CN108348587A - 抗肿瘤组合物 - Google Patents
抗肿瘤组合物 Download PDFInfo
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Abstract
本发明涉及一种药物组合物,其特征在于其包含至少一种痘病毒、编码癌细胞的至少一种特异性新抗原的裸核酸序列和抗CTLA4抗体。
Description
技术领域
本发明涉及药物组合物,其特征在于其包含编码肿瘤的至少一种特异性新抗原的至少一种核酸序列、痘病毒和抗CTLA4抗体。本发明还涉及根据本发明的组合物用于治疗癌症的用途。
背景技术
传统上,在肿瘤疾病的背景下,治疗包括使用化学或生物化合物(化学疗法)、辐射(放射疗法)和/或手术。虽然近年来已观察到靶向治疗特别是使用单克隆抗体或靶向特异性受体的其它分子取得了巨大进展,但仍然观察到高死亡率,并且继续设想进一步的治疗途径以便降低与这些疾病及其治疗相关联的相关死亡率和/或副作用。
在设想的新治疗途径中,可特别提及基因疗法和免疫疗法。
针对预先存在的癌细胞进行免疫的想法基于以下观察:癌细胞表达突变的蛋白、异常糖基化的蛋白或者在由病毒感染诱导的肿瘤的情况下表达病毒蛋白。在肿瘤内,这些蛋白的表达不诱导产生有效的免疫应答。实际上,肿瘤特别能够产生阻止启动靶向这些抗原和/或表达它们的细胞的免疫应答的微环境。此外,即使免疫应答被诱导,其由于在肿瘤中占优势的无反应性而不总是成功有效的。因此已假定,就产生的免疫应答而言更有效的是将与肿瘤细胞相关联的抗原注射到免疫系统具有活性的区域中。
在与肿瘤相关联的抗原中,还可提及从引起癌化的细胞群中的突变的累积获得的肿瘤新抗原。这些突变可由例如暴露于紫外线辐射或来自烟草或其它种类的致癌物质造成。一些直接参与致癌作用,其它仅处于“乘客”状态,但是由于蛋白序列中氨基酸的变化,所有这些都有可能被免疫系统认为与自身不同并且因此具有抗原性。
在癌症治疗的背景下,已根据三个主要领域使用基因疗法。第一领域包括在肿瘤部位上注射编码适用于提升免疫系统局部抑制的免疫刺激分子的基因。例如,将编码白细胞介素的基因直接注射到肿瘤中。局部白细胞介素产生被认为能够使免疫系统具有正常活性并且破坏癌细胞。然而,用这种类型的策略获得的结果已令人失望。
第二研究领域包括将编码细胞毒性分子或诱导直接或间接产生细胞毒性分子的基因注射到癌细胞中。该策略被认为能够破坏肿瘤细胞并且任选地将抗原释放到体内,从而能够激活免疫系统。
最后的研究领域包括使用编码与肿瘤相关联的抗原的核酸给患者接种疫苗。实际上,由患者的细胞而不是其原位注射产生抗原,使得可以设想优异的抗原呈递以更好地与癌细胞中发生的抗原呈递保持一致。
然而,在这些各种治疗的背景下观察到的抗肿瘤应答不比常规治疗的背景下观察到的临床应答好得多。
因此,期望具有能够长期控制肿瘤体积和提高受治疗的患者存活率的新颖的产品和/或新颖的方法。
发明内容
本发明涉及药物组合物,其特征在于其包含编码癌细胞的至少一种特异性新抗原的至少一种核酸序列、至少一种痘病毒和抗CTLA4抗体。
这三种成分的特异性组合使得可以获得对由核酸序列编码的(一个或多个)新抗原靶向的免疫应答。痘病毒使得可以既增强核酸序列的转染又增强对(一个或多个)新抗原产生的免疫应答的质量。抗CTLA-4抗体还使得可以增强对(一个或多个)新抗原的免疫应答。核酸序列的使用使得可以设想快速且个性化地产生编码(一个或多个)新抗原的序列。实际上,当前的技术能够对患者的癌细胞的基因型进行完全测序,并且通过患者的组成性比较而鉴别特异性突变。如果这些突变是非同义的,则属于由肿瘤表达的编码序列,并且由于其特征而被认为是免疫原性的,则后者可用于诱导对肿瘤的免疫。
肿瘤基因组中的突变和所得的新抗原是限于给定患者的肿瘤或形成该肿瘤的克隆的独特的组合。
使用新抗原作为用于使患者对其自己的肿瘤细胞免疫的手段是新颖的概念。其实现因需要在短时间内生产与由给定患者的肿瘤携带的新抗原相对应的个体化药物制剂而变得复杂。
