CN113318225A - 肿瘤免疫增强剂及其制法和应用 - Google Patents
肿瘤免疫增强剂及其制法和应用 Download PDFInfo
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明涉及肿瘤免疫增强剂及其制法和应用。具体地,本发明提供了一种肿瘤免疫增强剂,其包含一种或多种以SEQ ID NO:1‑9所示序列为核心结构的多肽。本发明还提供了包含所述肿瘤免疫增强的药物组合物及其应用。本发明的肿瘤免疫增强剂可以增强肿瘤抗原的T细胞应答,可以用于制备肿瘤疫苗。
Description
技术领域
本发明涉及免疫领域,更具体地涉及肿瘤免疫增强剂及其制法和应用。
技术背景
肿瘤发生发展的根本原因是组织细胞的遗传物质发生了促使细胞异常生长的突变。虽然肿瘤细胞基因突变数目可多达数千个,但是真正启动肿瘤发生的突变基因(驱动基因)可能只涉及两到三个。部分驱动基因已经被用于肿瘤治疗药物设计的靶点。研究发现这类靶向药物的临床疗效取决于肿瘤细胞的其它非驱动突变基因和未靶向的驱动基因的表达情况,因而这类药物临床疗效十分有限。肿瘤疫苗的最新研究进展表明,我们可以利用那些改变氨基酸残基编码的基因突变设计出可以治愈肿瘤的疫苗,这是肿瘤治疗上一个重要的里程碑。
一旦编码突变的基因表达成蛋白,就有可能被抗原呈递细胞分解产生可被T细胞识别的肿瘤特异抗原,这种抗原被称为肿瘤新生抗原。由于识别新抗原的T细胞不受中枢耐受限制,因此新抗原被认为具有强免疫原性,可以激发肿瘤特异杀伤性CD8+T细胞(CTL))应答。临床研究已经证实在肿瘤组织中确实存在这样的新生抗原特异的CTL,并且这类CTL的活性决定了多种肿瘤治疗方法如T细胞生长因子IL-2,免疫检查点抑制剂(PD-1和CTLA-4单克隆抗体)以及体外扩增TILs输注等的疗效。
由于绝大多数肿瘤的新生抗原是病人特有的,因此针对新生抗原的疫苗必须根据每个患者的基因突变来定制。另外,在单个肿瘤中遗传突变具有多克隆特性。为了解决肿瘤的这种异质性,肿瘤疫苗需要采用多靶点设计策略。在公布的肿瘤疫苗临床研究中使用的新生抗原T表位数在20个以上。通过CD4和CD8T细胞应答检测发现只有约1/3的新生抗原可以引发抗肿瘤T细胞应答,其中90%以上的T细胞是CD4+。由于肿瘤疫苗要达到治疗功效,需要激发肿瘤特异杀伤性CD8+T细胞应答。这类细胞激活和记忆形成,以及肿瘤浸润需要I型辅助T细胞。因此,可以推测,目前癌症疫苗中使用的大多数新生抗原都不能有效引发I型辅助T细胞应答。
增强I型辅助T细胞反应的方法之一是使用外源的T辅助多肽。例如破伤风类毒素T辅助肽和pan-DR肽(PARDE)已被用于临床试验。结果发现这些多肽不能有效诱导抗肿瘤的CD8+CTL应答。
综上所述,本领域尚缺乏令人满意的抗肿瘤的免疫增强剂。因此,本领域需要开发有效的抗肿瘤免疫应答的免疫增强剂。
发明内容
本发明的目的在于提供有效的抗肿瘤免疫应答的免疫增强剂及其制法和应用。
在本发明的第一方面,提供了一种肿瘤免疫增强剂,所述的肿瘤免疫增强剂包含一种或多种具有式I结构的多肽,或其药学上可接受的盐:
Z0-Z1-Z2 (I)
式中,
Z0为无,或1-10个氨基酸残基构成的肽段;
Z2为无,或1-10个氨基酸残基构成的肽段;
Z1为选自下组的肽段:
(a)如SEQ ID NO:1-9所示的多肽;
(b)将SEQ ID NO:1-9氨基酸序列经过一个、两个或三个氨基酸残基取代、缺失或添加而形成的,且能够与人和鼠II型组织相容性抗原结合的衍生多肽。
在另一优选例中,所述的衍生多肽保留了≥70%的SEQ ID NO:1-9所示多肽的与人和鼠的II型组织相容性抗原结合的活性。
在另一优选例中,所述的衍生多肽与SEQ ID NO:1-9所示多肽的相同性≥80%,较佳地≥90%,更佳地≥95%。
在另一优选例中,所述Z1与组织相容性抗原结合的IC50为5-50nm。
在另一优选例中,Z0和Z2不同时为无;
在另一优选例中,Z0和Z2中至少含有2-8个,较佳地3-6个亲水性氨基酸残基。
在另一优选例中,Z2为无,且Z0为2-8个,较佳地3-6个亲水性氨基酸残基构成的肽段。
在另一优选例中,Z0为无,且Z2为2-8个,较佳地3-6个亲水性氨基酸残基构成的肽段。
在另一优选例中,所述的亲水性氨基酸选自下组:精氨酸、赖氨酸。
在另一优选例中,Z0和Z2中至少一个含有(Arg)n结构,其中,n为3-6的正整数。
在另一优选例中,所述的式I结构为N端至C端的结构。
在另一优选例中,所述的式I结构为C端至N端的结构。
