccactatct ccccttcctg ccctcaactg aggacgttta cgactgcagg 600
gtggagcact ggggcttgga tgagcctctt ctcaagcact gggagtttga tgctccaagc 660
cctctcccag agactacaga gaacgtggtg tgtgccctgg gcctgactgt gggtctggtg 720
ggcatcatta ttgggaccat cttcatcatc aagggattgc gcaaaagcaa tgcagcagaa 780
cgcagggggc ctctgtaa 798
<210> 60
<211> 264
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 60
Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val
1 5 10 15
Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile
20 25 30
Gly Trp Thr Lys Pro Ile Thr Ile Gly Lys His Ala His Gly Asp Gln
35 40 45
Tyr Lys Ile Ile Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
50 55 60
Gly Ser Ile Ile Gln Ala Glu Phe Tyr Leu Asn Pro Asp Gln Ser Gly
65 70 75 80
Glu Phe Met Phe Asp Phe Asp Gly Asp Glu Ile Phe His Val Asp Met
85 90 95
Ala Lys Lys Glu Thr Val Trp Arg Leu Glu Glu Phe Gly Arg Phe Ala
100 105 110
Ser Phe Glu Ala Gln Gly Ala Leu Ala Asn Ile Ala Val Asp Lys Ala
115 120 125
Asn Leu Glu Ile Met Thr Lys Arg Ser Asn Tyr Thr Pro Ile Thr Asn
130 135 140
Asp Lys Phe Thr Pro Pro Val Val Asn Val Thr Trp Leu Arg Asn Gly
145 150 155 160
Lys Pro Val Thr Thr Gly Val Ser Glu Thr Val Phe Leu Pro Arg Glu
165 170 175
Asp His Leu Phe Arg Lys Phe His Tyr Leu Pro Phe Leu Pro Ser Thr
180 185 190
Glu Asp Val Tyr Asp Cys Arg Val Glu His Trp Gly Leu Asp Glu Pro
195 200 205
Leu Leu Lys His Trp Glu Phe Asp Ala Pro Ser Pro Leu Pro Glu Thr
210 215 220
Thr Glu Asn Val Val Cys Ala Leu Gly Leu Thr Val Gly Leu Val Gly
225 230 235 240
Ile Ile Ile Gly Thr Ile Phe Ile Ile Lys Gly Leu Arg Lys Ser Asn
245 250 255
Ala Ala Glu Arg Arg Gly Pro Leu
260
<210> 61
<211> 795
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic polynucleotide
<400> 61
atggccataa gtggagtccc tgtgctagga tttttcatca tagctgtgct gatgagcgct 60
caggaatcat gggctatcaa agaagaacat gtgatcggtt ggacgaaacc aatcactatt 120
ggcaagcatg ctcatggaga ccagtacaag atcatcggag gaggaagtgg cggcggcggc 180
agcggtggtg gtggttcgat catccaggcc gagttctatc tgaatcctga ccaatcaggc 240
gagtttatgt ttgactttga tggtgatgag attttccatg tggatatggc aaagaaggag 300
acggtctggc ggcttgaaga atttggacga tttgccagct ttgaggctca aggtgcattg 360
gccaacatag ctgtggacaa agccaacttg gaaatcatga caaagcgctc caactatact 420
ccgatcacca atgacaagtt caccccacca gtggtcaatg tcacgtggct tcgaaatgga 480
aaacctgtca ccacaggagt gtcagagaca gtcttcctgc ccagggaaga ccaccttttc 540
cgcaagttcc actatctccc cttcctgccc tcaactgagg acgtttacga ctgcagggtg 600
gagcactggg gcttggatga gcctcttctc aagcactggg agtttgatgc tccaagccct 660
ctcccagaga ctacagagaa cgtggtgtgt gccctgggcc tgactgtggg tctggtgggc 720
atcattattg ggaccatctt catcatcaag ggattgcgca aaagcaatgc agcagaacgc 780
agggggcctc tgtaa 795
<210> 62
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic polypeptide
<400> 62
Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val
1 5 10 15
Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile
20 25 30
Claims (28)
1.一种蛋白质,其包含共价附着于成熟的MHC II类肽的癌症抗原性肽,所述癌症抗原性肽能直接非共价结合所述MHC II类肽。
2.权利要求1的蛋白质,其中所述癌症抗原性肽在所述成熟的MHC II类肽的N-末端。
3.权利要求1的蛋白质,进一步包含共价连接所述癌抗原性肽和所述成熟的MHC II类肽的肽接头。
4.权利要求3的蛋白质,其中所述肽接头由一或多个甘氨酸组成、由一或多个丝氨酸组成、或者由一或多个甘氨酸和一或多个丝氨酸的组合组成。
5.权利要求1的蛋白质,进一步包含共价附着于所述癌症抗原性肽的N-末端的信号肽。
6.权利要求1的蛋白质,其中所述成熟的MHC II类肽是成熟的HLA-DRA α链肽。
7.权利要求1的蛋白质,其中所述癌症抗原性肽的长度为8-30个氨基酸。
8.权利要求1的蛋白质,其中所述癌症抗原性肽的长度为15-24个氨基酸。
9.抗原呈递细胞,其包含权利要求1的蛋白质。
10.权利要求9的抗原呈递细胞,其中所述蛋白质在所述抗原呈递细胞的细胞表面。
11.权利要求9的抗原呈递细胞,其中所述抗原呈递细胞是树突细胞或B细胞。
12.权利要求9的抗原呈递细胞,其中所述抗原呈递细胞是树突细胞。
13.核酸,其编码权利要求1-8之一的蛋白质。
14.权利要求13的核酸,其中所述核酸是mRNA。
15.权利要求13的核酸,其中所述核酸是dsDNA。
16.权利要求13的核酸,其中所述核酸形成无复制能力的病毒载体核酸的一部分。
17.权利要求16的核酸,其中所述无复制能力的病毒载体核酸是无复制能力的慢病毒载体。
18.权利要求16的核酸,其中所述无复制能力的病毒载体核酸是无复制能力的DNA病毒载体或者无复制能力的RNA病毒载体。
19.权利要求13的核酸,其中所述核酸在药学可接受的脂质体构建体或药学可接受的聚合构建体内。
20.药物制剂,其包含权利要求13的核酸和药学可接受的赋形剂。
21.树突细胞或B细胞,其包含权利要求13的核酸。
22.一种治疗有需要的患者中癌症的方法,所述方法包括:
(i)将权利要求9-12之一的抗原呈递细胞与CD4+T细胞在体外接触,从而激活所述CD4+T细胞,其中CD4+T细胞和抗原呈递细胞来自所述患者;
(ii)使所述CD4+T细胞扩展,从而形成多个扩展的CD4+T细胞;及
(iii)给所述患者施用有效量的所述多个扩展的CD4+T细胞。
23.权利要求22的方法,其中所述癌症是转移性多形性胶质母细胞瘤(GBM)。
24.一种治疗有需要的患者中癌症的方法,所述方法包括给所述患者施用有效量的权利要求13的核酸。
25.权利要求24的方法,其中所述核酸是mRNA。
26.权利要求24的方法,其中所述核酸形成核酸-脂质体复合物的一部分。
27.权利要求24的方法,其中所述有效量有效地激活所述患者中的CD4+T细胞。
28.权利要求24的方法,其中所述核酸形成无复制能力的病毒载体的一部分。
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US20220313803A1 (en) * | 2019-01-07 | 2022-10-06 | Brightpath Biotherapeutics Co., Ltd. | Novel neoantigens and cancer immunotherapy using same |
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