迄今为止,肿瘤学的治疗性免疫已使用两种主要种类的产品。第一类包括通常通过注射给药被认为是肿瘤中存在的抗原的肽或蛋白,存在佐剂物质中的它们的整体,其使用有时引起顾虑。第二类包括给药编码抗原的核酸,该抗原被认为存在于肿瘤中但通常对应于由肿瘤优先表达的蛋白,但是该抗原不一定与非肿瘤型式不同,并且不一定符合新抗原的定义。
在这两类产品中,使用基因疗法的免疫疗法,特别是基于使用病毒载体的那些免疫疗法,在肿瘤治疗中已显示出可重现的显著疗效。使用基因疗法的免疫疗法,尤其是具有病毒基础的那些免疫疗法,被免疫系统自然地感知为危险信号。它们更具免疫原性,并且原则上不需要使用佐剂。病毒成分(特别是如果其包含痘病毒)诱导先天性应答,从而促进对所表达的抗原的适应性免疫应答的发展。
表达序列的基因修饰病毒的设计和药物生产在技术上是可行的选项,所述序列编码存在于患者肿瘤中的一个或多个新抗原;然而,其涉及很难普及的长期且昂贵的操作。
相反,质粒或双链闭合线性核酸或编码一个或多个新抗原的其它基因表达载体的生产是最多在几周内可行的简单的、相对便宜的操作。
共同注射编码一个或多个新抗原的核酸和病毒特别是痘病毒的原理,易于能够在短时间内产生对应于由患者肿瘤携带的新抗原的个性化药物制剂,同时受益于提供免疫应答发展所必需的危险信号的病毒的存在。
此外,痘病毒由于其膜的磷脂成分而易于促进核酸渗透到存在于注射部位附近的细胞中,并且因此促进由核酸编码的抗原蛋白的表达。
在DNA表达载体的情况下,核酸序列促进特异性传感器识别其中这些载体已渗透的细胞的细胞质中的双链DNA。该识别是促进免疫应答的生物应答的来源。
因此,核酸序列和痘病毒具有互补的不同作用途径,并且使得可以获得优异的应答。
痘病毒的进一步的优点在于其任选地表达除了新抗原之外的可在注射部位处表达和呈现的附加肿瘤抗原的能力。举例来说,在由该病毒诱导的肿瘤的情况下可提及HPVE6和E7蛋白,或者在腺癌的情况下可提及MUC1蛋白。
抗CTLA4抗体是免疫应答的阴性检验点的抑制剂。迄今为止,它们通过全身静脉路径给药,至少在治疗恶性皮肤黑素瘤和非小细胞肺癌方面具有显著疗效,但换来不可忽视的不良作用。
抗CTLA4抗体或抗体片段的共同给药易于促进由免疫疗法诱导的免疫应答,特别是基因表达载体和痘病毒的组合。为此,减少到通常全身剂量的1/20或更少的剂量被认为已足够。在这些剂量下并且在共同注射后,注射部位的引流区淋巴结中的浓度被认为高于经由全身路径的浓度,而全身浓度本身大大降低,不良作用的风险同样大大降低。
在本发明的范围内,术语“核酸序列”是指DNA或RNA型编码核酸序列。该核酸序列不包含在病毒基因组中或封装在病毒颗粒中。
根据本发明的一个实施例,所述核酸序列选自包含以下的组:质粒和线性DNA或RNA的载体。
根据本发明的一个实施例,所述核酸序列是裸露的,即其不与促进其在真核细胞中渗透的分子诸如例如阳离子聚合物、病毒聚合物、脂质和/或脂质体相关联。
根据本发明的优选的实施例,所述核酸序列是双链闭合线性核酸。此外,闭合线性核酸由于其生产方法而伴随着非常少的生产残余物,特别是细菌,这使得可以避免繁琐的纯化步骤并且使得能够更快且更便宜地使用。
闭合线性核酸是本领域技术人员公知的,其结构、其功能以及能够生产其的工艺特别描述于文献CN10380337、EP2601312、GB101013153、JP12013521110、US2013216562、WO12017210、AU2010209532、CA2514130、CN102301010、DK2346431、EA021069、EA201101141、EP2391731、EP2612925、ES2400890、GB100901593、HK1159693、IL213930、IN050060CN2011、JP12016147、KR20110107846、MX2011007937、NZ594004、SG173102、US2012282283、US9109250、W010086626中。
在本发明的范围内,术语“与癌细胞相关联的新抗原”是指由癌细胞通过与患者的组成性序列比较而以突变形式表达的蛋白。
根据本发明的优选的实施例,抗CTLA-4抗体优选选自包含易普利姆玛(ipilimumab)和曲美母单抗(tremelimumab)的组。其也可由对CTLA-4靶向的抗体片段或包含对CLTA4特异性靶向的互补位的任何分子组成。为了清楚起见,规定术语“抗CTLA4抗体”不适用于编码抗CLTA4抗体的核酸。