在另一优选例中,“一”为共价键(如肽键),或者当Z0为无时,则Z0和Z1之间的“-”不存在,或者当Z2为无时,则Z1与Z2之间的“-”不存在。
在另一优选例中,所述的肿瘤免疫增强剂具有增强肿瘤免疫的活性。
在另一优选例中,所述的肿瘤免疫增强剂能够诱导杀伤性T细胞应答。
在另一优选例中,所述的具有式I结构的多肽包含一个或多个CD4+Th表位肽。
在另一优选例中,所述的具有式I结构的多肽为CD4+T细胞抗原受体配体。
在另一优选例中,所述的肿瘤免疫增强剂包含Z1为SEQ ID NO:1所示的式I结构的多肽、Z1为SEQ ID NO:2所示的式I结构的多肽和Z1为SEQ ID NO:3所示的式I结构的多肽。
在本发明的第二方面,提供了一种多聚体,所述多聚体由m个单体串联形成,并具有增强肿瘤免疫的功能,其中,m为≥2的正整数,而所述各个单体各自独立地具有式I结构:
Z0-Z1-Z2 (I)
式中,
Z0为无,或1-10个氨基酸残基构成的肽段;
Z2为无,或1-10个氨基酸残基构成的肽段;
Z1为选自下组的肽段:
(a)如SEQ ID NO:1-9所示的多肽;
(b)将SEQ ID NO:1-9氨基酸序列经过一个、两个或三个氨基酸残基取代、缺失或添加而形成的,且能够与组织相容性抗原结合的衍生多肽。
在另一优选例中,m为2、3、4、5、或6。
在另一优选例中,两个单体之间直接通过肽键连接、或者通过肽接头连接。
在另一优选例中,所述的肽接头为柔性肽接头、刚性肽接头、或其组合。
在另一优选例中,所述的肽接头为3-10个氨基酸的肽接头。
在本发明的第三方面,提供了一种分离的核酸分子,编码一多肽,所述多肽具有式I结构,或者所述多肽是由m个单体串联形成的多聚体,其中,各个单体各自独立地具有式I结构,m为≥2的正整数。
在另一优选例中,所述的核酸分子选自下组:DNA、RNA或其组合。
在本发明的第四方面,提供了一种药物组合物,它含有:
(a)本发明第一方面所述的肿瘤免疫增强剂或其药学上可接受的盐、本发明第二方面所述的多聚体、本发明第三方面所述的分离的核酸分子、和/或本发明第四方面所述的药物组合物;和
(b)药学上可接受的载体或赋形剂。
在另一优选例中,所述组合物的剂型为注射剂。
在另一优选例中,所述的组合物为缓释剂型。
另一优选例中,所述的组合物中含有的本发明第一方面所述的肿瘤免疫增强剂或其药学上可接受的盐、或本发明第二方面所述的多聚体可以以选自下组的形式存在:
蛋白质分子(完整分子、亚基、结构域、多肽及重组工程分子)、脂类、多糖类、脂类与多糖复合物。
在另一优选例中,所述的药物组合物还含有:
(c)肿瘤抗原。
在另一优选例中,所述的肿瘤抗原为肿瘤新生抗原肽。
在另一优选例中,所述的肿瘤抗原是原本无法有效引发抗肿瘤免疫反应的抗原。
在另一优选例中,所述的肿瘤抗原是天然的、人工合成的、或其组合。
在另一优选例中,所述的肿瘤抗原选自下组:短肽、完整蛋白、肿瘤细胞裂解物、或其组合。
在另一优选例中,所述的肿瘤抗原来自中高度频率编码子非同义突变的恶性肿瘤,包括但不限于:
恶性黑色素瘤、乳腺癌、肺癌、肠癌、肝癌、食管癌、宫颈癌、膀胱癌、肾细胞癌、多形性胶质瘤。
在另一优选例中,所述的药物组合物为肿瘤疫苗组合物。
在另一优选例中,所述的疫苗选自下组:全细胞疫苗、细胞裂解物疫苗、肿瘤组织裂解疫苗、肿瘤细胞外泌体疫苗。
在本发明的第五方面,提供了一种物质的用途,所述物质选自下组:本发明第一方面所述的肿瘤免疫增强剂或其药学上可接受的盐、本发明第二方面所述的多聚体、或本发明第三方面所述的分离的核酸分子,并且所述物质被用于制备提高肿瘤抗原的抗肿瘤活性的药物,或用于制备抗肿瘤的瘤苗组合物。
在另一优选例中,所述的药物或瘤苗组合物还用于选自下组的一种或多种用途:
(a)诱导辅助性T细胞应答,较佳地为I型辅助型T细胞应答;
(b)诱导CD8+T细胞应答,较佳地为肿瘤特异杀伤性CD8+T细胞应答;
(c)诱导B细胞应答
在本发明的第六方面,提供了一种预防和/或治疗哺乳动物肿瘤的方法,包括步骤:给需要的对象施用本发明第一方面所述的肿瘤免疫增强剂或其药学上可接受的盐、本发明第二方面所述的多聚体、本发明第三方面所述的分离的核酸分子、或本发明第四方面所述的药物组合物。
在另一优选例中,所述的对象是人。
在另一优选例中,所述的肿瘤抗原来自中高度频率编码子非同义突变的恶性肿瘤,如:
黑色素瘤、乳腺癌、肺癌、肠癌、肝癌、食管癌、宫颈癌、膀胱癌、肾细胞癌、多形性胶质瘤。
在另一优选例中,所述的方法还包括:需要的对象施用肿瘤抗原。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了在本发明的一个实施例中,UThE增强黑色素瘤弱新生抗原的抗肿瘤免疫应答。
