CN107530432B - 药物 - Google Patents
药物 Download PDFInfo
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- CN107530432B CN107530432B CN201680020132.8A CN201680020132A CN107530432B CN 107530432 B CN107530432 B CN 107530432B CN 201680020132 A CN201680020132 A CN 201680020132A CN 107530432 B CN107530432 B CN 107530432B
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Abstract
本发明提供药物，其含有：Toll样受体激动剂；LAG‑3蛋白、其突变体或其衍生物。
Description
技术领域
本发明涉及药物，其含有：Toll样受体激动剂；和LAG-3蛋白、其突变体或其衍生物。
背景技术
近年来，开发了以在癌细胞中特异性表达的癌抗原作为靶标的癌症免疫疗法。其中，“癌症疫苗疗法”是通过向患者直接施予癌抗原从而在患者的体内诱导出对于癌抗原的特异性免疫应答而使癌症消退缩小的方法。作为向患者施予的癌抗原，可使用癌抗原蛋白自身、源于癌抗原的肽、编码它们的核酸、呈递癌抗原的树突细胞、及癌细胞自身等。
为了增强基于癌抗原的免疫应答的诱导，也可与癌抗原一同施予佐剂。作为佐剂，可利用刺激各种免疫活性细胞的细胞因子、Toll样受体(TLR)激动剂等。
作为用于佐剂的TLR激动剂，也可使用TLR1～TLR10中的任一种激动剂(例如非专利文献1及2)。例如，TLR3是识别源于病毒的双链RNA、并促进显示出强抗病毒作用的I型干扰素的产生的自然免疫系统分子之一。已知的是，可使用作为TLR3激动剂而已知的、双链RNA类似物Poly I:C(也被称为聚肌苷酸-聚胞苷酸，Polyinosinic:polycytidylic acid)作为疫苗用佐剂(例如专利文献1)。另外，TLR9为识别源于细菌、病毒的非甲基化CpG DNA而发挥作用的自然免疫系统分子之一。作为TLR9的配体的CpG ODN(合成核酸CpG寡脱氧核苷酸)也具有疫苗用佐剂效果是已知的。
另外，已知的是，LAG-3也可作为疫苗用佐剂而使用(例如专利文献2)。LAG-3是淋巴细胞激活基因(lymphocyte activation gene 3)的翻译产物，也被称为CD223。已知LAG-3与MHC II类分子结合，在活化的T细胞的增殖、T细胞的稳态维持方面进行负调节，在调节性T细胞(Treg)的功能方面起到重要作用，并且还参与浆细胞样树突细胞的稳态的控制。
现有技术文献
专利文献
专利文献1：日本特表2011-506309号公报
专利文献2：日本特表2001-510806号公报
非专利文献：
非专利文献1：Onco Immunology 1:5,699-716；August 2012
非专利文献2：Onco Immunology 2:8,e25238；August 2013
发明内容
发明所要解决的课题
本发明的课题在于，提供包含佐剂的新型组合的药物。
用于解决课题的手段
本申请的发明人将各种佐剂单独使用或组合而使用，并进行了各种研究，结果发现了例如作为对诱导癌症免疫有用的药物的新型组合。