根据优选的实施例,所述核酸序列进一步包含调控元件,该调控元件提供真核细胞中的癌细胞的特异性新抗原的表达。
根据优选的实施例,提供与真核细胞中的癌细胞相关联的(一个或多个)新抗原的表达的调控元件包含宿主细胞中的基因转录启动子和翻译起始区。所述核酸序列可包含各自编码与肿瘤相关联的不同新抗原的多个序列。在多个新抗原的情况下,编码后者的序列可置于相同或不同调控元件的依赖性下。
根据优选的实施例,痘病毒是活的或灭活的。
根据优选的实施例,痘病毒不包含异源序列。
根据优选的实施例,痘病毒衍生于痘苗病毒、金丝雀痘病毒或禽痘病毒。
根据优选的实施例,所述痘病毒衍生于选自哥本哈根(Copenhagen)株、惠氏(Wyeth)株和改良安卡拉(Modified Ankara)(MVA)株的痘苗病毒。
根据优选的实施例,所述痘病毒衍生于哥本哈根株痘苗病毒。根据优选的实施例,所述痘病毒衍生于MVA株痘苗病毒。
在本发明的范围内,术语“衍生”是指所述病毒属于所述菌株。
根据进一步的优选的实施例,所述痘病毒包含至少编码与癌细胞相关联的抗原的必要区的异源DNA序列。
根据优选的实施例,至少编码与癌细胞相关联的抗原的必要区的DNA序列处于痘病毒基因启动子的控制下。
根据优选的实施例,至少编码与癌细胞相关联的抗原的必要区的序列置于痘苗病毒基因启动子的控制下,并且特别是选自以下的启动子:胸苷激酶(TK)、7.5K、H5R以及K1L基因启动子。
根据甚至更优选的实施例,所述启动子是痘苗病毒7.5K蛋白基因的启动子。
根据优选的实施例,将至少编码与癌细胞相关联的抗原的必要区的DNA序列插入所用病毒的非必要区内部。
根据优选的实施例,非必要区是TK基因。
在所述痘病毒衍生于哥本哈根株痘苗病毒的情况下,至少编码与癌细胞相关联的抗原的必要区的序列优先插入所述痘苗病毒的TK和/或KIL基因座处。
在所述痘病毒衍生于MVA株痘苗病毒的情况下,至少编码与癌细胞相关联的抗原的必要区的序列优先插入在所述痘苗病毒的切除区I至VI中的至少一个处,并且特别是II和/或III。
本发明还涉及根据本发明的组合物,该组合物进一步包含使其能够通过注射到人或动物而进行给药的药学上可接受的基质。
根据本发明的优选的实施例,所述药学上可接受的基质使得能够经由无针注射装置注射所述组合物。
在本发明的范围内,术语“无针注射装置”是指用于人或兽医学中治疗用途而使用加压液体流渗透组织进行液体活性物质的皮内、皮下或肌内注射的装置。该液体可为或多或少粘性的、液体混合物或凝胶。
核酸的给药通常需要使用与注射相结合的电穿孔技术。经由无针系统的加压注射是进一步的解决方案。其由于加压注射还具有确保组织空间中优异的扩散的优点。如果需要,其用途还能够临时制备待注射产品的混合物。无针加压注射系统的使用比具有常规针的系统更易于促进优异的组织渗透,并且因此促进更多数量的细胞的转染。目的是从而促进对由核酸序列表达的新抗原的免疫应答。
本发明还涉及部件组,其包含编码癌细胞的至少一种特异性新抗原的核酸序列、至少一种痘病毒和对CTLA4靶向的抗体或抗体片段。
所述部件组可特别用于临时制备根据本发明的组合物。
本发明还涉及根据本发明的组合物用于治疗癌症或肿瘤的用途。
本发明还涉及根据本发明的组合物用于治疗以下的用途:宫颈癌、ENT瘤或由HPV病毒诱导的任何其它肿瘤、与慢性乙型肝炎病毒或丙型肝炎病毒相关联的肝癌,或表达MUC1蛋白的癌症。
具体实施方式
根据本发明的优选的实施例,使用活检或手术样本分析待治疗患者的癌细胞。提取并测序癌细胞的DNA和RNA以及从血液样品中获得的组成性DNA。
将健康细胞的DNA序列与癌细胞的DNA序列进行比较,并且鉴定包含在编码区和表达区中的体细胞突变。
