CN111093699A - 用于治疗癌症的新抗原疫苗组合物 - Google Patents
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Abstract
本发明提供了包含与至少一种T细胞增强子氨基酸序列融合的至少四种不同的肿瘤特异性新抗原的多肽,编码该多肽的核酸序列,包含该核酸序列的载体和包含该载体的载体集合。还提供了用于治疗癌症的物质组合物,所述组合物以混合物或单独的形式包含疫苗和至少一种检查点分子的调节剂或另一种类型的免疫调节剂,所述疫苗包含本发明的多肽、核酸序列、载体或载体的集合。
Description
本发明提供了一种多肽,其包含与至少一种T细胞增强子氨基酸序列融合的至少四种不同的肿瘤特异性新抗原;编码该多肽的核酸序列;包含该核酸序列的载体和包含该载体的载体集合。还提供了用于治疗癌症的物质组合物,所述组合物以混合物或单独的形式包含疫苗和至少一种检查点分子的调节剂或另一种类型的免疫调节剂,所述疫苗包含本发明的多肽、核酸序列、载体或载体集合。
发明背景
最近,已经开发出用于治疗癌症的新方法。免疫系统与肿瘤之间相互作用的研究确定了逃避宿主免疫应答的关键途径,从而允许开发免疫检查点抑制剂(CPI)抗体以释放T细胞抗肿瘤活性的力量。尽管它们取得了成功,但检查点抑制剂在少数接受治疗的患者中有效。对CPI治疗期间T细胞免疫应答模式的分析表明,在CPI治疗期间可以重新激活非常有限的针对肿瘤细胞的T细胞特异性(Alsaab,H.O.等人(2017)Front Pharmacol,8:p.561)。
Fritsch,E.F.等人(2014)Cancer Immunol Res.2(6):522-9已经鉴定出几种肿瘤抗原并将其分类为不同类别:癌胚系、组织分化抗原和衍生自突变的自身蛋白的新抗原。CPI治疗期间针对自身抗原的免疫应答的贡献仍然是有争议的问题(综述于Fritsch,E.F.等人(2014),同上)。在CPI治疗期间显示会被重新激活的特定且优选的癌症抗原类别是新抗原。最近,有力的证据支持以下观点:肿瘤中表达的基因编码序列发生突变而在肿瘤中产生的新抗原代表了针对癌症的疫苗接种的有希望的靶点(Kandoth,C.等人(2013)Nature502(7471):333)。衍生自基因组编码区遗传变化的突变蛋白可以形成癌症特异性新抗原。癌症新抗原是仅存在于肿瘤细胞而不存在于正常细胞上的抗原。新抗原是由肿瘤细胞中的DNA突变产生的,并显示在T细胞介导的免疫应答识别和杀死肿瘤细胞中起重要作用。
下一代测序(NGS)的出现允许以及时且廉价的方式确定癌症基因组的完整序列,这揭示了人类肿瘤的突变谱(Ott,P.A.等人(2017)Nature 547(7662):217)。最常见的突变类型是非同义单核苷酸变体(SNV),并且在肿瘤中发现的单核苷酸变体的中位数根据其组织学而变化很大。例如NSCLC和黑色素瘤的一些肿瘤具有较高的突变负荷,突变的中位数超过200,而一些异常情况下的突变超过1000。
最近,已经在I期临床研究中评估了基于RNA或肽的两种不同个性化疫苗接种方法。获得的数据表明,疫苗接种可以在癌症患者中既扩大有限数量的预先存在的新抗原特异性T细胞的数量,又诱导更广泛的新T细胞特异性(Ott,P.A.等人(2017)supra和Sahin,U.等人(2017)Nature 547(7662):222)。两种方法的主要局限在于这些疫苗接种方法靶向的新抗原的最大数量。基于已公开的数据,基于肽的方法的上限为二十种肽,由于某些情况下无法合成肽,因此并未在所有患者中达到该上限。所述基于RNA的方法的上限甚至更低,因为每种疫苗仅包含10个突变。尚无显示这些疫苗接种方法疗效的临床数据。在癌症疫苗接种中,重要的是要避免通过产生疫苗诱导的T细胞无法识别的肿瘤变体而导致的肿瘤逃逸。用于治疗癌症的癌症疫苗的挑战是诱导能够立即识别和消除最大数量癌细胞的看似多样的免疫T细胞群体,因此,需要疫苗编码相当大量的肿瘤抗原。
此外,WO2017/118702A1公开了具有通过接头连接的仅10种新抗原的构建体的实例,然而证明了仅几种新抗原的免疫原性而不是疗效。实际上,以前的研究都没有显示出在高肿瘤负荷模型中的疗效。
在癌症疫苗接种中,重要的是要避免通过产生疫苗诱导的T细胞无法识别的抗原而导致的肿瘤逃逸。用于治疗癌症的癌症疫苗的挑战是诱导能够立即识别和消除最大数量癌细胞的看似多样的免疫T细胞群体,因此,需要疫苗编码相当大量的肿瘤抗原。
基于我们的临床前数据,预期基于有限数量新抗原的疫苗非常适合作为预防癌症或治疗微小残留病的独立疗法,微小残留病为通过如循环肿瘤细胞游离DNA的分子方法诊断出的癌症。微小残留病通常低于使用影像学方法的检出限,影像学方法例如为计算机断层扫描(CT)扫描、磁共振成像(MRI)、采用放射性示踪剂的同位素诊断,该放射性示踪剂在正电子发射断层扫描(PET)中通过闪烁法进行检测。核医学的临床研究表明,可检测的最小病灶的直径为约1.5cm。此外,基于我们的临床前数据,预期只有满足a)基于许多新抗原(即>25)和b)结合如检查点分子抑制剂的免疫调节剂这两个条件的疫苗才能有效控制既定肿瘤,既定肿瘤是指可以通过影像学诊断的肿瘤块。
为了克服现有技术的这些和其他缺点,基于靶向有限数量的新抗原的疫苗,本发明提供了多核苷酸序列和包含这些核酸的载体,该多核苷酸序列编码头尾相连(即31)并与至少一种T细胞增强子氨基酸序列融合的多种不同的肿瘤新抗原,该T细胞增强子氨基酸序列例如为组织纤溶酶原激活物(TPA)前导序列或恒定链。如果将包含这样的核酸的载体疫苗与检查点分子的调节剂组合施用,则产生高治疗率。
本发明基于以下发现:激活针对非常弱的免疫原如肿瘤中存在的那些免疫原,包括大多数新抗原的免疫系统需要有效的免疫平台,并且需要与编码抗原的特定结构组合。
许多新抗原衍生自点突变,即非同义SNV,这是在肿瘤中发现的最常见的突变类型。蛋白质序列中的单个氨基酸变化很少会产生能够诱导有效免疫应答的新表位,在大多数情况下,这种微小变化要么根本不产生新表位,要么可能产生非常弱的新表位。基于腺病毒的遗传疫苗接种平台,特别是类人猿衍生的腺病毒(GAd)病毒载体已显示出对诱导T细胞应答非常有效,并且适合以人工基因形式编码大型抗原,该人工基因由编码来自彼此连接的不同蛋白质片段的多核苷酸组成。
出乎意料的是,当发明人在新抗原的情况下使用该平台时,无法诱导任何免疫应答。发明人鉴定了当与癌症新抗原序列融合时能够使免疫原性恢复的特异性序列,其在本申请中称为“T细胞增强子氨基酸序列”。这种T细胞增强子氨基酸序列适合克服新抗原缺乏免疫原性或免疫原性差的问题。优选地,这些序列融合至新抗原编码序列的上游。在T细胞增强子氨基酸序列中,发明人鉴定了组织纤溶酶原前导序列(TPA)前导序列和恒定链(INV)、其变体和片段,它们显示出使免疫原性恢复的能力。发明人还发现新抗原不需要通过接头连接以恢复免疫原性。
本发明的另一个相关方面涉及有效的癌症疫苗接种所需的免疫原性新抗原的数量。发明人发现,尽管在预防情况下,基于类人猿衍生的腺病毒载体的编码少量新抗原的遗传疫苗作为独立疗法非常有效,但其在用于存在大的既定肿瘤的治疗情况下是无效的,并且不能与能够逆转T细胞衰竭的免疫调节分子例如抗PD-1抗体协同作用。相反,没有使用接头而头尾连接并与T细胞增强子融合的编码超过三十种新抗原的更大的疫苗构建体在与抗PD-1抗体联合施用时,显示出有效的协同抗肿瘤活性。
附图说明
图1:编码与CT26五表位序列(pentatope)(CT26-5)连接的人INV全长(CT26-5-INV)或TPA(CT26-5 TPA)序列GAd载体的免疫原性。通过ELISpot分析获得免疫动物脾细胞的报告值。疫苗接种(5×10^8vp的剂量)后三周离体刺激脾细胞,其中五种合成肽的池对应于含有五种突变的新抗原的序列。应答表示为每百万个脾细胞产生IFNγ的T细胞的数量。
图2:GAd-CT26-31 TPA和GAd-CT26-5 TPA载体的免疫原性。将GAd载体以5×10^8vp的剂量肌内注射,并在免疫后三周通过IFN-γELISpot测量T细胞应答,此处表示为每百万个脾细胞产生INFγ的T细胞的数量。显示了针对癌症突变导致的免疫原性的应答。两种载体都具有新抗原#5、#18、#28。虚线表示阳性应答的阈值。
图3:用编码CT26新抗原的GAd-CT26-5和GAd-CT26-31载体进行预防接种有效控制了肿瘤的发展。向小鼠(n=8-10/组)接种GAd-CT26-5或GAd-CT26-31,并在免疫后2周用CT26细胞进行皮下注射(s.c.)。随时间监测肿瘤的生长。显示了在GAd接种后28天测得的肿瘤体积与未治疗(模拟)小鼠的肿瘤体积。
图4:用GAd-CT26-5和GAd-CT26-31载体进行早期疫苗接种可有效控制肿瘤的生长。用CT26细胞通过静脉注射(i.v.)接种小鼠(n=8-10/组)(第0天),保持不处理(对照)或在第3天注射5×10^8vp的GAd-CT26-5或GAd-CT26-31。显示了在第16天计数的肺结节数量。
图5:GAd疫苗在具有高肿瘤负荷的动物中的疗效需要靶向许多新抗原并与抗PD1组合。用CT26细胞皮下注射接种小鼠。一周后,根据肿瘤体积(平均70mm3至100mm3)将小鼠随机化。从第0天开始GAd疫苗的治疗。A)显示了在接种GAd-CT26-31的小鼠与对照(未经治疗)小鼠中,随时间推移在单个小鼠中的肿瘤生长。B)抗PD1以及抗PD1与GAd-CT26-5或GAd-CT26-31的组合的疗效。在第0天施用疫苗(肌内注射(im)),每周两次施用抗PD1,直到第16天(腹膜内注射(ip))。显示了随时间推移在单个小鼠中的肿瘤生长。通过卡方检验来计算统计数据,以评估治愈的小鼠(应答者)与无应答小鼠的数目。
图6:在接受GAd-CT26-31和抗PD1治疗的携带肿瘤的小鼠中,通过IFN-γELISpot测量的新抗原特异性T细胞应答(第30天)。测定在对应于免疫原性新抗原的合成肽的存在下刺激的脾细胞的应答,并表示为每百万个脾细胞产生IFN-γ的T细胞的数量。
图7:在CD4+ T细胞(CD4耗尽)或CD8+ T细胞(CD8耗尽)的消耗性抗体存在的情况下或在未耗尽T细胞的对照组中,用GAd-CT26-31和抗PD1治疗的携带肿瘤的小鼠中的肿瘤生长。数据代表至少2个独立实验。统计显著性由*(Fisher精确检验,P<0.05)或NS(不具有显著性)表示。
图8:来自联合治疗的小鼠(左)和仅接受抗PD1治疗的小鼠(右)之间的肿瘤内TCR多样性(克隆型的数量)的显著差异(单向威尔科克森检验)。联合治疗应答小鼠(左侧,实心圆圈),联合治疗非应答小鼠(左侧,实心框),仅抗PD1的治疗应答小鼠(右侧,朝上的三角形),仅抗PD1处理的非应答小鼠(右侧,朝下的三角形)。
发明内容
在第一方面,本发明涉及包含至少25种不同的肿瘤特异性新抗原和至少一种T细胞增强子氨基酸序列的多肽。
在第二方面,本发明涉及编码本发明第一方面的多肽的核酸。
在第三方面,本发明涉及包含与表达控制序列可操作连接的本发明第二方面的核酸的载体。
在第四方面,本发明涉及一种或多于一种表达载体的集合,每种表达载体包含根据本发明第二方面的核酸,其中每种表达载体选自质粒;黏粒;RNA;与佐剂一起配制的RNA;配制在脂质体颗粒中的RNA;自扩增RNA(SAM);与佐剂一起配制的SAM;配制在脂质体颗粒中的SAM;病毒载体;优选α病毒载体、委内瑞拉马脑炎(VEE)病毒载体、辛德毕斯(SIN)病毒载体、塞姆利基森林病毒(SFV)载体、猿猴或人巨细胞病毒(CMV)载体、淋巴细胞脉络丛脑膜炎病毒(LCMV)载体、逆转录病毒载体或慢病毒载体。优选为有复制能力或无复制能力的类人猿衍生的腺病毒载体,其优选衍生自黑猩猩或倭黑猩猩或大猩猩的腺病毒载体;痘病毒载体;牛痘病毒载体或经修饰的安卡拉牛痘病毒(MVA)载体。
在第五方面,本发明涉及包含疫苗和检查点分子的至少一种调节剂或编码所述调节剂的核酸或包含编码所述调节剂的核酸的载体的组合物,该疫苗包含第一方面的多肽、本发明第二方面的核酸、本发明第三方面要求保护的的载体或本发明第四方面的载体集合,该组合物用于预防或治疗对象的增殖性疾病。
在第六方面,本发明涉及一种疫苗接种试剂盒,其在独立包装中包括:
(i)疫苗,其包含本发明第一方面的多肽、本发明第二方面的核酸、本发明第三方面的载体或本发明第四方面的载体集合;和
(ii)检查点分子的至少一种调节剂或编码该调节剂的核酸或包含编码该调节剂的核酸的载体。
发明详述
在下面详细描述本发明之前,应当理解,本发明不限于本文描述的特定方法、方案和试剂,因为它们可以变化。还应理解,本文所使用的术语仅出于描述特定实施方案的目的,而不旨在限制本发明的范围,本发明的范围仅由所附权利要求书来限制。除非另外限定,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常所理解的含义相同的含义。