即，本发明的内容如下。
〔1〕
药物，所述药物含有：
Toll样受体激动剂；和
LAG-3蛋白、其突变体或其衍生物。
〔2〕
如〔1〕所述的药物，所述药物用于联合施予以下成分：
Toll样受体激动剂；和
LAG-3蛋白、其突变体或其衍生物。
〔3〕
如〔1〕或〔2〕所述的药物，其中，所述Toll样受体激动剂为Toll样受体3激动剂或Toll样受体9激动剂。
〔4〕
如〔1〕至〔3〕中任一项所述的药物，其中，所述Toll样受体激动剂为Poly I:C或其盐。
〔5〕
如〔1〕至〔4〕中任一项所述的药物，其中，所述LAG-3蛋白、其突变体或其衍生物为LAG-3蛋白与IgG的融合蛋白。
〔6〕
如〔1〕至〔5〕中任一项所述的药物，所述药物还含有至少1种诱导对于癌细胞的特异性免疫应答的物质。
〔7〕
如〔6〕所述的药物，所述药物用于联合施予以下成分：
Toll样受体激动剂；
LAG-3蛋白、其突变体或其衍生物；和
至少1种诱导对于癌细胞的特异性免疫应答的物质。
〔8〕
如〔6〕或〔7〕所述的药物，其中，所述诱导对于癌细胞的特异性免疫应答的物质为源于癌抗原的肽。
〔9〕
如〔8〕所述的药物，所述药物含有2种以上源于癌抗原的肽。
〔10〕
如〔1〕至〔9〕中任一项所述的药物，所述药物用于癌症疫苗疗法。
〔11〕
如〔1〕至〔10〕中任一项所述的药物，其为抗癌剂。
〔12〕
佐剂，其用于诱导对于癌细胞的特异性免疫应答、或癌症疫苗疗法，所述佐剂含有：
Toll样受体激动剂；和
LAG-3蛋白、其突变体或其衍生物。
〔13〕
组合，其用于诱导对于癌细胞的特异性免疫应答、或癌症疫苗疗法，所述组合含有：
Toll样受体激动剂；和
LAG-3蛋白、其突变体或其衍生物。
〔14〕
治疗或预防患者的疾病的方法，所述方法中，对需要的患者施予下述成分：
Toll样受体激动剂；和
LAG-3蛋白、其突变体或其衍生物。
〔15〕
诱导对于癌细胞的特异性免疫应答的方法，所述方法中，对需要的患者施予下述成分：
Toll样受体激动剂；和
LAG-3蛋白、其突变体或其衍生物。
发明效果
通过本发明，可提供包含佐剂的新型组合的药物。
附图说明
[图1]图1示出了对使用了源于癌抗原的肽的癌症疫苗中的各种佐剂的效果进行比较的试验方案的概要。
[图2]图2示出了图1的试验中、使用了PBS作为对照的1组的肿瘤大小的变化。
[图3]图3示出了图1的试验中、使用了IFA作为佐剂的2组的肿瘤大小的变化。
[图4]图4示出了图1的试验中、使用了PT作为佐剂的3组的肿瘤大小的变化。
[图5]图5示出了图1的试验中、使用了Poly I:C作为佐剂的4组的肿瘤大小的变化。
[图6]图6示出了图1的试验中、使用了Poly I:C和CpG的组合作为的佐剂5组的肿瘤大小的变化。
[图7]图7示出了图1的试验中、使用了LAG-3作为佐剂的6组的肿瘤大小的变化。
[图8]图8示出了图1的试验中、使用了LAG-3和Poly I:C作为佐剂的7组的肿瘤大小的变化。
[图9A]图9A示出了与图1同样的试验中的肿瘤组织的苏木精·曙红染色图像。
[图9B]图9B示出了与图1同样的试验中的肿瘤组织的细胞核及免疫细胞的荧光染色图像。
[图10]图10示出了对已在与图1同样的试验中利用癌症疫苗(使用LAG-3和PolyI:C作为佐剂)抑制了肿瘤大小的增大的小鼠于后日再次接种肿瘤细胞、并对肿瘤大小的增大进行测定的结果。