图2显示了在本发明的另一个实施例中,UThE增强黑色素瘤弱新生抗原的抗肿瘤免疫应答(肿瘤预防)。图2A和图2B分别显示了随肿瘤注射后的天数变化的肿瘤体积变化。
图3显示了在本发明的另一个实施例中,UThE有效增强对黑色素瘤的治疗效果。
图4显示了一个实施例中,疫苗免疫后小鼠血清样品抗UThE抗体检测结果。
图5显示了另一个实施中,疫苗免疫后小鼠血清样品抗UThE抗体检测结果。
图6显示了另一个实施中,疫苗免疫后小鼠血清样品抗新生抗原抗体的检测结果。
图7显示了另一个实施中,疫苗免疫后小鼠血清样品抗新生抗原抗体的检测结果。
图8显示了另一个实施中,疫苗免疫后小鼠脾脏肿瘤特异CD8+CTL检测结果。
具体实施方式
本发明人经过广泛而深入地研究,首次发现一类衍生自白喉毒素和破伤风毒素蛋白的通用Th表位肽,其能够增强肿瘤新生抗原疫苗特异性CD8+CTL免疫应答。实验表明,本发明的这类多肽能够增强肿瘤疫苗抗肿瘤免疫应答功效。在此基础上,完成了本发明。
具体地,本发明提供了UThE1-UThE9,其是由15-21个氨基酸残基组成的多肽分子,与小鼠I I型组织相容性抗原分子有中度亲和力,IC50为5-50nm。由于这些多肽分子疏水性过强,合成时需要在N端或C端添加多个亲水性氨基酸残基(如精氨酸残基或赖氨酸残基)。这些多肽分子都带有一个或多个Th表位,可以支持在超过80%的人群中诱导辅助性T细胞应答的功能。
活性多肽
在本发明中,术语“本发明多肽”、“UThE多肽”、“Th表位肽”或“UThE1--UThE9”可互换使用,都指具有式I结构的多肽:
Z0-Z1-Z2 (I)
式中,
Z0为无,或1-10个氨基酸残基构成的肽段;
Z2为无,或1-10个氨基酸残基构成的肽段;
Z1为选自下组的肽段:
(a)如SEQ ID NO:1-9所示的多肽;
(b)将SEQ ID NO:1-9氨基酸序列经过一个、两个或三个氨基酸残基取代、缺失或添加而形成的,且能够与II型组织相容性抗原结合的衍生多肽。
本发明多肽包括具有增强肿瘤免疫的功能的、SEQ ID NO:1-9序列的变异形式。这些变异形式包括(但并不限于):1-4个(较佳地1-3个,更佳地1-2个,最佳地1个)氨基酸的缺失、插入和/或取代,以及在C末端和/或N末端添加或缺失一个或数个(通常为4个以内,较佳地为3个以内,更佳地为2个以内)氨基酸。例如,在本领域中,用性能相近或相似的氨基酸进行取代时,通常不会改变蛋白质的功能。又比如,在C端和/或N端添加或缺失一个或数个氨基酸通常也不会改变蛋白质的结构和功能。此外,所述术语还包括单体和多聚体形式本发明多肽。该术语还包括线性以及非线性的多肽(如环肽)。
由于本发明多肽分子的疏水性过强,合成时需要在N端或C端添加多个亲水性氨基酸残基(如精氨酸残基或赖氨酸残基)。一种典型的本发明多肽是在SEQ ID NO:1-9所示多肽的N端或C端添加3-6个精氨酸。
本发明还包括UTHE多肽的活性片段、衍生物和类似物。如本文所用,术语“片段”、“衍生物”和“类似物”是指基本上保持增强肿瘤免疫的功能或活性的多肽。本发明的多肽片段、衍生物或类似物可以是(i)有一个或多个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的多肽,或(ii)在一个或多个氨基酸残基中具有取代基团的多肽,或(i ii)DTHE多肽与另一个化合物(比如延长多肽半衰期的化合物,例如聚乙二醇)融合所形成的多肽,或(iv)附加的氨基酸序列融合于此多肽序列而形成的多肽(与前导序列、分泌序列或6His等标签序列融合而形成的蛋白)。根据本文的教导,这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。
一类优选的活性衍生物指与式I的氨基酸序列相比,有至多4个,较佳地至多3个,更佳地至多2个,最佳地1个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
表A
最初的残基 | 代表性的取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Lys;Arg | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser | Ser |
Gln(Q) | Asn | Asn |
Glu(E) | Asp | Asp |
Gly(G) | Pro;Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe | Leu |