优选地,本文所用的术语如"Amultilingual glossary of biotechnologicalterms:(IUPAC Recommendations)",Leuenberger,H.G.W,Nagel,B.和Klbl,H.编(1995),Helvetica Chimica Acta,CH-4010Basel,Switzerland)中所定义,并如Axel Kleemann和Jurgen Engel的"Pharmaceutical Substances:Syntheses,Patents,Applications",Thieme Medical Publishing,1999;Susan Budavari等人编辑的"Merck Index:AnEncyclopedia of Chemicals,Drugs,and Biologicals",CRC Press,1996和美国Pharmcopeial Convention,Inc.出版的the United States Pharmacopeia-25/NationalFormulary-20,Rockville Md.,2001中所描述。
在整个说明书和随后的权利要求书中,除非上下文另有要求,否则词语“包括”、“包含”和“含有”将被理解为暗示包括所陈述的特征、整数或步骤,或特征、整数或步骤的组,但不排除任何其他特征、整数或步骤,或整数或步骤的组。在以下段落中,更详细地定义了本发明的不同方面。除非明确指出相反的情况,否则如此定义的每个方面可以与一个或多于一个其他方面组合。特别地,任何被指示为优选或有利的特征可以与被指示为优选或有利的任何其他特征组合。
在本说明书的全文中引用了一些文件。无论是上文还是下文,本文引用的每个文件(包括所有专利、专利申请、科学出版物、制造商的说明书、说明书等)均通过引用全文并入本文。本文中的任何内容均不得解释为承认本发明由于在先的发明而不享有早于此类公开的权利。
定义
在下文中,提供了本说明书中经常使用的术语的一些定义。在说明书的其余部分中,这些术语在其使用的每种情况下将分别具有所限定的含义和优选的含义。
术语“多核苷酸”和“核酸”在本文中可互换使用,并且应理解为由核苷酸单体形成的聚合物或低聚大分子。核苷酸单体由核碱基、五碳糖(例如但不限于核糖或2'-脱氧核糖)和一个至三个磷酸基团组成。通常,通过单个核苷酸单体之间的磷酸二酯键形成核酸。在本发明的上下文中,优选的核酸分子包括但不限于核糖核酸(RNA)、经修饰的RNA、脱氧核糖核酸(DNA)及其混合物,例如RNA-DNA杂合物。例如,核酸可以化学合成,例如根据磷酸三酯法化学合成(参见,例如,Uhlmann,E.和Peyman,A.(1990)Chemical Reviews,90,543-584)。
如本文所用,术语“蛋白质”、“肽”、“多肽”、和“蛋白”在全文可互换使用。这些术语在本发明的上下文中用于指天然存在的肽如天然存在的蛋白质和可能包含天然或非天然存在的氨基酸的合成肽。
在本发明的上下文中使用术语“新抗原”是指不存在于正常/生殖细胞中但存在于转化的细胞特别是癌细胞中的抗原。新抗原可包含一种或多于一种,例如,2种、3种、4种、5种或多于5种新表位。优选地,选择本发明的多肽中包含的每种新抗原的长度,以确保它们包含正常/生殖细胞中存在的表位的可能性很小。通常,可以确定新抗原在产生新表位的氨基酸变化的C末端和/或N末端包含12个或少于12个氨基酸。
突变的癌蛋白由发生在DNA水平的突变产生,其中突变的蛋白可以包含:
a)由点突变非同义SNV引起的一个或多于一个单个氨基酸变化;和/或
b)由产生移码肽的插入/缺失引起的非野生型氨基酸序列;和/或
c)由外显子边界的改变或由产生内含子保留的突变引起的非野生型氨基酸序列;和/或
d)由基因融合事件产生的突变癌蛋白。
由基因组点突变非同义SNV引起的一个或多于一个单个氨基酸改变所产生的新抗原在本发明的上下文中称为单个氨基酸突变肽。
在本发明的上下文中使用术语“移码肽”是指核酸的蛋白质编码区段的完整的非野生型翻译产物,该核酸包含引起开放阅读框(ORF)移位的插入或缺失突变。
在本发明的上下文中使用的术语“开放阅读框”缩写为“ORF”,是指可以翻译成连续的氨基酸区段的核苷酸序列。通常,ORF在给定的阅读框中包含起始密码子、长度通常是3个核苷酸的倍数的随后区域,但不包含终止密码子(TAG、TAA、TGA、UAG、UAA或UGA)。ORF编码蛋白质,其中可以翻译成的氨基酸形成肽连接的链。
在本发明的上下文中,由外显子边界的改变或由产生内含子保留的突变引起的非野生型氨基酸序列所产生的新抗原称为剪接位点突变肽。
在本发明的上下文中,由基因融合事件产生的突变癌蛋白所产生的新抗原称为通读突变肽。
术语“表达盒”在本发明的上下文中用于指包含至少一个待表达、可操作地连接至转录和翻译控制序列的核酸序列的核酸分子,该核酸序列例如为编码与本发明的恒定链或其一部分融合的新抗原序列的核酸。优选地,表达盒包括用于有效表达给定基因的顺式调节元件,例如启动子、起始位点和/或聚腺苷酸化位点。优选地,表达盒包含在患者细胞中表达核酸所需的所有附加元件。因此,典型的表达盒包含与待表达的核酸序列可操作连接的启动子,以及转录物的有效聚腺苷酸化、核糖体结合位点和翻译终止所需的信号。表达盒的附加元件可以包括例如增强子。表达盒优选还在结构基因下游包含转录终止区,以提供有效的终止。终止区可以从与启动子序列相同的基因获得,或者可以从不同的基因获得。
在本发明的上下文中使用的术语“可操作地连接”是指元件的排列,其中如此描述的部分被配置为执行其通常的功能。当核酸与另一核酸序列处于功能关系时,该核酸“可操作地连接”。例如,如果启动子影响一个或多于一个转基因的转录,则其可操作地连接至一个或多于一个转基因。此外,可操作地连接至编码序列的控制元件能够实现编码序列的表达。控制元件不必与编码序列邻接,只要它们起到指导其表达的作用即可。因此,例如,在启动子序列和编码序列之间可以存在中间的未翻译但仍被转录的序列,并且仍然可以认为该启动子序列与编码序列“可操作地连接”。
术语“载体”或“表达载体”可互换使用,并且是指多核苷酸或多核苷酸与蛋白质的混合物,其能够被引入细胞中或能够将本发明的核酸集合或作为本发明核酸集合的一部分的一种核酸引入细胞中,优选引入哺乳动物细胞中。载体的实例包括但不限于质粒、黏粒、噬菌体、病毒或人工染色体。特别地,使用载体将启动子和核酸集合或作为本发明核酸集合的一部分的一种核酸转移到合适的宿主细胞中。表达载体可以包含“复制子”多核苷酸序列,其促进表达载体在宿主细胞中的自主复制。一旦进入宿主细胞,表达载体就可以独立于宿主染色体DNA进行复制或与宿主染色体DNA同时复制,并且可以生成该载体及其插入的DNA的多个拷贝。在使用无复制能力的表达载体的情况下(出于安全原因通常会存在这种情况),该载体可能不复制,而只是直接表达核酸。根据表达载体的类型,表达载体可以从细胞中丢失,即仅瞬时表达由核酸编码的新抗原,或者可以在细胞中是稳定的。表达载体通常包含表达盒,即允许核酸转录成mRNA分子的必需元件。
术语“表达控制序列”是指适合于确定或测量表达的标签。合适的标签是本领域已知的。在本发明的上下文中,合适的标签可以是其肽序列与本发明的多肽连接的蛋白质标签。蛋白质标签可以例如涵盖亲和标签、增溶标签、色谱标签、表位标签或荧光标签。将亲和标签附加到蛋白质上,以便可以使用亲和技术从原始生物来源中纯化蛋白质。亲和标签包括几丁质结合蛋白(CBP)、麦芽糖结合蛋白(MBP)和谷胱甘肽-S-转移酶(GST)。聚(His)标签是一种广泛使用的蛋白质标签,其与金属基质结合。使用增溶标签,尤其是针对在伴侣蛋白缺陷型物种中表达的重组蛋白,以帮助蛋白质正确折叠并防止其沉淀。增溶标签包括硫氧还蛋白(TRX)和聚(NANP)。一些亲和标签具有作为增溶剂的双重作用,例如MBP和GST。色谱标签用于改变蛋白质的色谱特性,以在特定的分离技术中提供不同的分辨率。通常,色谱标签由聚阴离子氨基酸组成,例如FLAG标签。表位标签是短肽序列,其被选择是因为可以在许多不同物种中可靠地产生高亲和力抗体。表位标签通常来自病毒基因,这解释了它们的高免疫应答性。表位标签包括V5标签、Myc标签和HA标签。尽管这些标签也可用于抗体纯化,但它们对于蛋白质印迹、免疫荧光和免疫沉淀实验特别有用。荧光标签用于视觉读取蛋白质。GFP及其变体是最常用的荧光标签。GFP的更高级应用包括将其用作折叠报告分子(折叠为荧光,不折叠为无色)。荧光团的其他实例包括荧光素、罗丹明和磺基吲哚菁染料Cy5。
此类标签的实例包括但不限于AviTag、钙调蛋白标签、聚谷氨酸标签、E标签、FLAG标签、HA标签、His标签、Myc标签、S标签、SBP标签、Softag1、Softag 3、Strep标签、TC标签、V5标签、VSV标签、Xpress标签、Isopep标签、Spy标签、BCCP标签、谷胱甘肽-S-转移酶标签、绿色荧光蛋白标签、麦芽糖结合蛋白标签、Nus标签、硫氧还蛋白标签、Fc标签和Ty标签。最优选的是HA标签(根据SEQ ID NO:41的HA肽序列)。
在本发明的上下文中使用的术语“抗原”指由免疫应答分子识别的任何结构,免疫应答分子例如为抗体、T细胞受体(TCR)等。优选的抗原是与特定疾病相关的细胞蛋白。抗原被适应性免疫系统的高度可变的抗原受体(B细胞受体或T细胞受体)识别,并可引发体液或细胞免疫应答。引起这种应答的抗原也称为免疫原。不论细胞中的蛋白质的一部分是外来的还是细胞的,它们都被加工成较小的肽,并由主要组织相容性复合物(MHC)呈递。
术语“表位”,也称为抗原决定簇,在本发明的上下文中用于指抗原片段,优选与免疫系统的分子结合的肽,免疫系统的分子例如为B细胞受体、T细胞受体或抗体。与抗体或B细胞结合的表位称为“B细胞表位”,与T细胞结合的表位称为“T细胞表位”。在本文中,术语“结合”优选地涉及特异性结合,其被定义为在抗体或T细胞受体(TCR)与各自表位之间缔合常数为1×105M-1或高于1×105M-1,优选1×106M-1、1×107M-1、1×108M-1或高于1×108M-1的结合。本领域技术人员非常了解如何确定缔合常数(参见例如Caoili,S.E.(2012)Advances in Bioinformatics Vol.2012)。优选地,抗体与表位的特异性结合通过抗体的Fab(片段,抗原结合)区域介导,B细胞的特异性结合由B细胞受体所包含的抗体的Fab区域介导,T细胞的特异性结合由T细胞受体的可变(V)区介导。T细胞表位呈递在抗原呈递细胞的表面,并与主要组织相容性(MHC)分子结合。存在至少两种不同类别的MHC分子,分别称为I类、II类MHC。通过MHC-I途径呈递的表位引起细胞毒性T淋巴细胞(CD8+细胞)应答,而通过MHC-II途径呈递的表位引起T辅助细胞(CD4+细胞)应答。由I类MHC分子呈递的T细胞表位通常是长度为8个至11个氨基酸的肽,而由II类MHC分子呈递的T细胞表位通常是长度为13个至17个氨基酸的肽。III类MHC分子还以糖脂的形式呈递非肽表位。因此,术语“T细胞表位”优选是指可以由I类MHC或II类MHC分子呈递的8个至11个或13个至17个氨基酸长的肽。表位通常由氨基酸的化学活性表面基团组成,其可以带有或不带有糖侧链,并且通常具有特定的三维结构特征以及特定的电荷特征。构象性表位和非构象性表位的区别在于,在存在变性溶剂的情况下,与前者的结合丧失而与后者的结合没有丧失。
术语“T细胞增强子氨基酸序列”是指当与抗原序列融合时在基因疫苗接种的情况下增加针对新抗原的T细胞诱导的多肽序列。T细胞增强子的实例是恒定链序列或其片段;组织型纤溶酶原激活物前导序列,其任选地包含六个另外的下游氨基酸残基;PEST序列;细胞周期蛋白破坏盒;泛素化信号;SUMO化信号。
在本发明的上下文中使用的术语“制剂”和“组合物”旨在包括活性化合物的制剂,例如具有载剂和/或赋形剂的本发明的类人猿腺病毒载体的制剂。
在本发明上下文中使用的“药学上可接受的”是指由美国联邦或州政府的监管机构批准或在美国药典或其他公认的药典中列出的可用于动物尤其是人类。
如本文所用,术语“载剂”是指药理学上无活性的物质,例如但不限于与治疗活性成分一起施用的稀释剂、赋形剂、表面活性剂、稳定剂、生理缓冲溶液或载剂。这样的药物载剂可以是液体或固体。液体载剂包括但不限于无菌液体,例如水和油中的盐溶液,油包括但不限于石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等。盐溶液以及葡萄糖水溶液和甘油溶液也可以用作液体载剂,特别是用于注射溶液。当药物组合物静脉内施用时,盐溶液是优选的载剂。合适的药物载剂的实例在E.W.Martin的"Remington'sPharmaceutical Sciences"中进行了描述。
合适的药物“赋形剂”包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。
“表面活性剂”包括阴离子表面活性剂、阳离子表面活性剂和非离子表面活性剂,例如但不限于脱氧胆酸钠、十二烷基硫酸钠、Triton X-100以及聚山梨酯,例如聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯65和聚山梨酯80。