[图11A]图11A示出了将从在与图1同样的试验中接种了癌症疫苗的小鼠中采集淋巴结、继而进行分离得到的免疫细胞、与预先照射射线进行灭活的肿瘤细胞共同培养后，对免疫细胞的增殖能力进行测定的结果。
[图11B]图11B示出了在与图11A同样地进行共同培养后、对细胞上清液中的细胞因子等的量进行测定的结果。
[图12A]图12A示出了从在与图1同样的试验中接种了癌症疫苗的小鼠中采集淋巴结、继而进行分离得到的CD8阳性免疫细胞的细胞表面标记分子PD-1、BTLA、TIGIT、及LAG-3的表达进行测定的结果
[图12B]图12B示出了从在与图1同样的试验中接种了癌症疫苗的小鼠中采集淋巴结、继而进行分离得到的CD4阳性免疫细胞的细胞表面标记分子PD-1、BTLA、TIGIT、及LAG-3的表达进行测定的结果。
[图13]图13A示出了免疫细胞增殖能力的测定结果，图13B示出了FN-gamma产生量的测定结果。
[图14]图14示出了使用了PBS作为对照的1组的肿瘤大小的变化。
[图15]图15示出了使用了Poly I:C作为佐剂的2组的肿瘤大小的变化。
[图16]图16示出了使用了LAG-3和Poly I:C作为佐剂的3组的肿瘤大小的变化。
[图17]图17示出了不使用P1A肽、而仅使用了LAG-3和Poly I:C的4组的肿瘤大小的变化。
[图18]图18示出了使用了RIBOXXOL作为佐剂的5组的肿瘤大小的变化。
[图19]图19示出了使用了LAG-3和RIBOXXOL的组合作为佐剂的6组的肿瘤大小的变化。
[图20]图20示出了使用了LAG-3和MPL的组合作为佐剂的7组的肿瘤大小的变化。
[图21]图21示出了使用了LAG-3和咪喹莫特的组合作为佐剂的8组的肿瘤大小的变化。
[图22]图22示出了使用了LAG-3和CpG的组合作为佐剂的9组的肿瘤大小的变化。
[图23]图23示出了使用了IFA作为佐剂的1组的肿瘤大小的变化。
[图24]图24示出了使用了Poly I:C作为佐剂的2组的肿瘤大小的变化。
[图25]图25示出了使用了LAG-3作为佐剂的3组的肿瘤大小的变化。
[图26]图26示出了使用了LAG-3和Poly I:C作为佐剂的4组的肿瘤大小的变化。
具体实施方式
通过具体实施方式对本发明进行更具体的说明，但本发明不限于以下的具体实施方式，可实施各种变更。
本发明涉及的药物含有：Toll样受体激动剂(TLR激动剂)；和LAG-3蛋白、其突变体或其衍生物。
本说明书中，“Toll样受体激动剂(TLR激动剂)”是指与任一种Toll样受体(TLR)结合后，可向TLR施加与TLR同天然的配体结合时同样(不是很确定，后有多处)的刺激的分子。作为TLR激动剂，已知有Trends in Immunology Vol.30 No.1,23-32；Immunity 33,October 29,2010,492-503；及World Journal of Vaccines,2011,1,33-78中记载的那样的TLR的激动剂，可将这些已知的TLR的激动剂用作本发明中的TLR激动剂，例如，可使用TLR3激动剂、TLR4激动剂、TLR7激动剂、TLR8激动剂、TLR9激动剂或TLR10激动剂。其中，TLR激动剂可以是TLR3激动剂或TLR9激动剂。
本说明书中，“TLR3激动剂”是指与TLR3结合后，可向TLR3施加与TLR3同天然的配体结合时同样的刺激的分子。TLR3可识别源于病毒的双链RNA，激活自然免疫系统。作为TLR3激动剂，已知有与双链RNA的结构相似的合成双链多核苷酸Poly I:C，但不限于此。用于本发明时，Poly I:C也可以是其盐，例如为钠盐。作为TLR3激动剂，也可使用RIBOXXOL。