Leu(L) | Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Leu;Val;Ile;Ala;Tyr | Leu |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala | Leu |
本发明还提供DTHE多肽的类似物。这些类似物与天然DTHE多肽的差别可以是氨基酸序列上的差异,也可以是不影响序列的修饰形式上的差异,或者兼而有之。类似物还包括具有不同于天然L-氨基酸的残基(如D-氨基酸)的类似物,以及具有非天然存在的或合成的氨基酸(如β、γ-氨基酸)的类似物。应理解,本发明的多肽并不限于上述例举的代表性的多肽。
修饰(通常不改变一级结构)形式包括:体内或体外的多肽的化学衍生形式如乙酰化或羧基化。修饰还包括糖基化,如那些在多肽的合成和加工中或进一步加工步骤中进行糖基化修饰而产生的多肽。这种修饰可以通过将多肽暴露于进行糖基化的酶(如哺乳动物的糖基化酶或去糖基化酶)而完成。修饰形式还包括具有磷酸化氨基酸残基(如磷酸酪氨酸,磷酸丝氨酸,磷酸苏氨酸)的序列。还包括被修饰从而提高了其抗蛋白水解性能或优化了溶解性能的多肽。
本发明多肽还可以以由药学上或生理学可接受的酸或碱衍生的盐形式使用。这些盐包括(但不限于)与如下酸形成的盐:氢氯酸、氢溴酸、硫酸、柠檬酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、琥珀酸、草酸、富马酸、马来酸、草酰乙酸、甲磺酸、乙磺酸、苯磺酸、或羟乙磺酸。其他盐包括:与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐,以及以酯、氨基甲酸酯或其他常规的“前体药物”的形式。
肿瘤免疫增强剂
本发明提供了一种肿瘤免疫增强剂,其包含一种或多种具有式I结构的多肽。
本发明的肿瘤免疫增强剂能够增强肿瘤新生抗原疫苗特异性CD8+CTL免疫应答,具有增强肿瘤疫苗抗肿瘤免疫应答的活性。
在优选的实施方式中,本发明的肿瘤免疫增强剂包括SEQ ID NO:1-3所示的多肽或其衍生多肽。
肿瘤新生抗原多肽
癌症细胞在基因变异的基础上产生的带有特异性氨基酸序列变异的蛋白被称为“新生抗原”(neoantigen)。这是因为如果没有氨基酸序列的改变,这些蛋白应该是没有抗原性的。而一旦发生变异,这些蛋白那就会引起自身免疫细胞的注意,并引起一系列的免疫反应。
本发明的肿瘤免疫增强剂能够增强肿瘤新生抗原,特别是原本无法有效引发抗肿瘤免疫反应的抗原的免疫应答。所述的肿瘤抗原可以是天然的、人工合成的、或其组合。所述的肿瘤抗原可以是:短肽、完整蛋白、肿瘤细胞裂解物、或其组合。
在优选的实施方式中,使用四个不同黑色素瘤细胞B16F10NeoAg,作为疫苗,其在单独施用时不能产生抗原特异抗肿瘤CTL。
本发明涉及的细胞裂解物是将细胞悬浮于等体积磷酸缓冲液中,冻融法使细胞破裂,10,000g离心10分钟去除沉淀后上清作为细胞裂解物。
编码序列
本发明还涉及编码DTHE多肽的多聚核苷酸。一种优选的编码序列编码SEQ ID NO:1-9所示的短肽。
本发明的多聚核苷酸可以是DNA形式或RNA形式。DNA可以是编码链或非编码链。本发明多聚核苷酸的全长序列或其片段通常可以用PCR扩增法、重组法或人工合成的方法获得。目前,已经可以完全通过化学合成来得到编码本发明多肽(或其片段,或其衍生物)的DNA序列。然后可将该DNA序列引入本领域中已知的各种现有的DNA分子(或如载体)和细胞中。
本发明也涉及包含本发明的多聚核苷酸的载体,以及用本发明的载体或UTHE多肽编码序列经基因工程产生的宿主细胞。
UThE多肽的制备
本发明多肽可以是重组多肽或合成多肽。本发明的多肽可以是化学合成的,或重组的。相应地,本发明多肽可用常规方法人工合成,也可用重组方法生产。
在优选的实施方式中,可以通过化学合成法合成末端带6个Arg的UThE多肽,HPLC纯化收率大于20%,纯度大于99.9%。
一种优选的方法是使用液相合成技术或固相合成技术,如Boc固相法、Fmoc固相法或是两种方法联合使用。固相合成可快速获得样品,可根据目的肽的序列特征选用适当的树脂载体及合成系统。例如,Fmoc系统中优选的固相载体如连接有肽中C端氨基酸的Wang树脂,Wang树脂结构为聚苯乙烯,与氨基酸间的手臂是4-烷氧基苄醇;用25%六氢吡啶/二甲基甲酰胺室温处理20分钟,以除去Fmoc保护基团,并按照给定的氨基酸序列由C端逐个向N端延伸。合成完成后,用含4%对甲基苯酚的三氟乙酸将合成的胰岛素原相关肽从树脂上切割下来并除去保护基,可过滤除树脂后乙醚沉淀分离得到粗肽。将所得产物的溶液冻干后,用凝胶过滤和反相高压液相层析法纯化所需的肽。