“稳定剂”包括但不限于甘露糖醇、蔗糖、海藻糖、白蛋白以及蛋白酶和/或核酸酶拮抗剂。
可在本发明的上下文中使用的“生理缓冲溶液”包括但不限于氯化钠溶液、脱矿水、以及合适的有机或无机缓冲溶液,例如但不限于磷酸盐缓冲液、柠檬酸盐缓冲液、tris缓冲液(三(羟甲基)氨基甲烷)、HEPES缓冲液([4(2-羟乙基)哌嗪基]乙磺酸)或MOPS缓冲液(3-吗啉代-1-丙烷磺酸)。通常,各种缓冲液的选择取决于所需的缓冲液摩尔浓度。磷酸盐缓冲液适用于例如注射和输注溶液。
“有效量”或“治疗有效量”是足以达到预期目的的治疗剂的量。给定治疗剂的有效量将随诸如治疗剂的性质、给药途径、接受治疗剂的动物的大小和种类以及给药目的等因素而变化。每种情况下的有效量可以由技术人员根据本领域中已建立的方法凭经验确定。
如本文所用,对疾病或病症的“治疗”或“处理”是指完成以下一项或多于一项:(a)减少疾病的严重程度;(b)限制或预防所治疗病症的特征性症状的发展;(c)抑制所治疗病症的特征性症状的恶化;(d)限制或预防先前患有该病症的个体的该病症复发;和(e)限制或预防先前有该病症的症状的个体的症状复发。
本发明的各个方面和优选实施方案
在第一方面,本发明涉及包含至少四种不同的肿瘤特异性新抗原和至少一种T细胞增强子氨基酸序列的多肽。
本发明人出人意料地发现,在具有大的既定肿瘤的治疗情况下的治疗功效取决于引发T细胞应答的免疫原性新抗原的数量。这在联合施用检查点分子调节剂的情况下尤其明显。如果免疫原性新抗原的数量增加到超过3种,则治疗效果会大大改善。在上下文中,“免疫原性”是指能够在患者中引发T细胞应答。因此,通常优选地,至少4种、至少5种、至少6种、至少7种、至少8种、至少8种、至少9种或至少10种新抗原是免疫原性的(引发患者的T细胞应答)。技术人员非常了解如何测量患者的T细胞应答。下面的实施例部分概述了一种可能的方法。
为了一致地达到免疫原性新抗原的这种最小数量,特别优选的是,第一方面的多肽包含至少25种肿瘤特异性新抗原,优选至少26种、27种、28种、29种或30种肿瘤特异性新抗原,最优选至少31种肿瘤特异性新抗原。尽管本文的实施例部分显示了31种肿瘤特异性新抗原的使用,但当然有可能并且在本发明的范围内进一步增加其数量,例如至少35种、至少40种、至少45种或至少50种肿瘤特异性新抗原。优选地,多肽包含(包括端值)25种至200种,更优选25种至150种,甚至更优选25种至100种,或最优选25种至80种肿瘤特异性新抗原。更优选地,多肽包含(包括端值)31种至200种,更优选31种至150种,甚至更优选31种至100种,或最优选31种至80种肿瘤特异性新抗原。通常,对于本文所提及的任何最小数量,优选的是,肿瘤特异性新抗原的上限为80种。这不是因为不能包括超过80种,而是为了能够更快地制备疫苗。
优选的是,在至少25种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少26种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少27种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少28种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少29种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少30种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少31种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少35种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少40种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少45种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少50种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。此外,优选的是,在至少25种至200种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少25种至150种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少25种至100种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少25种至80种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少31种至200种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少31种至150种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少31种至100种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。优选的是,在至少31种至80种肿瘤特异性新抗原中,至少4种、至少5种、至少6种、至少7种、至少8种、至少9种或至少10种(优先级逐渐增加)新抗原是免疫原性的。
通常还优选的是,肿瘤至少为Tis或T1期(不包括Tx和T0),优选至少为T2期、T3期或T4期。可以同时是所有N期(例如,Nx或N0)和M期(例如,M0),并且在优选实施方案中,至少为N1期、N2期或N3期和/或M1期。这里指的是TNM分类,其定义了以下肿瘤分期:
T:原发性肿瘤的大小或直接范围
Tx:无法评估肿瘤
Tis:原位癌
T0:无肿瘤证据
T1、T2、T3、T4:原发性肿瘤的证据,大小和/或扩展随期数增加N:扩散到区域淋巴结的程度
Nx:无法评估淋巴结
N0:无区域淋巴结转移
N1:存在区域淋巴结转移;在某些部位,肿瘤扩散到最近区域淋巴结或少数区域淋巴结
N2:肿瘤扩散范围在N1和N3之间(并非所有部位都使用N2)
N3:肿瘤扩散到更远或有更多的区域淋巴结(并非所有部位都使用N3)M:远端转移的存在
M0:无远端转移
M1:转移到远端器官(超出区域淋巴结)
设想从本发明特别受益的示例性分期是Tis和N中的任何一个(优选N1或N2或N3)以及M中的任何一个(优选M1),T1和N中的任何一个(优选N1或N2或N3)以及M中的任何一个(优选M1),T2和N中的任何一个(优选N1或N2或N3)以及M中的任何一个(优选M1),T3和N中的任何一个(优选N1或N2或N3)以及M中的任何一个(优选M1),T4和N中的任何一个(优选N1或N2或N3)以及M中的任何一个(优选M1)。可以使用成像方法来检测肿瘤在患者中的存在及其扩散,成像方法例如为计算机断层扫描术(CT)扫描、磁共振成像(MRI)、采用放射性示踪剂的同位素诊断(放射性示踪剂在正电子发射断层扫描(PET)中通过闪烁法进行检测)或其组合。成像方法也可以与其他方法相结合,例如超声检查、内窥镜检查、X线乳腺摄影检查、血液中生物标志物检测、细针穿刺活检或其组合。可以通过成像方法检测到的肿瘤大小取决于所用方法,同位素成像检测的直径为约1.5cm,CT和MRI检测的直径为约3mm,基于PET的方法检测的直径为约7mm(Erdi.(2012)Molecular Imaging and Radionuclide Therapy 21(1):23)。
优选地,通过选自以下的方法确定是否存在肿瘤(“证据”):循环肿瘤无细胞DNA检测、计算机断层摄影(CT)扫描、磁共振成像(MRI)、采用放射性示踪剂的同位素诊断(放射性示踪剂在正电子发射断层扫描(PET)中通过闪烁法进行检测)、以及上述的任意组合。在一个实施方案中,一种或多于一种前述方法或它们的组合与以下方法组合:超声检查、内窥镜检查、X线乳腺摄影检查、血液中的生物标志物检测、细针活检和前述的任何组合。
在一个优选的实施方案中,肿瘤的特征在于病灶的直径为至少约3mm,优选直径为至少7mm,更优选直径为至少1.5cm。
优选地,肿瘤特异性新抗原独立地选自单个氨基酸突变肽、移码肽、通读突变肽和剪接位点突变肽。
在第一方面的优选实施方案中,多肽包含至少五个含有肿瘤特异性新抗原的蛋白质片段。优选的是,多肽包含至少十个含有肿瘤特异性新抗原的蛋白质片段。还优选的是,多肽包含至少十五个含有肿瘤特异性新抗原的蛋白质片段。还优选的是,多肽包含至少二十个含有肿瘤特异性新抗原的蛋白质片段。还优选的是,多肽包含至少二十五个含有肿瘤特异性新抗原的蛋白质片段。更优选的是,多肽包含至少三十个含有肿瘤特异性新抗原的蛋白质片段。
在本发明的第一方面的另一个实施方案中,多肽包含至少五种、至少十种、至少十五种、至少二十种,优选至少30种、至少35种、至少40种、至少45种、至少50种或多于50种肿瘤特异性新抗原。优选地,多肽包含5种至200种,更优选15种至150种,甚至更优选25种至100种,或更优选30种至50种肿瘤特异性新抗原。
在本发明的第一方面的另一个实施方案中,肿瘤特异性新抗原彼此独立地具有8个至50个长度的氨基酸。优选地,肿瘤特异性新抗原彼此独立地具有9个至45个长度的氨基酸。更优选地,肿瘤特异性新抗原彼此独立地具有10个至40个长度的氨基酸。还优选地,肿瘤特异性新抗原彼此独立地具有15个至35个长度的氨基酸。还优选地,肿瘤特异性新抗原彼此独立地具有12个至30个长度的氨基酸。更优选地,肿瘤特异性新抗原彼此独立地具有13个至28个长度的氨基酸。更优选地,肿瘤特异性新抗原彼此独立地具有14个至45个长度的氨基酸。甚至更优选地,肿瘤特异性新抗原彼此独立地具有15个至35个长度的氨基酸。最优选地,肿瘤特异性新抗原彼此独立地具有25个长度的氨基酸。
在本发明的第一方面的另一个实施方案中,每种肿瘤特异性新抗原彼此独立地具有8个至50个长度的氨基酸,优选地15个至35个长度的氨基酸,更优选地25个长度的氨基酸。
优选地,多肽包含5种至200种肿瘤特异性新抗原,该肿瘤特异性新抗原的长度为8个至50个氨基酸,优选15个至35个氨基酸,更优选25个氨基酸;更优选包含15种至150种肿瘤特异性新抗原,该肿瘤特异性新抗原的长度为8个至50个氨基酸,优选15个至35个氨基酸,更优选25个氨基酸;甚至更优选包含25种至100种肿瘤特异性新抗原,该肿瘤特异性新抗原的长度为8个至50个氨基酸,优选15个至35个氨基酸,更优选25个氨基酸;或更优选包含30种至50种肿瘤特异性新抗原,该肿瘤特异性新抗原的长度为8个至50个氨基酸,优选15个至35个氨基酸,更优选25个氨基酸。
肽内新抗原的总长度优选为100个至2000个氨基酸。更优选为500个至1000个氨基酸。
在本发明的第一方面的另一个实施方案中,每种肿瘤特异性新抗原独立地选自单个氨基酸突变肽、移码肽、通读突变肽和剪接位点突变肽。优选地,至少80%的肿瘤特异性新抗原是单个氨基酸突变肽,更优选地至少85%的肿瘤特异性新抗原是单个氨基酸突变肽,更优选至少90%的肿瘤特异性新抗原是单个氨基酸突变肽,更优选至少95%的肿瘤特异性新抗原的是单个氨基酸突变肽。
在本发明的第一方面的另一个优选实施方案中,肿瘤特异性新抗原彼此直接连接。
在本发明的第一方面的另一个优选的实施方案中,氨基酸接头序列包括在每种新抗原之间或新抗原组之间。合适的接头序列是本领域众所周知的,并且优选包含或组成为1个至10个氨基酸。接头优选组成为或包含小氨基酸,例如Ser和Gly。
在本发明的第一方面的另一个实施方案中,氨基酸接头序列包括在每种新抗原之间或新抗原组之间。优选地,接头可以源自天然存在的多结构域蛋白或通过设计产生。接头包括柔性接头和/或可被细胞蛋白酶加工的体内可裂解的接头。
在本发明的第一方面的另一个优选实施方案中,T细胞增强子氨基酸序列选自恒定链;组织型纤溶酶原激活物(TPA)的前导序列;PEST序列;细胞周期蛋白破坏盒;泛素化信号;SUMO化信号。
优选的是,T细胞增强子氨基酸序列位于多肽内的N末端,更优选位于本发明多肽的N末端。
在本发明的第一方面的另一个优选的实施方案中,TPA是扩展的TPA前导序列,其包含TPA前导序列和紧接TPA前导序列C末端的两个至十个,优选四个至八个,更优选六个TPA残基。发明人发现,具有这些附加残基提高了正确切割前导序列的可靠性(正确的含义是在与野生型TPA相同的残基处切割掉前导序列)。发现仅引入前导序列可能导致在新抗原部分的内部切割,而这会切割掉新抗原序列的一部分。优选地,TPA存在于根据本发明第一方面的多肽的N末端。可以包括在本发明的多肽中的优选TPA具有根据SEQ ID NO:42的氨基酸序列。
在本发明的第一方面的另一个优选实施方案中,恒定链选自:
(a)根据SEQ ID NO:36的人恒定链,根据SEQ ID NO:37的小鼠恒定链和根据SEQID NO:38的鳜鱼恒定链;
(b)根据(a)所述的恒定链的免疫刺激片段;和/或
(c)(a)或(b)的免疫刺激变体,其中该变体与根据(a)的恒定链或根据(b)的其片段具有至少70%的序列同一性。
优选地,恒定链是根据SEQ ID NO:36的人恒定链。还优选地,恒定链是根据SEQ IDNO:37的小鼠恒定链。还优选地,恒定链是根据SEQ ID NO:38的鳜鱼恒定链。这样的恒定链在现有技术例如WO 2007/062656中进行了描述。
优选地,恒定链是根据SEQ ID NO:36的人恒定链的免疫刺激片段。更优选的是,恒定链是根据SEQ ID NO:37的小鼠恒定链的免疫刺激片段。更优选的是,恒定链是根据SEQID NO:38的鳜鱼恒定链。这样的片段已经在现有技术例如WO 2010/057501和WO 2015/082922中进行了描述。特别优选的片段包含或组成为SEQ ID NO:38的片段,特别是包含或组成为SEQ ID NO:39或40的氨基酸序列。
还优选恒定链是根据SEQ ID NO:36的人恒定链的免疫刺激变体,其中所述变体与根据SEQ ID NO:36的恒定链具有至少70%的序列同一性,更优选至少75%的序列同一性,更优选至少80%的序列同一性,更优选至少85%的序列同一性,更优选至少90%的序列同一性,甚至更优选至少95%的序列同一性。还优选恒定链是根据SEQ ID NO:37的小鼠恒定链的免疫刺激变体,其中所述变体与根据SEQ ID NO:37的恒定链具有至少70%的序列同一性,更优选至少75%的序列同一性,更优选至少80%的序列同一性,更优选至少85%的序列同一性,更优选至少90%的序列同一性,甚至更优选至少95%的序列同一性。还优选恒定链是根据SEQ ID NO:38的鳜鱼恒定链的免疫刺激变体,其中所述变体与根据SEQ ID NO:38的恒定链具有至少70%的序列同一性,更优选至少75%的序列同一性,更优选至少80%的序列同一性,更优选至少85%的序列同一性,更优选至少90%的序列同一性,甚至更优选至少95%的序列同一性。
在本发明的上下文中,术语恒定链的免疫刺激片段的“免疫刺激变体”是指在评估新抗原的免疫刺激活性的测定法中测量的活性(参见例如以下实施例)为针对未改变的恒定链或其片段所测量的活性的至少50%,优选至少60%,更优选至少70%,更优选至少80%,最优选等于或高于未改变的恒定链或其片段的免疫刺激活性。
更优选的是,多肽不包含MITD(I类MHC运输信号),因为MITD在表达后将所述多肽引导至内质网膜,这是不希望的。因此,甚至更优选地,多肽通常不包含在表达后将多肽引导至内质网膜的元件。在一个特定的实施方案中,多肽在C末端连接至本文定义的标签(表达控制序列)。在该实施方案中,优选标签在多肽的C末端(即,没有其他元件)。如果多肽不包含标签,则优选多肽的C末端是新抗原(即,不存在不是新抗原的其他元件)。
在第二方面,本发明涉及编码本发明第一方面的多肽的核酸。
在第三方面,本发明涉及包含与表达控制序列可操作地连接的本发明第二方面的核酸的载体。
在第七方面的表达载体集合的优选实施方案中,所述集合的每个表达载体独立地选自质粒;黏粒;RNA;与佐剂一起配制的RNA;配制在脂质体颗粒中的RNA;自扩增RNA(SAM);与佐剂一起配制的SAM;配制在脂质体颗粒中的SAM;病毒载体;优选α病毒载体、委内瑞拉马脑炎(VEE)病毒载体、辛德毕斯(SIN)病毒载体、塞姆利基森林病毒(SFV)载体,还优选有复制能力或无复制能力的腺病毒载体,优选衍生自黑猩猩或倭黑猩猩或大猩猩的腺病毒载体,牛痘病毒载体或经修饰的安卡拉牛痘病毒(MVA)载体、猿猴或人巨细胞病毒(CMV)载体、淋巴细胞脉络丛脑膜炎病毒(LCMV)载体、逆转录病毒载体或慢病毒载体。优选的是,在一个集合中使用的所有表达载体是相同类型的,例如无复制能力的腺病毒载体。
最优选的表达载体是腺病毒载体,特别是衍生自人或非人类人猿的腺病毒载体。优选的衍生出腺病毒的类人猿是黑猩猩(Pan)、大猩猩(Gorilla)和猩猩(Pongo),优选倭黑猩猩(Pan paniscus)和常见的黑猩猩(Pan troglodytes)。通常,天然存在的非人类人猿腺病毒从相应类人猿的粪便样品中分离。最优选的载体是基于hAd5、hAd11、hAd26、hAd35、hAd49、ChAd3、ChAd4、ChAd5、ChAd6、ChAd7、ChAd8、ChAd9、ChAd10、ChAd11、ChAd16、ChAd17、ChAd19、ChAd20、ChAd22、ChAd24、ChAd26、ChAd30、ChAd31、ChAd37、ChAd38、ChAd44、ChAd55、ChAd63、ChAd73、ChAd82、ChAd83、ChAd146、ChAd147、PanAd1、PanAd2和PanAd3载体的非复制型腺病毒载体或有复制能力的Ad4和Ad7载体。人腺病毒hAd4、hAd5、hAd7、hAd11、hAd26、hAd35和hAd49是本领域众所周知的。基于天然存在的ChAd3、ChAd4、ChAd5、ChAd6、ChAd7、ChAd8、ChAd9、ChAd10、ChAd11、ChAd16、ChAd17、ChAd19、ChAd20、ChAd22、ChAd24、ChAd26、ChAd30、ChAd31、ChAd37、ChAd38、ChAd44、ChAd63和ChAd82的载体在WO 2005/071093中详细描述。基于天然存在的PanAd1、PanAd2、PanAd3、ChAd55、ChAd73、ChAd83、ChAd146和ChAd147的载体在WO 2010/086189中详细描述。
在第四方面,本发明涉及一种或多于一种表达载体的集合,每种表达载体包含根据权利要求11的核酸,其中每种表达载体选自质粒;黏粒;RNA;与佐剂一起配制的RNA;配制在脂质体颗粒中的RNA;自扩增RNA(SAM);与佐剂一起配制的SAM;配制在脂质体颗粒中的SAM;病毒载体;优选α病毒载体、委内瑞拉马脑炎(VEE)病毒载体、辛德毕斯(SIN)病毒载体、塞姆利基森林病毒(SFV)载体、猿猴或人巨细胞病毒(CMV)载体、淋巴细胞脉络丛脑膜炎病毒(LCMV)载体、逆转录病毒载体或慢病毒载体。优选为有复制能力或无复制能力的类人猿衍生的腺病毒载体,优选衍生自黑猩猩或倭黑猩猩或大猩猩的腺病毒载体,痘病毒载体,牛痘病毒载体或经修饰的安卡拉牛痘病毒(MVA)载体。
在第五方面,本发明涉及包含疫苗和检查点分子的至少一种调节剂或编码所述调节剂的核酸或包含编码所述调节剂的核酸的载体的组合物,该疫苗包含第一方面的多肽、本发明第二方面的核酸、本发明第三方面要求保护的载体或本发明第四方面的载体集合,该组合物用于预防或治疗对象的增殖性疾病。
在第五方面的一个优选实施方案中,检查点分子的调节剂选自:
(a)肿瘤坏死因子(TNF)受体超家族成员的激动剂,优选CD27(例如Varlilumab)、CD40(例如CP-870、893)、OX40(例如INCAGN01949或MEDI0562)、GITR(例如MEDI1873)或CD137(例如乌托米单抗(Utomilumab))的激动剂;
(b)PD-1(例如抗体,如派姆单抗或纳武单抗)、PD-L1(例如抗体,如阿特珠单抗)、CD274(阿特珠单抗或德瓦鲁单抗),A2AR(例如Preladenant)、B7-H3(例如MGA271)、B7-H4、BTLA、CTLA-4(例如曲美木单抗或AGEN1884)、IDO、KIR、LAG3、TIM-3(例如CA-327或RMT3-23)或VISTA(例如CA-170)的拮抗剂或B7-CD28超家族成员的拮抗剂,优选CD28或ICOS的拮抗剂或其配体的拮抗剂。
优选的免疫调节剂是T细胞生长因子,例如IL-2、IL-12或IL-15。
在本发明的第五方面的一个优选实施方案中,在开始施用疫苗之前开始检查点分子的调节剂的施用,或者其中在开始施用疫苗之后开始检查点抑制剂的施用,或者其中在开始施用疫苗的同时开始检查点抑制剂的施用。
在本发明的第五方面的一个优选实施方案中,疫苗接种方案是用两种不同病毒载体进行异源性初免加强免疫(prime boost)。优选的组合是用于初免的类人猿衍生的腺病毒载体和用于加强免疫的痘病毒载体、牛痘病毒载体或经修饰的安卡拉牛痘病毒(MVA)载体。优选地,这些病毒载体以至少1周,优选6周的间隔顺序施用。
在本发明的第五方面的一个优选实施方案中,所述对象患有以下疾病或具有患以下疾病的风险:
(a)唇、口腔和咽部的恶性肿瘤;和/或
(b)消化器官恶性肿瘤;和/或
(c)呼吸和胸内器官的恶性肿瘤;和/或
(d)骨和关节软骨的恶性肿瘤;和/或
(e)黑色素瘤和皮肤的其他恶性肿瘤;和/或
(f)间皮和软组织的恶性肿瘤;和/或
(g)乳腺恶性肿瘤;和/或
(h)女性生殖器官的恶性肿瘤;和/或
(i)男性生殖器官的恶性肿瘤;和/或
(j)尿路恶性肿瘤;和/或
(k)眼、脑和中枢神经系统其他部位的恶性肿瘤;和/或
(l)甲状腺和其他内分泌腺的恶性肿瘤;和/或
(m)淋巴、造血及相关组织的恶性肿瘤。
通常,优选的是,对象具有处于如上所述的TNM分期的肿瘤。
在一个优选的实施方案中,所述肿瘤的特征在于病灶直径为至少约3mm,优选直径为至少7mm,更优选直径为至少1.5cm。
在第六方面,本发明涉及一种疫苗接种试剂盒,其以独立的包装包括:
(i)疫苗,其包含本发明第一方面的多肽、本发明第二方面的核酸、本发明第三方面的载体或根据本发明第四方面的载体的集合;和
(ii)至少一种检查点分子的调节剂或编码该调节剂的核酸或包含编码该调节剂的核酸的载体。
实施例
实施例1:新抗原与恒定链或TPA序列的融合在GAd疫苗接种的情况下恢复免疫原性
编码含有衍生自CT26鼠肿瘤的五种新抗原的五表位序列(pentatope,该序列后接起始甲硫氨酸)(CT26-5;SEQ ID NO:32)的类人猿腺病毒载体不能诱导针对癌症抗原的免疫应答,除非将INV序列置于新抗原的N末端(CT26-5 INV;SEQ ID NO:33)。也可以通过将TPA序列的N末端与编码5种新抗原的序列融合(CT26-5TPA;SEQ ID NO:3)来获得恢复免疫原性的能力。
选定的新抗原由5个非同义单核苷酸变体(SNV)生成,这是在肿瘤中发现的最常见的突变类型。每种新抗原的氨基酸序列的突变氨基酸位于其中心,在上游和下游侧接12个野生型(wt)氨基酸,全长为25个氨基酸(表1)。新抗原序列首尾相连以形成与监测其表达的HA肽序列在下游融合的人工抗原(SEQ ID NO:41)。
对于3种疫苗中的每一种,以5×108GAd病毒颗粒(vp)的剂量进行单次肌内免疫后,对BalBC近交小鼠的免疫能力进行了评估。免疫后三周收集脾细胞,并在对应于5种新抗原的每一种的合成肽池的存在下刺激细胞,通过IFN-γELISpot进行测试。免疫应答(每百万个脾细胞产生IFN-γ的T细胞数)如图1所示。如果(i)抗原孔的平均值大于20个点形成菌落SFC/106PBMC,并且(ii)超过用肽稀释剂DMSO孵育的孔的背景值的3倍,则认为应答为阳性。如图1所示,在接种疫苗的动物中,添加INV或TPA均可将非免疫原性CT26-5抗原转化为免疫原性抗原,应答率为100%。
实施例2:在积极的治疗情况下,需要大量新抗原以获得疫苗和抗PD-1之间的协同活性
构建了第二类人猿腺病毒载体(GAd-CT26-31 TPA),该载体对应于编码具有N末端TPA序列的31种新抗原的更长的构建体(CT26-31 TPA,SEQ ID 35)。使用的优选TPA序列为SEQ ID NO:42的氨基酸序列。产生新抗原的选定突变为31个非同义SNV(表2),其中3个也存在于编码较短的CT26-5 TPA构建体的GAd-CT26-5 TPA载体中(表1)。在31种新抗原的每一种的氨基酸序列的中心处存在突变的氨基酸,在中心的上游和下游都侧接12个野生型氨基酸,使其全长为25个氨基酸(表1)。例外是新抗原ID 6(表2)和新抗原SEQ ID ID:16(表2),新抗原ID 6中对应于突变蛋白的N末端仅存在6个上游野生型氨基酸,新抗原SEQ ID ID:16中由在上游氨基酸区段中存在的附加SNV而产生附加突变(表2)。新抗原的氨基酸序列按表2所示的顺序头尾连接,并且为了监控表达而在组装的新抗原的C末端添加了HA肽序列(SEQID NO:41)。
GAd-CT26-5 TPA(短构建体)和GAd-CT26-31 TPA(长构建体)的免疫原性通过肌内注射一次5×108病毒颗粒(vp)的剂量来体内免疫初始BalbC小鼠而进行确定。免疫后3周,通过用于识别对应于疫苗构建体编码的突变的25聚体序列的单个肽的INFγELISpot来测量T细胞应答。较小的构建体(CT26-5 TPA)仅诱导针对3种新抗原的T细胞应答。相反,用CT26-31 TPA疫苗接种诱导了针对31种新抗原中的8种的T细胞应答(图2),包括与CT26-5构建体相同的3种新抗原。