本说明书中，“TLR4激动剂”是指与TLR4结合后，可向TLR4施加与TLR4同天然的配体结合时同样的刺激的分子。TLR4可识别源于细菌的脂多糖(LPS)，激活自然免疫系统。作为TLR4激动剂，已知有MPL，但不限于此。用于本发明时，MPL也可以是其盐，例如为钠盐。
本说明书中，“TLR5激动剂”是指与TLR5结合后，可向TLR5施加与TLR5同天然的配体结合时同样的刺激的分子。TLR5可识别源于细菌的鞭毛蛋白(Flagellin)，激活自然免疫系统。作为TLR5激动剂，已知有各种源于细菌的鞭毛蛋白或鞭毛蛋白的重组蛋白，但不限于这些。
本说明书中，“TLR7激动剂”是指与TLR7结合后，可向TLR7施加与TLR7同天然的配体结合时同样的刺激的分子。
另外，本说明书中，“TLR8激动剂”是指与TLR8结合后，可向TLR8施加与TLR8同天然的配体结合时同样的刺激的分子。
TLR7及TLR8可识别源于病毒的单链RNA，激活自然免疫系统。作为TLR7/8激动剂，已知有咪喹莫特，但不限于此。用于本发明时，咪喹莫特也可以是其盐，例如可以为钠盐。
本说明书中，“TLR9激动剂”是指与TLR9结合后，可向TLR9施加与TLR9同天然的配体结合时同样的刺激的分子。TLR9可识别源于细菌、病毒的CpG DNA，激活自然免疫系统。作为TLR9激动剂，一直有CpG ODN，但不限于此。用于本发明时，CpG ODN也可以是其盐，例如可以为钠盐。
本说明书中，“LAG-3蛋白、其突变体或其衍生物”是指LAG-3蛋白、其功能性突变体、或其功能性衍生物。本发明中使用的LAG-3蛋白可源于任何动物，例如，可以是源于与施予本发明涉及的药物的对象相同的动物的蛋白。因此，当本发明涉及的药物为向人施予的药物时，可使用人LAG-3。在人的情况下，LAG-3蛋白为具有NCBI登录号P18627.5所示的氨基酸序列的蛋白质。
就LAG-3蛋白的功能性突变体而言，可举出：(i)包含在LAG-3的氨基酸序列中添加、取代或缺失1个或多个氨基酸而得到的氨基酸序列的LAG-3的突变体，并且，所述突变体具有发挥本发明的效果所必需的LAG-3蛋白的功能；(ii)包含与LAG-3的氨基酸序列具有至少80％以上、或85％以上、90％以上、95％以上、98％以上、99％以上的序列同一性的氨基酸序列的LAG-3的突变体，并且，所述突变体具有发挥本发明的效果所必需的LAG-3的功能；(iii)LAG-3蛋白、上述(i)的突变体、或上述(ii)的突变体的部分多肽，并且，所述多肽具有发挥本发明的效果所必需的LAG-3蛋白的功能。
本说明书中“1个或多个”表示1个、2个、3个、4个、5个、6个、7个、8个、9个或10个。
本说明书中，“氨基酸”使用其最宽泛的含义，除了包括天然氨基酸以外，还包括人造的氨基酸突变体、衍生物。本说明书中，对于氨基酸而言，可举出天然蛋白质性的L-氨基酸；D-氨基酸；氨基酸突变体及衍生物等经过化学修饰的氨基酸；正亮氨酸、β-丙氨酸、鸟氨酸等天然非蛋白质性氨基酸；及具有本领域中已知的作为氨基酸特征的特性的以化学方式合成的化合物等。作为非天然氨基酸的例子，可举出α-甲基氨基酸(α-甲基丙氨酸等)、D-氨基酸、类组氨酸的氨基酸(β-羟基-组氨酸、高组氨酸(Homohistidine)、α-氟甲基-组氨酸及α-甲基-组氨酸等)、在侧链具有额外亚甲基的氨基酸(“高(homo)”氨基酸)及侧链中的羧酸官能团被磺酸基取代的氨基酸(半胱氨酸等)。