当使用Boc系统进行固相合成时,优选树脂为连接有肽中C端氨基酸的PAM树脂,PAM树脂结构为聚苯乙烯,与氨基酸间的手臂是4-羟甲基苯乙酰胺;在Boc合成系统中,在去保护、中和、偶联的循环中,用TFA/二氯甲烷(DCM)除去保护基团Boc并用二异丙基乙胺(DIEA/二氯甲烷中和。肽链缩合完成后,用含对甲苯酚(5-10%)的氟化氢(HF),在0℃下处理1小时,将肽链从树脂上切下,同时除去保护基团。以50-80%乙酸(含少量巯基乙醇)抽提肽,溶液冻干后进一步用分子筛Sephadex G10或Tsk-40f分离纯化,然后再经高压液相纯化得到所需的肽。可以使用肽化学领域内已知的各种偶联剂和偶联方法偶联各氨基酸残基,例如可使用二环己基碳二亚胺(DCC),羟基苯骈三氮唑(HOBt)或1,1,3,3-四脲六氟磷酸酯(HBTU)进行直接偶联。对于合成得到的短肽,其纯度与结构可用反相高效液相和质谱分析进行确证。
另一种方法是用重组技术产生本发明多肽。通过常规的重组DNA技术,可利用本发明的多聚核苷酸可用来表达或生产重组的DTHE多肽。一般来说有以下步骤:
(1).用本发明的编码DTHE多肽的多聚核苷酸(或变异体),或用含有该多聚核苷酸的重组表达载体转化或转导合适的宿主细胞;
(2).在合适的培养基中培养的宿主细胞;
(3).从培养基或细胞中分离、纯化蛋白质。
重组多肽可在细胞内、或在细胞膜上表达、或分泌到细胞外。如果需要,可利用其物理的、化学的和其它特性通过各种分离方法分离和纯化重组的蛋白。这些方法是本领域技术人员所熟知的。这些方法的例子包括但并不限于:常规的复性处理、用蛋白沉淀剂处理(盐析方法)、离心、渗透破菌、超处理、超离心、分子筛层析(凝胶过滤)、吸附层析、离子交换层析、高效液相层析(HPLC)和其它各种液相层析技术及这些方法的结合。
由于本发明多肽较短,因此可以考虑将多个多肽串联在一起,重组表达后获得多聚体形式的表达产物,然后通过酶切等方法形成所需的小肽。
药物组合物和施用方法
本发明还提供了一种药物组合物,其可以是治疗性的或预防性的(如疫苗)。本发明的药物组合物含有(a)安全有效量的本发明多肽或其药学上可接受的盐;以及(b)药学上可接受的载体或赋形剂。
为了本发明的目的,有效的剂量为给予个体约10微克-100毫克/剂,较佳地为100-1000微克/剂体重的本发明多肽。此外,本发明的多肽可以单用,也可与其他治疗剂一起使用(如配制在同一药物组合物中)。
在本发明中,预防性药物组合物可以是疫苗组合物,其包含本发明多肽和肿瘤抗原,并且通常与“药学上可接受的载体”组合。
术语“药学上可接受的载体”指用于治疗剂给药的载体。该术语指这样一些药剂载体:它们本身不诱导产生对接受该组合物的个体有害的抗体,且给药后没有过分的毒性。这些载体是本领域普通技术人员所熟知的。在Remington's Pharmaceutical Sciences(MackPub.Co.,N.J.1991)中可找到关于药学上可接受的赋形剂的充分讨论。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、佐剂及其组合。另外,这些载体中还可能存在辅助性的物质,如润湿剂或乳化剂、pH缓冲物质等。
此外,本发明的(疫苗)组合物还可含有额外的佐剂。代表性的疫苗佐剂包括(但并不限于)以下种类:无机佐剂,如氢氧化铝,明矾等;合成佐剂,如人工合成的双链多聚核苷酸(双链多聚腺苷酸、尿苷酸)、左旋咪唑、异丙肌苷等;油剂,如弗氏佐剂、花生油乳化佐剂、矿物油、植物油等。
通常,可将疫苗组合物或免疫原性组合物制成可注射剂,例如液体溶液或悬液;还可制成在注射前适合配入溶液或悬液、液体赋形剂的固体形式。该制剂还可乳化或包封在脂质体中,以增强佐剂效果。
组合物可制成单元或多元剂型。各剂型包含为了产生所期望的治疗效应而计算出预定量的活性物质,以及合适的药剂学赋形剂。
一旦配成本发明的组合物,可将其通过常规途径进行给药,其中包括(但并不限于):静脉内、瘤内、肌内、腹膜内、皮下、皮内、癌旁、或局部给药。待预防或治疗的对象可以是动物;尤其是人。
当本发明的组合物被用于实际治疗时,可根据使用情况而采用各种不同剂型的药物组合物。这些药物组合物可根据常规方法通过混合、稀释或溶解而进行配制,并且偶尔添加合适的药物添加剂,如赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、等渗剂(isotonicities)、防腐剂、润湿剂、乳化剂、分散剂、稳定剂和助溶剂,而且该配制过程可根据剂型用惯常方式进行。