编码和表达的突变序列使用适合于定义例如最具有抗原性的算法进行处理并且可用作靶标。特异于患者的癌细胞的被称为新抗原的这些表达的、编码的、非同义的、突变的序列随后通过DNA或DNA合成而产生,并且然后以表达载体(质粒或闭合线性核酸或RNA)的形式放置。根据本发明的优选的实施例,使用专利申请EP2391731中描述的方法,将编码与患者的肿瘤相关联的一个或多个新抗原的核酸序列根据其在真核细胞中的表达所需的序列的依赖性下置于闭合线性核酸内部。同样地,所述序列优选置于真核表达启动子的下游和转录终止序列的上游。其可由强真核启动子,特别是CMV早期启动子组成。启动子是病毒起源的或细胞起源的。通过除CMV以外的病毒启动子,可提及SV40病毒的早期或晚期启动子或劳斯(Rous)肉瘤病毒的LTR启动子。通过细胞启动子,可提及细胞骨架基因的启动子,诸如例如结蛋白启动子或肌动蛋白启动子。优选地,内含子可整合在编码与患者肿瘤相关联的一个或多个新抗原的所述序列内部。实际上,已知一些内含子增加核酸序列的转录。
组合物中使用的痘病毒优选为MVA病毒。后者通过在鸡胚细胞上连续传代衍生于痘苗病毒的安卡拉株。这些不同的传代诱导该病毒的衰减,这从而可用于最新的对天花的接种疫苗活动。
对不同MVA株的描述、适合于将任何外源基因任选地插入其基因组中的方法以及生产和纯化该病毒的方法可易于从以下文献中获得:WO0168820、WO0242480、W003008533、W003048184、W003053463、W003054175、WO03088994、WO03097675、WO03097844、WO03097845、WO03097846、WO04048582、WO04048606、WO05054484、WO06089690、WO06089690、WO08028665、WO08045346、WO08131926、WO08131927、WO08138533、WO09052328、WO9152969、WO10057650、WO10060632、WO10102822、WO11042180、WO11092029、WO12010280、WO12048817、WO12059243、WO13083254、WO13189611、WO14019718、WO14037124、WO14062778、WO14063832、WO9813500、WO9915692。
痘病毒还可包含编码影响患者的肿瘤的进一步的特异性抗原的序列。例如,编码HPV E6和E7抗原的序列或者编码HCV NS3、NS4、NS5B抗原或在肿瘤中异常糖基化的Muc1蛋白的序列。
最后,根据本发明的组合物将优选包含抗CTLA4抗体或抗体片段,甚至更优选易普利姆玛。在本发明的范围内,术语“抗体”还表示包含CTLA-4的至少一种特异性互补位的双特异性抗体。
优选地,根据本发明的组合物进一步包含药学上可接受的基质。在本发明的范围内,“药学上可接受的基质”表示与药物给药相容的所有基质、溶剂、稀释剂、赋形剂、佐剂、分散介质以及等同物。
适当缓冲用于本发明的组合物,以便适合于人在生理或微碱性pH下使用。
根据本发明的组合物可通过各种给药方法诸如例如皮下、皮内、肌内、静脉内、腹膜内、瘤内、血管内、动脉内路径给药于患者。
注射可用常规注射器和针进行,但优选经由生物喷射(器)(bioject(r))型无针注射装置进行。
根据本发明的组合物的给药可在从一天至一年范围内的一定时间间隔之后以单次或重复剂量进行。优选地,给药每周将连续进行七次,并且然后接着每三周进行一次。
合适的剂量可根据各种参数进行调整,特别是给药方法、使用的组合物、宿主的年龄、健康和体重、症状的性质和程度、相关联的治疗类型、治疗频率。
本领域技术人员能够确定根据本发明的组合物内的各元素的合适量。举例来说,痘病毒可以104pfu至109pfu的量使用,裸核酸序列的量在10μg和20mg之间,并且抗CTLA4抗体的量在10ng和20mg之间。
优选地,根据本发明的组合物可连同放射疗法、化学疗法、外科手术和/或进一步的免疫疗法产品诸如抗PD1和抗PDL1抗体或者多种这些治疗的组合同时使用。
Claims (13)
1.药物组合物,其特征在于,其包含编码癌细胞的至少一种特异性新抗原的至少一种核酸序列、至少一种痘病毒类型病毒颗粒和抗CTLA4抗体。
2.根据权利要求1所述的组合物,其特征在于,所述核酸序列进一步包含提供真核细胞中癌细胞的所述特异性新抗原的表达的调控元件。
3.根据前述权利要求中任一项所述的组合物,其特征在于,所述核酸序列选自包含以下的组:质粒、闭合线性DNA载体或RNA分子。