作为LAG-3蛋白的功能性衍生物，可举出LAG-3蛋白的全部或一部与其他蛋白质或多肽形成的融合蛋白、在LAG-3蛋白上附加糖链、脂质而得到的蛋白等。作为LAG-3蛋白的功能性衍生物的一例，包括LAG-3与IgG形成的融合蛋白。作为LAG-3蛋白的功能性衍生物，可例示Journal of Translational Medicine 2014,12:97中记载的衍生物。
本发明涉及的药物可含有：TLR激动剂；LAG-3蛋白、其突变体或其衍生物；以及诱导对于癌细胞的特异性免疫应答的物质。
本说明书中，“诱导对于癌细胞的特异性免疫应答的物质”只要是在生物体内破坏癌细胞或诱导癌细胞的凋亡等能够诱导免疫应答的物质即可，不受特别限定，可举出例如癌抗原蛋白、源于癌抗原的肽、编码它们的核酸、癌抗原呈递细胞、肿瘤细胞自身。
本说明书中，“癌抗原蛋白”是在被免疫系统作为异物识别并攻击的癌细胞中特异性表达的蛋白质。可以是在所有种类的癌症的癌细胞中表达的蛋白质，也可以是在特定种类的癌症的癌细胞中表达的蛋白质。作为癌抗原蛋白，优选免疫原性强、且在正常细胞中完全不表达的癌抗原蛋白。作为癌抗原蛋白，不受特别限定，可举出Clin Cancer Res 2009；15(17)5323中记载的癌抗原蛋白。具体而言，可举出WT1、MUC1、LMP2、HPVE6、HPVE7、EGFRvIII、HER-2/neu、MAGE-A3、非突变p53、HSP70、GPC3、MUC1、Casp8、CDAM1、cMyb、EVC1、EVC2、Helios、Fas、NY-ESO-1、PSMA、GD2、CEA、MelanA/MART1、Ras突变体、gp100、p53突变体、蛋白酶3(PR1)、bcr-abl、酪氨酸酶、存活素(Survivin)、PSA、hTERT、肉瘤易位断裂点(Sarcomatranslocation breakpoints)、EphA2、PAP、ML-IAP、AFP、EpCAM、ERG、NA17、PAX3、ALK、雄激素受体、细胞周期蛋白B1、聚唾液酸、MYCN、PhoC、TRP-2、GD3、岩藻糖基-GM1(Fucosyl GM1)、间皮素、PSCA、MAGE A1、sLe、CYP1B1、PLAC1、GM3、BORIS、Tn、GloboH、ETV6-AML、NY-BR-1、RGS5、SART3、STn、碳酸酐酶IX、PAX5、OY-TES1、精子蛋白17、LCK、HMWMAA、AKAP-4、SSX2、XAGE1、B7H3、Legumain、Tie2、Page4、VEGFR2、MAD-CT-1、FAP、PDGFR、MAD-CT-2、及Fos相关抗原1等，但不限于这些。
本说明书中，“源于癌抗原的肽”是指具有癌抗原蛋白的部分氨基酸序列的肽，或具有在该氨基酸序列中包括1个或2个氨基酸的添加、取代或缺失的序列的肽，或与该氨基酸序列具有90％以上、95％以上、98％以上、或99％以上的序列同一性的肽，并且，所述肽诱导攻击癌细胞的免疫。源于癌抗原的肽可由8个以上且11个以下的氨基酸残基构成。将该肽施予至患者的皮下后，该肽被树突细胞、巨噬细胞等抗原呈递细胞摄入，并与HLA分子一同被呈递至细胞表面。对于被呈递的肽显示出反应性的细胞损伤性T细胞(CTL)前体细胞进行克隆性增殖，增殖·分化而形成的成熟CTL经由淋巴流而向癌组织移动。成熟CTL可攻击表达具有与被施予的肽相同的序列的肽的癌细胞，从而诱导其凋亡。