本发明的药物组合物还可以缓释剂形式给药。例如,短肽DTHE或其盐可被掺入以缓释聚合物为载体的药丸或微囊中,然后将该药丸或微囊通过手术植入待治疗的组织。作为缓释聚合物的例子,可例举的有乙烯-乙烯基乙酸酯共聚物、聚羟基甲基丙烯酸酯(polyhydrometaacrylate)、聚丙烯酰胺、聚乙烯吡咯烷酮、甲基纤维素、乳酸聚合物、乳酸-乙醇酸共聚物等,较佳地可例举的是可生物降解的聚合物如乳酸聚合物和乳酸-乙醇酸共聚物。
当本发明的药物组合物被用于实际治疗时,作为活性成分的短肽DTHE或其药学上可接受的盐的剂量,可根据待治疗的每个病人的体重、年龄、性别、症状程度而合理地加以确定
本发明的主要优点包括:
(a)本发明利用复合抗原载体技术,最大程度识别肿瘤新生抗原;
(b)利用本发明多肽制备的疫苗的纯度和质量更加容易控制,安全性高,毒副作用小;
(c)人体免疫响应率高,更高效;
(e)本发明多肽可以提高体外免疫细胞激活效率。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
制备实施例1 UThE的合成
在本制备实施例中,采用化学合成方法,合成氨基酸序列如下表所示的UThE多肽,并将其中#1、#2、#3的组合用在以下实施案例中。
命名 | 氨基酸序列 | SEQ ID NO: |
UThE1 | LSELKTVTGTNPVFAGANYAAWAV | 1 |
UThE2 | TGTNPVFAGANYAAWAVNVAQVID | 2 |
UThE3 | SIALSSLMVAQAIPLVGELVDIGFAAY | 3 |
UThE4 | ITAENTPLPIAGVLLPTIPGKLD | 4 |
UThE5 | TTAALSILPGIGSVMGIADGAV | 5 |
UThE6 | IVAQSIALSSLMVAQAIPLVGELV | 6 |
UThE7 | GELVDIGFAAYNFVESIINLFQVV | 7 |
UThE8 | TNSVDDALINSTKIYS | 8 |
UThE9 | KAIHLVNNESSEVIVH | 9 |
制备实施例2 B16F10肿瘤新生抗原肽的制备
在本制备实施例中,采用化学合成方法,合成氨基酸序列如下的新生抗原肽(neoAg):
四种新生抗原肽(neoAg)的氨基酸序列如下:
neoAg命名 | 氨基酸序列 | SEQ ID NO: |
Pi4k2b | WLPQAKVPFSEETQNLILPYISDMNFV | 10 |
ddb1 | LVLSFVGQTRVLMINGEEVEETELMGF | 11 |
Pcdhga11 | RGQSQLFSLNPRGRSLVTAGRIDREEL | 12 |
Atp11a | SSPDEVALVEGVQSLGFTYLRLKDNYM | 13 |
制备实施例3肿瘤细胞裂解物的制备
细胞悬浮于等体积磷酸缓冲液中,冻融使细胞破裂后,10,000g离心10分钟去除沉淀后上清作为细胞裂解物。作为肿瘤抗原,分别制得B16F10细胞裂解物、LLC细胞裂解物、和Hepa1-6细胞裂解物。
实施例1 UThE增强黑色素瘤弱新生抗原的抗肿瘤免疫应答
选择临床前研究已显示在诱导小鼠抗肿瘤免疫反应方面无效的来自B16F10细胞系的四种新生抗原肽(neoAg)。B16F10为小鼠黑色素瘤细胞。
将四种neoAg肽(#1、#2、#3和#4)按重量比1:1:1:1混合,与UThE肽和佐剂一起配制成疫苗,免疫小鼠后,检测其抗肿瘤效果。具体方法如下:
C57BL6小鼠(6周龄,每实验组7只)免疫三次,间隔一周。每只小鼠每次免疫使用200微升疫苗,分别在靠近四肢侧身位点皮下注射50微升。200微升疫苗各成分用量为neoAg50微克,DThE50微克,Alum300微克,CpG20微克。疫苗注射液用PBS配制完成。实验组为:(1)PBS组(Alum+CpG+PBS);(2)neoAg组(neoAg+Alum+CpG+PBS);(3)neoAg+UTh组(neoAg+UThE+Alum+CpG+PBS)。第三次免疫后第3天,小鼠右侧近腋处皮下接种105个B16F10细胞。细胞悬浮于100微升PBS中。然后观察记录肿瘤生长情况。
结果如图1和表1所示。接种后第7天,小鼠开始出瘤。第15天时,PBS,NeoAg,NeoAg+UThE各组小鼠出瘤的平均体积(mean±SEM)分别为:785±153mm3,890±80mm3,328±65mm3。
表1
结果表明,与PBS组相比,在NeoAg组中,施用neoAg和佐剂(Alum+CpG)并不能抑制肿瘤的形成。在NeoAg+UTh组中,肿瘤生长显著地被抑制了。
实施例2 UThE增强黑色素瘤弱新生抗原的抗肿瘤免疫应答