为了确定疫苗中存在的免疫原性新抗原的总数是否代表关键因素,发明人评估了两种构建体在预防情况和积极治疗情况下的疫苗接种疗效。在预防情况下,发明人首先在肌内接种GAd-CT26-31 TPA或GAd-CT26-5 TPA(5×108vp/小鼠)一次,随后在接种后15天接种肿瘤细胞(每只小鼠2×106个细胞)。无论所用构建体类型如何,所有接种疫苗的小鼠(100%)均无肿瘤,而所有接种模拟疫苗的对照小鼠在4周后由于存在非常大的肿瘤而被处死。
为了模拟治疗情况,向BALB/c小鼠移植了CT26肿瘤细胞(每只小鼠2×106个细胞)。随时间推移测量肿瘤块,并在肿瘤块可见并达到平均体积70mm3时开始处理。然后,通过对既定肿瘤肌内注射单剂量的GAd-CT26-31 TPA或GAd-CT26-5 TPA疫苗(5×108vp),并腹膜内注射抗PD1抗体的初步处理,来评估只有GAd-CT26-31 TPA和GAd-CT26-5 TPA或其与抗PD1抗体(克隆RMP1-14,Bioxcell)联合处理的治疗效果。然后将抗PD-1抗体治疗持续2周(第3、6、9、13或16天)。
结果表明,无抗PD1抗体的GAd-CT26-31 TPA和GAd-CT26-5 TPA疫苗接种治疗在这种情况下是无效的,并且所有小鼠因为像未经治疗的小鼠一样存在很大的肿瘤,均在4周后被处死。因此,两种疫苗在单独使用时均无法治愈动物,这与预防情况不同。抗PD-1单一疗法或抗PD-1疗法与GAd-CT26-5 TPA疫苗接种的组合仅在15%的治疗小鼠中引起肿瘤缩小。相较而言,抗PD-1治疗与编码长构建体的GAd-CT26-31 TPA疫苗接种的组合在48%的治疗动物中提供了肿瘤缩小和完全治愈的显著抗癌活性。表3中汇总了数据,表明PD-1单一疗法或PD-1/GAd-CT26-5 TPA组合相对于PD-1/GAd-CT26-31 TPA组合的差异具有统计学显著性。这些结果证明,如果基因疫苗编码大量新抗原并且如果与免疫调节分子治疗相组合,则其能够根除已建立的肿瘤。
实施例3:三种不同情况下疫苗接种疗效的比较。
为了解决疫苗中新抗原的数量对于确定疫苗接种方案的有效是否重要的问题,发明人在三种不同的情况下评估了疫苗接种的疗效:1)预防情况;2)肺癌转移模型中的早期干预,和3)大型既定皮下肿瘤的晚期治疗情况。
在预防干预中,首先用5×10^8vp剂量的GAd-CT26-31或GAd-CT26-5免疫小鼠,两周后用CT26肿瘤细胞攻击小鼠,以评估疫苗接种的预防值。结果是无论所用构建体的类型如何,100%的疫苗接种小鼠未患肿瘤,而所有未治疗的小鼠均发展出大肿瘤(图3)。
同样,在早期治疗情况(模拟微小残留病)下,GAd-CT26-31和GAd-CT26-5在根除CT26细胞的肺转移方面同样有效(通过肺结节的数量进行测量),因为疫苗递送时肿瘤块尚未形成。静脉注射肿瘤细胞后3天进行疫苗接种(剂量为5×10^8vp)(图4)。
当对携带大型既定皮下肿瘤的小鼠接种GAd-CT26-31 TPA疫苗时,未观察到抗肿瘤活性(图5A)。对于抗PD-1单一疗法或抗PD-1疗法与GAd-CT26-5TPA的组合,观察到部分应答(图5b)。相反,PD1阻断剂与大构建体GAd-CT26-31 TPA的组合提供了显著的抗癌活性,在48%的治疗动物中产生肿瘤缩小和完全治愈(图5B)。与在预防情况下单独接种GAd-CT26-31 TPA相比,GAd-CT26-31 TPA和抗PD1的共同治疗诱导了对31种新抗原中的8种的T细胞应答(图2)。
实施例4:个性化疫苗的疗效取决于CD8+ T细胞应答
为了研究CD4+ T细胞和CD8+ T细胞对GAd-CT26-31 TPA的治疗性抗肿瘤作用的贡献,通过在治疗开始后一周注射(200μg)特异性抗体(α-mCD8,BioXcell克隆YTS169.4;α-mCD4,BioXcell克隆YTS191)将CD4+或CD8+ T细胞耗尽。CD8+ T细胞的耗尽完全失去了抗肿瘤作用(图8),这突出表明了CD8+ T细胞的重要作用。相反,CD4+ T细胞的耗尽并不影响治疗疗效(图7)。将CD8+ T细胞应答鉴定为疗效的调节因子也符合腺病毒载体产生强CD8+ T细胞应答的已知特性。
实施例5:组合的个性化疫苗和抗PD1治疗的疗效与肿瘤中TCR克隆性的增加相关
提取来自仅用抗PD1治疗或用抗PD-1治疗与GAd-CT26-31 TPA联合治疗的小鼠的CT26肿瘤的RNA,并进行RNA测序分析。应用手册的RNA测序工作流程报告的标准参数(https://mixcr.readthedocs.io/en/master/rnaseq.html)使用MIXCR工具根据RNA测序数据来评估T细胞受体(TCR)β的克隆性。使用R软件包tcR(https://cran.r-project.org/web/packages/tcR/vignettes/tcrvignette.html)进一步分析MIXCR产生的原始输出(序列和检测到的TCR克隆型的表达),以重建CDR3序列并获得总结统计。如图8所示,与单独的抗PD1治疗相比,用抗PD-1和GAd-CT26-5 TPA联合治疗导致肿瘤中存在明显更高数量的不同TCR克隆(克隆型)。
表1
CT26-5各个新抗原:突变的氨基酸以粗体和下划线标出
表2
CT26-31中存在的各个新抗原:突变的氨基酸以粗体和下划线标出
表3
序列表
<110> NOUSCOM股份公司
<120> 用于治疗癌症的新抗原疫苗组合物
<130> 854-20 PCT
<150> 17181026.0
<151> 2017-07-12
<150> 17200036.6
<151> 2017-11-03
<160> 44
<170> SIPOSequenceListing 1.0
<210> 1
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Pro Gly Pro Gln Asn Phe Pro Pro Gln Asn Met Phe Glu Phe Pro Pro
1 5 10 15
His Leu Ser Pro Pro Leu Leu Pro Pro
20 25
<210> 2
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Gly Ala Gln Glu Glu Pro Gln Val Glu Pro Leu Asp Phe Ser Leu Pro
1 5 10 15
Lys Gln Gln Gly Glu Leu Leu Glu Arg
20 25
<210> 3
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 3
Ala Val Phe Ala Gly Ser Asp Asp Pro Phe Ala Thr Pro Leu Ser Met
1 5 10 15
Ser Glu Met Asp Arg Arg Asn Asp Ala
20 25
<210> 4
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
His Ser Gly Gln Asn His Leu Lys Glu Met Ala Ile Ser Val Leu Glu
1 5 10 15
Ala Arg Ala Cys Ala Ala Ala Gly Gln
20 25
<210> 5
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Ile Leu Pro Gln Ala Pro Ser Gly Pro Ser Tyr Ala Thr Tyr Leu Gln
1 5 10 15
Pro Ala Gln Ala Gln Met Leu Thr Pro
20 25
<210> 6
<211> 19
<212> PRT
<213> 智人(Homo sapiens)
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Met Ser Tyr Ala Glu Lys Ser Asp Glu Ile Thr Lys Asp Glu Trp Met
1 5 10 15
Glu Lys Leu
<210> 7
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 7
Gly Ala Gly Lys Gly Lys Tyr Tyr Ala Val Asn Phe Ser Met Arg Asp
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Gly Ile Asp Asp Glu Ser Tyr Gly Gln
20 25
<210> 8
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 8
Tyr Arg Gly Ala Asp Lys Leu Cys Arg Lys Ala Ser Ser Val Lys Leu
1 5 10 15
Val Lys Thr Ser Pro Glu Leu Ser Glu
20 25
<210> 9
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Asp Ser Asn Leu Gln Ala Arg Leu Thr Ser Tyr Glu Thr Leu Lys Lys
1 5 10 15
Ser Leu Ser Lys Ile Arg Glu Glu Ser
20 25
<210> 10
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
His Ser Phe Ile His Ala Ala Met Gly Met Ala Val Thr Trp Cys Ala
1 5 10 15
Ala Ile Met Thr Lys Gly Gln Tyr Ser
20 25
<210> 11
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 11
Leu Arg Thr Ala Ala Tyr Val Asn Ala Ile Glu Lys Ile Phe Lys Val
1 5 10 15
Tyr Asn Glu Ala Gly Val Thr Phe Thr
20 25
<210> 12
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 12
Phe Glu Gly Ser Leu Ala Lys Asn Leu Ser Leu Asn Phe Gln Ala Val
1 5 10 15
Lys Glu Asn Leu Tyr Tyr Glu Val Gly
20 25
<210> 13
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 13
Asp Pro Arg Ala Ala Tyr Phe Arg Gln Ala Glu Asn Asp Met Tyr Ile
1 5 10 15
Arg Met Ala Leu Leu Ala Thr Val Leu
20 25
<210> 14
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 14
Leu Arg Ser Gln Met Val Met Lys Met Arg Glu Tyr Phe Cys Asn Leu
1 5 10 15
His Gly Phe Val Asp Ile Glu Thr Pro
20 25
<210> 15
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 15
Asp Leu Leu Ala Phe Glu Arg Lys Leu Asp Gln Thr Val Met Arg Lys
1 5 10 15
Arg Leu Asp Ile Gln Glu Ala Leu Lys
20 25
<210> 16
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 16
Ile Lys Arg Glu Lys Cys Trp Lys Asp Ala Thr Tyr Pro Glu Ser Phe
1 5 10 15
His Thr Leu Glu Ser Val Pro Ala Thr
20 25
<210> 17
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 17
Gly Arg Ser Ser Gln Val Tyr Phe Thr Ile Asn Val Asn Leu Asp Leu
1 5 10 15
Ser Glu Ala Ala Val Val Thr Phe Ser
20 25