本说明书中，“核酸”只要是编码癌抗原蛋白或源于癌抗原的肽的核酸则不受特别限定，包括RNA、DNA、PNA、LNA、或它们中的2种以上的嵌合体。上述核酸可以基于已知的方法插入载体等中而施予患者，从而在生物体内表达癌抗原蛋白或源于癌抗原的肽。
本说明书中“癌抗原呈递细胞”表示源于癌抗原的肽与HLA分子结合，并呈递至表面的抗原呈递细胞。作为抗原呈递细胞，可使用树突细胞、巨噬细胞。树突细胞的CTL诱导能力特别高。呈递抗原的树突细胞可通过以下方法获得：从例如患者自身的末梢血中分离单核细胞，使其分化为未成熟树突细胞，然后向培养基中添加癌抗原蛋白或源于癌抗原的肽，进而使其分化为成熟树突细胞。
作为当前正在进行开发的癌症疫苗，有使用利用肿瘤细胞提取物进行致敏得到的树突细胞、利用癌抗原与GM-CSF融合蛋白进行致敏得到的树突细胞、源于HPV的L1蛋白的非感染性病毒样颗粒和佐剂的组合等的疫苗，这些也包含于“诱导对于癌细胞的特异性免疫应答的物质”。
本发明涉及的药物可含有2种以上“诱导对于癌细胞的特异性免疫应答的物质”。例如，本发明涉及的药物可含有2种以上源于不同的癌抗原蛋白的癌抗原源肽。
本发明涉及的药物可用于癌症疫苗疗法。这种情况下，TLR激动剂和LAG-3蛋白、其突变体或其衍生物作为佐剂而发挥功能，增强经由“诱导对于癌细胞的特异性免疫应答的物质”的免疫应答的诱导。如后述的实施例所示的那样，将TLR激动剂和LAG-3蛋白组合进行使用时，即使是在分别单独使用时无法获得效果的低用量，也能够得到极高的抗肿瘤效果。
本说明书中，“佐剂”表示通过与诱导免疫应答的物质一同进行施予来增强该免疫应答的诱导的分子组。
癌症疫苗疗法可用于癌症的预防或治疗。本说明书中，癌症的预防或治疗是指下述中至少一种：肿瘤大小的减小、增大的延迟或停止、癌症的转移的阻碍(延迟或停止)、癌细胞的增殖的阻碍(延迟或停止)、癌症的复发的阻碍(延迟或停止)、及与癌症相关的一种或多种症状的缓和。
本说明书中，用语“癌症”使用其最宽泛的含义，可举出星形细胞瘤、少突神经胶质瘤、脑膜瘤、神经纤维瘤、神经胶质母细胞瘤、室管膜瘤、神经鞘瘤、神经纤维肉瘤、神经母细胞瘤、垂体部肿瘤(例如、垂体腺瘤)、髓母细胞瘤、黑色素瘤、脑肿瘤、前列腺癌、头颈癌、食道癌、肾癌、肾细胞癌、胰腺癌、乳癌、肺癌、结肠癌、大肠癌、胃癌、皮肤癌、卵巢癌、膀胱癌、纤维肉瘤、扁平上皮癌、神经外胚层、甲状腺肿瘤、淋巴瘤、白血病、多发性骨髓瘤、肝细胞癌、间皮瘤及类表皮癌等，但不限于这些。
本发明也包括用于癌症疫苗疗法的佐剂，其含有：TLR激动剂；和LAG-3蛋白、其突变体或其衍生物。TLR激动剂是用于与LAG-3蛋白、其突变体或其衍生物联合施予的佐剂，LAG-3蛋白、其突变体或其衍生物也可以是用于与TLR激动剂联合施予的佐剂。该佐剂可以与各种“诱导对于癌细胞的特异性免疫应答的物质”一同施予至患者。此处，所谓“一同”并非表示同时地进行施予，而是表示在患者的体内或体外，以使TLR激动剂、和LAG-3蛋白、其突变体或其衍生物能够发挥作为癌症疫苗疗法中的佐剂的功能的方式向患者施予TLR激动剂、和AG-3蛋白、其突变体、或其衍生物。
本发明中，可以是用于与LAG-3蛋白、其突变体或其衍生物联合施予的含有TLR激动剂的药物，也可以是用于与TLR激动剂联合施予的含有LAG-3蛋白、其突变体或其衍生物的药物。