本实施例的方法与实施例1基本相同,不同点在于给疫苗的配制和免疫次数,使用B16F10细胞裂解物或neoAg作为肿瘤抗原。方法如下:
C57BL/6小鼠(6周龄,每实验组5只)免疫四次,每次间隔一周。每只小鼠分四个靠近四肢侧身位点注射疫苗,每点注射50微升。一免与二免每200微升疫苗组分用量为neoAg或B16F10细胞裂解物25微克,UThE25微克佐剂(adj)25微克,MF59100微升。佐剂包括12.5ugCpG,12.5微克PolyI:C,用PBS配制。三免与四免,每200微升疫苗各成分用量为neoAg或B16F10细胞裂解物12.5微克,UThE12.5微克,佐剂(adj)12.5微克,MF59微升。佐剂包括6.25微克CpG,6.25微克PolyI:C,用PBS配制。各组的施用情况如下:
第四次免疫后第三天,小鼠近右侧腋下皮下接种105个B16F10细胞。细胞悬浮于100微升PBS中。然后观察记录肿瘤生长情况。瘤可见后,每隔一天测量瘤体积。
结果如图2和表2所示。在注射肿瘤细胞后至第19天期间,肿瘤的生长快慢和体积大小顺序为:adj组>UThE+adj组>neo+adj组>neo+UThE+adj组>Lys+UThE+Adj组。其中,Lys+UThE+Adj组的小鼠在第19天时还没有出现肿瘤。此外,Neo+UThE+Adj组的小鼠瘤体也较小且生长较慢(图2A)。
在第19天时,adj组,UTEh+adj组,neo+adj组,neo+UThE+adj组和Lys+UThE+Adj组的瘤体积平均数(mean±SEM)分别为:801.1±821.7mm3,517.4±615.5mm3,431.8±886.7mm3,317.8±314.4mm3(图2B)。
表2
上述结果表明,当原本无免疫反应的抗原肽(NeoAg或B16F10细胞裂解物)与UThE肽一起施用时,在接种疫苗的小鼠中显著的抑制肿瘤生长,采用肿瘤细胞裂解物+UThE肽时,可完全抑制肿瘤的生长。
实施例3 UThE有效增强对黑色素瘤B16F10的治疗效果
在实施例1-3中,已经证实了预先施用UThE肽可以作为肿瘤增强剂,增强肿瘤抗原肽的抗肿瘤效果。在本实施例中,进一步验证在荷瘤小鼠体内给予肿瘤免疫增强剂UThE肽,是否可以增强对肿瘤的治疗效果。
方法如下:模拟肿瘤治疗,先接种肿瘤细胞,再用UThE肿瘤增强剂进行治疗。
将B16F10细胞1*105接种于小鼠右侧前肢靠近腋下,5天后,对小鼠进行免疫。每个小鼠接种疫苗100微升,分两个侧身靠近后肢注射位点,每点50微升。每200微升疫苗各成分用量为:UThE25微克,佐剂Adj25ug,MF59100微升。佐剂包括CpG12.5微克,PolyI:C25微克,用PBS配制。共免疫四次,每次间隔一周。肿瘤开始出现后,量取瘤体大小并称取小鼠体重。
结果如图3和表3所示。
表3
结果表明,在荷瘤小鼠中,施用UThE可以有效增强小鼠的细胞免疫,抑制肿瘤细胞的生长。
实施例4 UThE增强新生抗原肽NeoAg的体液免疫反应ELISA法检测
小鼠免疫后的血清,用0.1%BSA的PBS按照1:100体积比进行稀释。96孔板中加入100微升新生抗原肽溶液(10微克/毫升pH9.5碳酸缓冲液),4℃包被过夜。然后,96孔板用0.1%BSA的PBS室温封闭2小时。吸走封闭液后,加入100微升稀释后血清,室温孵育1小时,之后吸走血清,96孔板用0.05%Tween 20PBS洗涤三次(每次孵育5分钟),加入1:5000稀释后HRP-偶联的羊抗鼠IgG,IgG1,IgG2a,IgG2b。室温孵育1小时之后吸走抗体溶液。96孔板用0.05%Tween 20PBS洗涤三次,重蒸水洗涤一次,按照说明书进行TMB显色。酶标仪上读取450nm的吸光度。
结果如图4-图7所示。
图4显示了免疫小鼠血清样品中UThE抗体的ELISA检测结果。小鼠经过四次免疫DThE+CpG+polyI:C+MF59疫苗,每次间隔一周,免疫后10天接种7.5*104个B16F10细胞,小鼠瘤体积达到1500mm3或肿瘤接种后第30天,小鼠处死取血。由于IgG1和IgG2同时存在并且其浓度比率大于1,T辅助细胞应答是I型+II型混合型,II型应答较强。
图5显示了免疫小鼠血清样品中UThE抗体的ELISA检测结果。小鼠经过四次免疫neoAg+UThE+CpG+polyI:C+MF59疫苗,每次间隔一周,免疫后10天接种7.5*104个B16F10细胞,小鼠瘤体积达到1500mm3或肿瘤接种后第30天,小鼠处死取血。由于IgG1和IgG2同时存在并且其浓度比率大于1,T辅助细胞应答是I型+II型混合型,II型应答较强。