<210> 18
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 18
Lys Pro Leu Arg Arg Asn Asn Ser Tyr Thr Ser Tyr Ile Met Ala Ile
1 5 10 15
Cys Gly Met Pro Leu Asp Ser Phe Arg
20 25
<210> 19
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 19
Thr Thr Cys Leu Ala Val Gly Gly Leu Asp Val Lys Phe Gln Glu Ala
1 5 10 15
Ala Leu Arg Ala Ala Pro Asp Ile Leu
20 25
<210> 20
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 20
Ile Tyr Glu Phe Asp Tyr His Leu Tyr Gly Gln Asn Ile Thr Met Ile
1 5 10 15
Met Thr Ser Val Ser Gly His Leu Leu
20 25
<210> 21
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 21
Pro Asp Ser Phe Ser Ile Pro Tyr Leu Thr Ala Leu Asp Asp Leu Leu
1 5 10 15
Gly Thr Ala Leu Leu Ala Leu Ser Phe
20 25
<210> 22
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 22
Tyr Ala Thr Ile Leu Glu Met Gln Ala Met Met Thr Leu Asp Pro Gln
1 5 10 15
Asp Ile Leu Leu Ala Gly Asn Met Met
20 25
<210> 23
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 23
Ser Trp Ile His Cys Trp Lys Tyr Leu Ser Val Gln Ser Gln Leu Phe
1 5 10 15
Arg Gly Ser Ser Leu Leu Phe Arg Arg
20 25
<210> 24
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 24
Tyr Asp Asn Lys Gly Ile Thr Tyr Leu Phe Asp Leu Tyr Tyr Glu Ser
1 5 10 15
Asp Glu Phe Thr Val Asp Ala Ala Arg
20 25
<210> 25
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 25
Ala Gln Ala Ala Lys Asn Lys Gly Asn Lys Tyr Phe Gln Ala Gly Lys
1 5 10 15
Tyr Glu Gln Ala Ile Gln Cys Tyr Thr
20 25
<210> 26
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 26
Gln Pro Met Leu Pro Ile Gly Leu Ser Asp Ile Pro Asp Glu Ala Met
1 5 10 15
Val Lys Leu Tyr Cys Pro Lys Cys Met
20 25
<210> 27
<211> 23
<212> PRT
<213> 智人(Homo sapiens)
<400> 27
His Arg Gly Ala Ile Tyr Gly Ser Ser Trp Lys Tyr Phe Thr Phe Ser
1 5 10 15
Gly Tyr Leu Leu Tyr Gln Asp
20
<210> 28
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 28
Val Ile Gln Thr Ser Lys Tyr Tyr Met Arg Asp Val Ile Ala Ile Glu
1 5 10 15
Ser Ala Trp Leu Leu Glu Leu Ala Pro
20 25
<210> 29
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 29
Pro Arg Gly Val Asp Leu Tyr Leu Arg Ile Leu Met Pro Ile Asp Ser
1 5 10 15
Glu Leu Val Asp Arg Asp Val Val His
20 25
<210> 30
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 30
Gln Ile Glu Gln Asp Ala Leu Cys Pro Gln Asp Thr Tyr Cys Asp Leu
1 5 10 15
Lys Ser Arg Ala Glu Val Asn Gly Ala
20 25
<210> 31
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 31
Ala Leu Ala Ser Ala Ile Leu Ser Asp Pro Glu Ser Tyr Ile Lys Lys
1 5 10 15
Leu Lys Glu Leu Arg Ser Met Leu Met
20 25
<210> 32
<211> 137
<212> PRT
<213> 智人(Homo sapiens)
<400> 32
Met Leu Leu Pro Phe Tyr Pro Pro Asp Glu Ala Leu Glu Ile Gly Leu
1 5 10 15
Glu Leu Asn Ser Ser Ala Leu Pro Pro Thr Ile Leu Pro Gln Ala Pro
20 25 30
Ser Gly Pro Ser Tyr Ala Thr Tyr Leu Gln Pro Ala Gln Ala Gln Met
35 40 45
Leu Thr Pro Lys Pro Leu Arg Arg Asn Asn Ser Tyr Thr Ser Tyr Ile
50 55 60
Met Ala Ile Cys Gly Met Pro Leu Asp Ser Phe Arg Val Ile Gln Thr
65 70 75 80
Ser Lys Tyr Tyr Met Arg Asp Val Ile Ala Ile Glu Ser Ala Trp Leu
85 90 95
Leu Glu Leu Ala Pro His Ile His Arg Ala Gly Gly Leu Phe Val Ala
100 105 110
Asp Ala Ile Gln Val Gly Phe Gly Arg Ile Gly Lys His Phe Gly Tyr
115 120 125
Pro Tyr Asp Val Pro Asp Tyr Ala Ser
130 135
<210> 33
<211> 368
<212> PRT
<213> 智人(Homo sapiens)
<400> 33
Met His Arg Arg Arg Ser Arg Ser Cys Arg Glu Asp Gln Lys Pro Val
1 5 10 15
Met Asp Asp Gln Arg Asp Leu Ile Ser Asn Asn Glu Gln Leu Pro Met
20 25 30
Leu Gly Arg Arg Pro Gly Ala Pro Glu Ser Lys Cys Ser Arg Gly Ala
35 40 45
Leu Tyr Thr Gly Phe Ser Ile Leu Val Thr Leu Leu Leu Ala Gly Gln
50 55 60
Ala Thr Thr Ala Tyr Phe Leu Tyr Gln Gln Gln Gly Arg Leu Asp Lys
65 70 75 80
Leu Thr Val Thr Ser Gln Asn Leu Gln Leu Glu Asn Leu Arg Met Lys
85 90 95
Leu Pro Lys Pro Pro Lys Pro Val Ser Lys Met Arg Met Ala Thr Pro
100 105 110
Leu Leu Met Gln Ala Leu Pro Met Gly Ala Leu Pro Gln Gly Pro Met
115 120 125
Gln Asn Ala Thr Lys Tyr Gly Asn Met Thr Glu Asp His Val Met His
130 135 140
Leu Leu Gln Asn Ala Asp Pro Leu Lys Val Tyr Pro Pro Leu Lys Gly
145 150 155 160
Ser Phe Pro Glu Asn Leu Arg His Leu Lys Asn Thr Met Glu Thr Ile
165 170 175
Asp Trp Lys Val Phe Glu Ser Trp Met His His Trp Leu Leu Phe Glu
180 185 190
Met Ser Arg His Ser Leu Glu Gln Lys Pro Thr Asp Ala Pro Pro Lys
195 200 205
Glu Ser Leu Glu Leu Glu Asp Pro Ser Ser Gly Leu Gly Val Thr Lys
210 215 220
Gln Asp Leu Gly Pro Val Pro Met Leu Leu Pro Phe Tyr Pro Pro Asp
225 230 235 240
Glu Ala Leu Glu Ile Gly Leu Glu Leu Asn Ser Ser Ala Leu Pro Pro
245 250 255
Thr Ile Leu Pro Gln Ala Pro Ser Gly Pro Ser Tyr Ala Thr Tyr Leu
260 265 270
Gln Pro Ala Gln Ala Gln Met Leu Thr Pro Lys Pro Leu Arg Arg Asn
275 280 285
Asn Ser Tyr Thr Ser Tyr Ile Met Ala Ile Cys Gly Met Pro Leu Asp
290 295 300
Ser Phe Arg Val Ile Gln Thr Ser Lys Tyr Tyr Met Arg Asp Val Ile
305 310 315 320
Ala Ile Glu Ser Ala Trp Leu Leu Glu Leu Ala Pro His Ile His Arg
325 330 335
Ala Gly Gly Leu Phe Val Ala Asp Ala Ile Gln Val Gly Phe Gly Arg
340 345 350
Ile Gly Lys His Phe Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser
355 360 365
<210> 34
<211> 165
<212> PRT
<213> 智人(Homo sapiens)
<400> 34
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Gln Glu Ile His Ala Arg Leu Leu Pro
20 25 30
Phe Tyr Pro Pro Asp Glu Ala Leu Glu Ile Gly Leu Glu Leu Asn Ser
35 40 45
Ser Ala Leu Pro Pro Thr Ile Leu Pro Gln Ala Pro Ser Gly Pro Ser
50 55 60
Tyr Ala Thr Tyr Leu Gln Pro Ala Gln Ala Gln Met Leu Thr Pro Lys
65 70 75 80
Pro Leu Arg Arg Asn Asn Ser Tyr Thr Ser Tyr Ile Met Ala Ile Cys
85 90 95
Gly Met Pro Leu Asp Ser Phe Arg Val Ile Gln Thr Ser Lys Tyr Tyr