4.根据前述权利要求中任一项所述的组合物,其特征在于,所述核酸序列是闭合线性核酸序列。
5.根据权利要求2至权利要求4中任一项所述的组合物,其特征在于,提供与所述真核细胞中癌细胞相关联的所述(一个或多个)新抗原的所述表达的所述调控元件包含所述宿主细胞中的基因转录启动子和翻译起始区。
6.根据前述权利要求中任一项所述的组合物,其特征在于,所述痘病毒是非重组体或包含异源DNA序列,所述异源DNA序列至少编码与癌细胞相关联的抗原的必要区。
7.根据前述权利要求中任一项所述的组合物,其特征在于,所述痘病毒是活的或灭活的。
8.根据权利要求6或权利要求7中任一项所述的组合物,其特征在于,至少编码与癌细胞相关联的抗原的所述必要区的所述DNA序列处于所用的痘病毒的基因的启动子的控制下。
9.根据前述权利要求中任一项所述的组合物,其特征在于,所述痘病毒颗粒衍生于痘苗病毒、金丝雀痘病毒或禽痘病毒。
10.根据前述权利要求中任一项所述的组合物,其特征在于,其包含药学上可接受的基质,从而使所述组合物能够通过注射给人或动物而进行给药。
11.根据前述权利要求所述的组合物,其特征在于,所述药学上可接受的基质使得能够经由无针注射装置注射所述组合物。
12.根据前述权利要求中任一项所述的组合物,其旨在用于治疗癌症或肿瘤。
13.根据权利要求12所述的组合物,其旨在用于治疗宫颈癌、ENT瘤或由HPV病毒诱导的任何其它肿瘤、与慢性乙型肝炎病毒或丙型肝炎病毒相关联的肝癌,或表达MUC1蛋白的癌症。
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US10441654B2 (en) | 2014-01-24 | 2019-10-15 | Children's Hospital Of Eastern Ontario Research Institute Inc. | SMC combination therapy for the treatment of cancer |
CN116676324B (zh) * | 2023-07-28 | 2023-10-27 | 四川大学华西医院 | 基于Kil蛋白构建释放抗肿瘤效应蛋白的系统及方法 |
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HK1253315A1 (zh) | 2019-06-14 |
RU2018115534A3 (zh) | 2020-02-26 |
JP7211815B2 (ja) | 2023-01-24 |
FR3042121A1 (fr) | 2017-04-14 |
CA2999948C (fr) | 2024-04-23 |
RU2728748C2 (ru) | 2020-07-31 |
EP3359185B1 (fr) | 2022-04-06 |
US20210138053A1 (en) | 2021-05-13 |
LT3359185T (lt) | 2022-06-27 |
WO2017060650A1 (fr) | 2017-04-13 |
DK3359185T3 (da) | 2022-07-04 |
IL258430A (en) | 2018-06-28 |
IL258430B (en) | 2022-03-01 |
FR3042122A1 (fr) | 2017-04-14 |
FR3042122B1 (fr) | 2020-01-17 |
JP2018531238A (ja) | 2018-10-25 |
CA2999948A1 (fr) | 2017-04-13 |
RU2018115534A (ru) | 2019-11-08 |
KR20180059547A (ko) | 2018-06-04 |
ES2919134T3 (es) | 2022-07-22 |
EP3359185A1 (fr) | 2018-08-15 |
US20180296653A1 (en) | 2018-10-18 |
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