图6显示了免疫小鼠血清样品中neoAg抗体的ELISA检测结果。小鼠经过四次免疫neoAg+CpG+polyI:C+MF59疫苗,每次间隔一周,免疫后10天接种7.5*104个B16F10细胞,小鼠瘤体积达到1500mm3或肿瘤接种后第30天,小鼠处死取血。产生的抗体主要是IgG2,因此,T辅助细胞应答是I型的。
图7显示了免疫小鼠血清样品中neoAg抗体的ELISA检测结果。小鼠经过四次免疫neoAg+UThE+CpG+polyI:C+MF59疫苗,每次间隔一周,免疫后10天接种7.5*104个B16F10细胞,小鼠瘤体积达到1500mm3或肿瘤接种后第30天,小鼠处死取血。由于IgG1和IgG2同时存在并且其浓度比率大于1,T辅助细胞应答是I型+II型混合型,II型应答较强。
图4至图7的结果表明,UThE肽作为一种肿瘤免疫增强剂,可显著增强肿瘤新生抗原的体液免疫应答。
实施例5 UThE多肽促进neo-Ag特异CD8+CTL细胞应答
在本实施例中,验证UThE多肽是否促进neoAg特异CTLT细胞应答。
方法如下:免疫后的小鼠脾脏淋巴细胞与UThE或neoAg抗原递呈细胞共孵育5天后,使用T淋巴细胞或CD8+T分离试剂盒纯化淋巴细胞。在包被了INF-γ捕捉抗体的免疫斑点96孔板中加入100微升含104个纯化的淋巴细胞培养液。37℃,5%CO2培养16小时。然后用免疫斑点试剂盒检测分泌INF-γ的T细胞数量。
UThE或neoAg抗原递呈细胞树突状细胞制备方法:
小鼠脾脏淋巴细胞制备方法:
ELIspot实验结果如图8所示。结果表明:UThE肽作为一种肿瘤免疫增强剂,可显著增强肿瘤新生抗原特异性的CD8+CTL细胞应答,因此可有效增强肿瘤疫苗的免疫效果。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 无锡派列博生物医药科技有限公司
<120> 肿瘤免疫增强剂及其制法和应用
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Claims (10)
1.一种肿瘤免疫增强剂,其特征在于,所述的肿瘤免疫增强剂包含一种或多种具有式I结构的多肽,或其药学上可接受的盐:
Z0-Z1-Z2 (I)
式中,
Z0为无,或1-10个氨基酸残基构成的肽段;
Z2为无,或1-10个氨基酸残基构成的肽段;
Z1为选自下组的肽段:
(a)如SEQ ID NO:1-9所示的多肽;
(b)将SEQ ID NO:1-9氨基酸序列经过一个、两个或三个氨基酸残基取代、缺失或添加而形成的,且能够与人和鼠II型组织相容性抗原结合的衍生多肽。
2.如权利要求1所述的肿瘤免疫增强剂,其特征在于,Z0和Z2中至少含有2-8个,较佳地3-6个亲水性氨基酸残基。
3.如权利要求1所述的肿瘤免疫增强剂,其特征在于,Z0和Z2中至少一个含有(Arg)n结构,其中,n为3-6的正整数。
4.如权利要求1所述的肿瘤免疫增强剂,其特征在于,所述的肿瘤免疫增强剂具有增强肿瘤免疫的活性。
5.一种多聚体,其特征在于,所述多聚体由m个单体串联形成,并具有增强肿瘤免疫的功能,其中,m为≥2的正整数,而所述各个单体各自独立地具有式I结构:
Z0-Z1-Z2 (I)
式中,
Z0为无,或1-10个氨基酸残基构成的肽段;
Z2为无,或1-10个氨基酸残基构成的肽段;
Z1为选自下组的肽段:
(a)如SEQ ID NO:1-9所示的多肽;
(b)将SEQ ID NO:1-9氨基酸序列经过一个、两个或三个氨基酸残基取代、缺失或添加而形成的,且能够与组织相容性抗原结合的衍生多肽。
6.一种分离的核酸分子,其特征在于,编码一多肽,所述多肽具有式I结构,或者所述多肽是由m个单体串联形成的多聚体,其中,各个单体各自独立地具有式I结构,m为≥2的正整数。
7.一种药物组合物,其特征在于,它含有:
(a)权利要求1所述的肿瘤免疫增强剂或其药学上可接受的盐、权利要求5所述的多聚体、和/或权利要求6所述的分离的核酸分子;和
(b)药学上可接受的载体或赋形剂。
8.如权利要求7所述的药物组合物,其特征在于,所述的药物组合物还含有:
(c)肿瘤抗原。
9.如权利要求7所述的药物组合物,其特征在于,所述的药物组合物为肿瘤疫苗组合物。
10.一种物质的用途,其特征在于,所述物质选自下组:权利要求1所述的肿瘤免疫增强剂或其药学上可接受的盐、权利要求5所述的多聚体、权利要求6所述的分离的核酸分子,并且所述物质被用于制备提高肿瘤抗原的抗肿瘤活性的药物,或用于制备抗肿瘤的瘤苗组合物。
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