100 105 110
Met Arg Asp Val Ile Ala Ile Glu Ser Ala Trp Leu Leu Glu Leu Ala
115 120 125
Pro His Ile His Arg Ala Gly Gly Leu Phe Val Ala Asp Ala Ile Gln
130 135 140
Val Gly Phe Gly Arg Ile Gly Lys His Phe Gly Tyr Pro Tyr Asp Val
145 150 155 160
Pro Asp Tyr Ala Ser
165
<210> 35
<211> 807
<212> PRT
<213> 智人(Homo sapiens)
<400> 35
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Gln Glu Ile His Ala Arg Pro Gly Pro
20 25 30
Gln Asn Phe Pro Pro Gln Asn Met Phe Glu Phe Pro Pro His Leu Ser
35 40 45
Pro Pro Leu Leu Pro Pro Gly Ala Gln Glu Glu Pro Gln Val Glu Pro
50 55 60
Leu Asp Phe Ser Leu Pro Lys Gln Gln Gly Glu Leu Leu Glu Arg Ala
65 70 75 80
Val Phe Ala Gly Ser Asp Asp Pro Phe Ala Thr Pro Leu Ser Met Ser
85 90 95
Glu Met Asp Arg Arg Asn Asp Ala His Ser Gly Gln Asn His Leu Lys
100 105 110
Glu Met Ala Ile Ser Val Leu Glu Ala Arg Ala Cys Ala Ala Ala Gly
115 120 125
Gln Ile Leu Pro Gln Ala Pro Ser Gly Pro Ser Tyr Ala Thr Tyr Leu
130 135 140
Gln Pro Ala Gln Ala Gln Met Leu Thr Pro Met Ser Tyr Ala Glu Lys
145 150 155 160
Ser Asp Glu Ile Thr Lys Asp Glu Trp Met Glu Lys Leu Gly Ala Gly
165 170 175
Lys Gly Lys Tyr Tyr Ala Val Asn Phe Ser Met Arg Asp Gly Ile Asp
180 185 190
Asp Glu Ser Tyr Gly Gln Tyr Arg Gly Ala Asp Lys Leu Cys Arg Lys
195 200 205
Ala Ser Ser Val Lys Leu Val Lys Thr Ser Pro Glu Leu Ser Glu Asp
210 215 220
Ser Asn Leu Gln Ala Arg Leu Thr Ser Tyr Glu Thr Leu Lys Lys Ser
225 230 235 240
Leu Ser Lys Ile Arg Glu Glu Ser His Ser Phe Ile His Ala Ala Met
245 250 255
Gly Met Ala Val Thr Trp Cys Ala Ala Ile Met Thr Lys Gly Gln Tyr
260 265 270
Ser Leu Arg Thr Ala Ala Tyr Val Asn Ala Ile Glu Lys Ile Phe Lys
275 280 285
Val Tyr Asn Glu Ala Gly Val Thr Phe Thr Phe Glu Gly Ser Leu Ala
290 295 300
Lys Asn Leu Ser Leu Asn Phe Gln Ala Val Lys Glu Asn Leu Tyr Tyr
305 310 315 320
Glu Val Gly Asp Pro Arg Ala Ala Tyr Phe Arg Gln Ala Glu Asn Asp
325 330 335
Met Tyr Ile Arg Met Ala Leu Leu Ala Thr Val Leu Leu Arg Ser Gln
340 345 350
Met Val Met Lys Met Arg Glu Tyr Phe Cys Asn Leu His Gly Phe Val
355 360 365
Asp Ile Glu Thr Pro Asp Leu Leu Ala Phe Glu Arg Lys Leu Asp Gln
370 375 380
Thr Val Met Arg Lys Arg Leu Asp Ile Gln Glu Ala Leu Lys Ile Lys
385 390 395 400
Arg Glu Lys Cys Trp Lys Asp Ala Thr Tyr Pro Glu Ser Phe His Thr
405 410 415
Leu Glu Ser Val Pro Ala Thr Gly Arg Ser Ser Gln Val Tyr Phe Thr
420 425 430
Ile Asn Val Asn Leu Asp Leu Ser Glu Ala Ala Val Val Thr Phe Ser
435 440 445
Lys Pro Leu Arg Arg Asn Asn Ser Tyr Thr Ser Tyr Ile Met Ala Ile
450 455 460
Cys Gly Met Pro Leu Asp Ser Phe Arg Thr Thr Cys Leu Ala Val Gly
465 470 475 480
Gly Leu Asp Val Lys Phe Gln Glu Ala Ala Leu Arg Ala Ala Pro Asp
485 490 495
Ile Leu Ile Tyr Glu Phe Asp Tyr His Leu Tyr Gly Gln Asn Ile Thr
500 505 510
Met Ile Met Thr Ser Val Ser Gly His Leu Leu Pro Asp Ser Phe Ser
515 520 525
Ile Pro Tyr Leu Thr Ala Leu Asp Asp Leu Leu Gly Thr Ala Leu Leu
530 535 540
Ala Leu Ser Phe Tyr Ala Thr Ile Leu Glu Met Gln Ala Met Met Thr
545 550 555 560
Leu Asp Pro Gln Asp Ile Leu Leu Ala Gly Asn Met Met Ser Trp Ile
565 570 575
His Cys Trp Lys Tyr Leu Ser Val Gln Ser Gln Leu Phe Arg Gly Ser
580 585 590
Ser Leu Leu Phe Arg Arg Tyr Asp Asn Lys Gly Ile Thr Tyr Leu Phe
595 600 605
Asp Leu Tyr Tyr Glu Ser Asp Glu Phe Thr Val Asp Ala Ala Arg Ala
610 615 620
Gln Ala Ala Lys Asn Lys Gly Asn Lys Tyr Phe Gln Ala Gly Lys Tyr
625 630 635 640
Glu Gln Ala Ile Gln Cys Tyr Thr Gln Pro Met Leu Pro Ile Gly Leu
645 650 655
Ser Asp Ile Pro Asp Glu Ala Met Val Lys Leu Tyr Cys Pro Lys Cys
660 665 670
Met His Arg Gly Ala Ile Tyr Gly Ser Ser Trp Lys Tyr Phe Thr Phe
675 680 685
Ser Gly Tyr Leu Leu Tyr Gln Asp Val Ile Gln Thr Ser Lys Tyr Tyr
690 695 700
Met Arg Asp Val Ile Ala Ile Glu Ser Ala Trp Leu Leu Glu Leu Ala
705 710 715 720
Pro Pro Arg Gly Val Asp Leu Tyr Leu Arg Ile Leu Met Pro Ile Asp
725 730 735
Ser Glu Leu Val Asp Arg Asp Val Val His Gln Ile Glu Gln Asp Ala
740 745 750
Leu Cys Pro Gln Asp Thr Tyr Cys Asp Leu Lys Ser Arg Ala Glu Val
755 760 765
Asn Gly Ala Ala Leu Ala Ser Ala Ile Leu Ser Asp Pro Glu Ser Tyr
770 775 780
Ile Lys Lys Leu Lys Glu Leu Arg Ser Met Leu Met Gly Tyr Pro Tyr
785 790 795 800
Asp Val Pro Asp Tyr Ala Ser
805
<210> 36
<211> 232
<212> PRT
<213> 智人(Homo sapiens)
<400> 36
Met His Arg Arg Arg Ser Arg Ser Cys Arg Glu Asp Gln Lys Pro Val
1 5 10 15
Met Asp Asp Gln Arg Asp Leu Ile Ser Asn Asn Glu Gln Leu Pro Met
20 25 30
Leu Gly Arg Arg Pro Gly Ala Pro Glu Ser Lys Cys Ser Arg Gly Ala
35 40 45
Leu Tyr Thr Gly Phe Ser Ile Leu Val Thr Leu Leu Leu Ala Gly Gln
50 55 60
Ala Thr Thr Ala Tyr Phe Leu Tyr Gln Gln Gln Gly Arg Leu Asp Lys
65 70 75 80
Leu Thr Val Thr Ser Gln Asn Leu Gln Leu Glu Asn Leu Arg Met Lys
85 90 95
Leu Pro Lys Pro Pro Lys Pro Val Ser Lys Met Arg Met Ala Thr Pro
100 105 110
Leu Leu Met Gln Ala Leu Pro Met Gly Ala Leu Pro Gln Gly Pro Met
115 120 125
Gln Asn Ala Thr Lys Tyr Gly Asn Met Thr Glu Asp His Val Met His
130 135 140
Leu Leu Gln Asn Ala Asp Pro Leu Lys Val Tyr Pro Pro Leu Lys Gly
145 150 155 160
Ser Phe Pro Glu Asn Leu Arg His Leu Lys Asn Thr Met Glu Thr Ile
165 170 175
Asp Trp Lys Val Phe Glu Ser Trp Met His His Trp Leu Leu Phe Glu
180 185 190
Met Ser Arg His Ser Leu Glu Gln Lys Pro Thr Asp Ala Pro Pro Lys
195 200 205
Glu Ser Leu Glu Leu Glu Asp Pro Ser Ser Gly Leu Gly Val Thr Lys
210 215 220
Gln Asp Leu Gly Pro Val Pro Met
225 230
<210> 37
<211> 215
<212> PRT
<213> 智人(Homo sapiens)
<400> 37
Met Asp Asp Gln Arg Asp Leu Ile Ser Asn His Glu Gln Leu Pro Ile
1 5 10 15
Leu Gly Asn Arg Pro Arg Glu Pro Glu Arg Cys Ser Arg Gly Ala Leu
20 25 30
Tyr Thr Gly Val Ser Val Leu Val Ala Leu Leu Leu Ala Gly Gln Ala
35 40 45
Thr Thr Ala Tyr Phe Leu Tyr Gln Gln Gln Gly Arg Leu Asp Lys Leu
50 55 60
Thr Ile Thr Ser Gln Asn Leu Gln Leu Glu Ser Leu Arg Met Lys Leu
65 70 75 80
Pro Lys Ser Ala Lys Pro Val Ser Gln Met Arg Met Ala Thr Pro Leu
85 90 95
Leu Met Arg Pro Met Ser Met Asp Asn Met Leu Leu Gly Pro Val Lys
100 105 110
Asn Val Thr Lys Tyr Gly Asn Met Thr Gln Asp His Val Met His Leu
115 120 125
Leu Thr Arg Ser Gly Pro Leu Glu Tyr Pro Gln Leu Lys Gly Thr Phe
130 135 140
Pro Glu Asn Leu Lys His Leu Lys Asn Ser Met Asp Gly Val Asn Trp
145 150 155 160
Lys Ile Phe Glu Ser Trp Met Lys Gln Trp Leu Leu Phe Glu Met Ser
165 170 175
Lys Asn Ser Leu Glu Glu Lys Lys Pro Thr Glu Ala Pro Pro Lys Glu
180 185 190
Pro Leu Asp Met Glu Asp Leu Ser Ser Gly Leu Gly Val Thr Arg Gln
195 200 205
Glu Leu Gly Gln Val Thr Leu
210 215
<210> 38
<211> 281
<212> PRT
<213> 智人(Homo sapiens)
<400> 38
Met Ala Asp Ser Ala Glu Asp Ala Pro Met Ala Arg Gly Ser Leu Ala
1 5 10 15
Gly Ser Asp Glu Ala Leu Ile Leu Pro Ala Gly Pro Thr Gly Gly Ser
20 25 30
Asn Ser Arg Ala Leu Lys Val Ala Gly Leu Thr Thr Leu Thr Cys Leu
35 40 45
Leu Leu Ala Ser Gln Val Phe Thr Ala Tyr Met Val Phe Gly Gln Lys
50 55 60
Glu Gln Ile His Thr Leu Gln Lys Asn Ser Glu Arg Met Ser Lys Gln
65 70 75 80
Leu Thr Arg Ser Ser Gln Ala Val Ala Pro Met Lys Met His Met Pro
85 90 95
Met Asn Ser Leu Pro Leu Leu Met Asp Phe Thr Pro Asn Glu Asp Ser
100 105 110
Lys Thr Pro Leu Thr Lys Leu Gln Asp Thr Ala Val Val Ser Val Glu
115 120 125
Lys Gln Leu Lys Asp Leu Met Gln Asp Ser Gln Leu Pro Gln Phe Asn
130 135 140
Glu Thr Phe Leu Ala Asn Leu Gln Gly Leu Lys Gln Gln Met Asn Glu
145 150 155 160
Ser Glu Trp Lys Ser Phe Glu Ser Trp Met Arg Tyr Trp Leu Ile Phe
165 170 175
Gln Met Ala Gln Gln Lys Pro Val Pro Pro Thr Ala Asp Pro Ala Ser
180 185 190
Leu Ile Lys Thr Lys Cys Gln Met Glu Ser Ala Pro Gly Val Ser Lys
195 200 205
Ile Gly Ser Tyr Lys Pro Gln Cys Asp Glu Gln Gly Arg Tyr Lys Pro
210 215 220
Met Gln Cys Trp His Ala Thr Gly Phe Cys Trp Cys Val Asp Glu Thr
225 230 235 240
Gly Ala Val Ile Glu Gly Thr Thr Met Arg Gly Arg Pro Asp Cys Gln
245 250 255
Arg Arg Ala Leu Ala Pro Arg Arg Met Ala Phe Ala Pro Ser Leu Met
260 265 270
Gln Lys Thr Ile Ser Ile Asp Asp Gln
275 280
<210> 39
<211> 27
<212> PRT
<213> 智人(Homo sapiens)
<400> 39
Gly Gln Lys Glu Gln Ile His Thr Leu Gln Lys Asn Ser Glu Arg Met
1 5 10 15
Ser Lys Gln Leu Thr Arg Ser Ser Gln Ala Val
20 25
<210> 40
<211> 16
<212> PRT
<213> 智人(Homo sapiens)
<400> 40
Gln Ile His Thr Leu Gln Lys Asn Ser Glu Arg Met Ser Lys Gln Leu
1 5 10 15
<210> 41
<211> 11
<212> PRT
<213> 流感病毒(Influenza virus)
<400> 41
Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser
1 5 10
<210> 42
<211> 29
<212> PRT
<213> 智人(Homo sapiens)
<400> 42
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser Gln Glu Ile His Ala Arg
20 25
<210> 43
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 43
Leu Leu Pro Phe Tyr Pro Pro Asp Glu Ala Leu Glu Ile Gly Leu Glu
1 5 10 15
Leu Asn Ser Ser Ala Leu Pro Pro Thr
20 25
<210> 44
<211> 25
<212> PRT
<213> 智人(Homo sapiens)
<400> 44
His Ile His Arg Ala Gly Gly Leu Phe Val Ala Asp Ala Ile Gln Val
1 5 10 15
Gly Phe Gly Arg Ile Gly Lys His Phe
20 25
Claims (17)
1.一种多肽,其包含至少25种不同的肿瘤特异性新抗原和至少一种T细胞增强子氨基酸序列。
2.根据权利要求1所述的多肽,其包含至少31种肿瘤特异性新抗原。
3.根据权利要求1或2所述的多肽,其中每种肿瘤特异性新抗原彼此独立地具有8个至50个长度的氨基酸,优选15个至35个长度的氨基酸,更优选25个长度的氨基酸。
4.根据权利要求1至3中任一项所述的多肽,其中每种肿瘤特异性新抗原独立地选自单个氨基酸突变肽、移码肽、通读突变肽和剪接位点突变肽。
5.根据权利要求1至4中任一项所述的多肽,其中肿瘤特异性新抗原中的至少4种引发患者中的T细胞应答。
6.根据权利要求1至5中任一项所述的多肽,其中肿瘤特异性新抗原彼此直接连接。
7.根据权利要求1至6中任一项所述的多肽,其中T细胞增强子氨基酸序列选自恒定链;组织型纤溶酶原激活物(TPA)的前导序列;PEST序列;细胞周期蛋白破坏盒;泛素化信号;和SUMO化信号。
8.根据权利要求7所述的多肽,其中:
(i)TPA是具有根据SEQ ID NO:42的氨基酸序列的扩展的TPA前导序列,并且优选存在于多肽的N末端;和/或
(ii)恒定链选自:
(a)根据SEQ ID NO:36的人恒定链,根据SEQ ID NO:37的小鼠恒定链和根据SEQ IDNO:38的鳜鱼恒定链;
(b)根据(a)的恒定链的免疫刺激片段;和/或
(c)(a)或(b)的免疫刺激变体,其中该变体与根据(a)的恒定链或根据(b)的其片段具有至少70%的序列同一性。
9.一种核酸,其编码权利要求1至8中任一项的多肽。
10.一种载体,其包含与表达控制序列可操作地连接的权利要求9的核酸。
11.一种或多于一种表达载体的集合,每种表达载体包含根据权利要求9的核酸,其中每种表达载体选自质粒;黏粒;RNA;与佐剂一起配制的RNA;配制在脂质体颗粒中的RNA;自扩增RNA(SAM);与佐剂一起配制的SAM;配制在脂质体颗粒中的SAM;病毒载体;优选α病毒载体、委内瑞拉马脑炎(VEE)病毒载体、辛德毕斯(SIN)病毒载体、塞姆利基森林病毒(SFV)载体、猿猴或人巨细胞病毒(CMV)载体、淋巴细胞脉络丛脑膜炎病毒(LCMV)载体、逆转录病毒载体或慢病毒载体,优选有复制能力或无复制能力的类人猿衍生的腺病毒载体,优选衍生自黑猩猩或倭黑猩猩或大猩猩的腺病毒载体,痘病毒载体,牛痘病毒载体或经修饰的安卡拉牛痘病毒(MVA)载体。
12.一种用于预防或治疗对象的增殖性疾病的组合物,其包含疫苗和至少一种检查点分子的调节剂或免疫调节剂或编码所述调节剂或免疫调节剂的核酸或包含编码所述调节剂或免疫调节剂的核酸的载体,所述疫苗包含权利要求1至8中任一项的多肽、权利要求9的核酸、权利要求10的载体或权利要求11的载体的集合。
13.根据权利要求12所述的组合物,其中检查点分子的调节剂选自:
(a)肿瘤坏死因子(TNF)受体超家族成员的激动剂,优选CD27、CD40(例如CP-870,893)、OX40、GITR或CD137的激动剂;和/或
(b)PD-1、PD-L1、CD274、A2AR、B7-H3(例如MGA271)、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、TIM-3或VISTA的拮抗剂或B7-CD28超家族成员的拮抗剂,优选CD28或ICOS的拮抗剂,或它们的配体的拮抗剂;和/或
(c)另外的免疫调节剂,其为T细胞生长因子,如IL-2、IL-12、IL-15。
14.根据权利要求12或13所述的组合物,其中在开始施用疫苗之前开始检查点分子的调节剂的施用,或者其中在开始施用疫苗之后开始检查点抑制剂的施用,或者其中在开始施用疫苗的同时开始检查点抑制剂的施用,其中优选的接种方案是用两种不同病毒载体进行异源性初免加强免疫。
15.根据权利要求12至14所述的组合物,其中所述对象患有以下疾病或具有患以下疾病的风险:
(a)唇、口腔和咽部的恶性肿瘤;和/或
(b)消化器官恶性肿瘤;和/或
(c)呼吸和胸内器官的恶性肿瘤;和/或
(d)骨和关节软骨的恶性肿瘤;和/或
(e)黑色素瘤和皮肤的其他恶性肿瘤;和/或
(f)间皮和软组织的恶性肿瘤;和/或
(g)乳腺恶性肿瘤;和/或
(h)女性生殖器官的恶性肿瘤;和/或
(i)男性生殖器官的恶性肿瘤;和/或
(j)尿路恶性肿瘤;和/或
(k)眼、脑和中枢神经系统其他部位的恶性肿瘤;和/或
(l)甲状腺和其他内分泌腺的恶性肿瘤;和/或
(m)淋巴、造血及相关组织的恶性肿瘤。
16.根据权利要求12至14所述的组合物,其中所述对象患有根据TNM分类处于至少T1期且具有N期和M期的任何分期的肿瘤,和/或特征在于病灶直径为至少约3mm的肿瘤。
17.一种疫苗接种试剂盒,其以独立的包装包括:
(i)疫苗,其包含权利要求1至8中任一项的多肽、权利要求9的核酸、权利要求10的载体、或权利要求11的载体的集合;和
(ii)至少一种检查点分子的调节剂或编码该调节剂的核酸或包含编码该调节剂的核酸的载体。
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PCT/EP2018/069047 WO2019012091A1 (en) | 2017-07-12 | 2018-07-12 | NEOANTIGEN-BASED VACCINE COMPOSITION FOR THE TREATMENT OF CANCER |
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