另外，本发明中，可以是用于与诱导对于癌细胞的特异性免疫应答的物质、和LAG-3蛋白、其突变体或其衍生物联合施予的含有TLR激动剂的药物，该含有TLR激动剂的药物是以LAG-3蛋白、其突变体或其衍生物作为佐剂、并且诱导对于癌细胞的特异性免疫应答的物质，优选的是，所述药物能够针对源于癌抗原的肽而增强免疫应答的诱导。本发明中，可以是用于与诱导对于癌细胞的特异性免疫应答的物质和TLR激动剂联合施予的、含有LAG-3蛋白、其突变体或其衍生物的药物，该含有LAG-3蛋白、其突变体或其衍生物的药物是以TLR激动剂作为佐剂、并且诱导对于癌细胞的特异性免疫应答的物质，优选的是，所述药物能够针对源于癌抗原的肽而增强免疫应答的诱导。
本发明涉及的含有TLR激动剂、和LAG-3蛋白、其突变体或其衍生物的药物也可以使用TLR激动剂、和LAG-3蛋白、其突变体或其衍生物作为药物的有效成分。本发明涉及的含有TLR激动剂、和LAG-3蛋白、其突变体或其衍生物作为有效成分的药物也可以如后述的实施例中所示的那样，作为显示出高抗肿瘤效果的抗癌剂而使用。本说明书中，“抗癌剂”表示能够用于癌症的预防或治疗的药剂。作为抗癌剂的药物可含有TLR激动剂、和LAG-3蛋白、其突变体或其衍生物作为有效成分，也可进一步含有诱导对于癌细胞的特异性免疫应答的物质。
另外，本发明中，作为抗癌剂的药物可含有诱导对于癌细胞的特异性免疫应答的物质、优选源于癌抗原的肽作为有效成分，含有TLR激动剂、和LAG-3蛋白、其突变体或其衍生物作为佐剂。
本发明涉及的药物的各成分可以溶解于水溶性溶剂中，以制药上允许的盐的形态进行制剂，由此施予至患者。作为这样的制药上允许的盐的形态，可举出生理上可接受的水溶性的盐、例如钠盐、钾盐、镁盐、及钙盐等形式、于生理性pH进行缓冲得到的形态。另外，除了水溶性溶剂以外，也可使用非水溶性溶剂，作为这样的非水溶性溶剂，可举出例如乙醇及丙二醇等醇。
本发明涉及的药物可作为药物组合物而使用，药物组合物的任一种形式均可进行口服或非口服施予，其剂型不受特别限定。作为药物组合物的剂型，可制成例如液体制剂(例如注射剂)、分散剂、悬浮剂、片剂、丸剂、粉末剂、栓剂、散剂、细粒剂、颗粒剂、胶囊剂、糖浆剂、滴鼻剂、滴耳剂。
本发明涉及的药物在用作癌症疫苗的情况下也可进行口服或非口服施予。作为非口服施予，可使用例如腹腔内施予、皮下施予、皮内施予、肌肉内施予、静脉内施予、或鼻腔内施予。
本发明涉及的药物的制剂化可按照已知的方法进行。对于本发明的药物的制剂化而言，可使用药学上允许的载体、添加物(赋形剂、粘合剂、分散剂、崩解剂、润滑剂、溶解剂、助溶剂、着色剂、矫味矫臭剂、稳定剂、乳化剂、悬浮剂、吸收促进剂、表面活性剂、pH调节剂、防腐剂及抗氧化剂等)。作为载体及添加物的例子，可举出水、食盐水、磷酸缓冲液、葡萄糖(dextrose)、甘油、乙醇等药学上允许的有机溶剂、胶原蛋白、聚乙烯醇、聚乙烯吡咯烷酮、羧基乙烯基聚合物、羧甲基纤维素钠、聚丙烯酸酸钠、海藻酸钠、水溶性葡聚糖、羧甲基淀粉钠、果胶、谷氨酸、天冬氨酸、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、黄原酸胶、阿拉伯胶、酪蛋白、琼脂、聚乙二醇、二甘油、甘油、丙二醇、凡士林、石蜡、硬脂醇、硬脂酸、人血清白蛋白、甘露糖醇、山梨糖醇、乳糖、葡萄糖、玉米淀粉、微晶纤维素、表面活性剂、重亚硫酸钠、重硫酸钠、硫代硫酸钠苯扎氯铵、氯丁醇、硫柳汞、乙酸苯汞、硝酸苯汞、对羟基苯甲酸甲酯、苯乙醇、氨、二硫代苏糖醇、β-巯基乙醇、碳酸钠、硼酸钠、磷酸钠、乙酸钠、重碳酸钠、白糖、粉糖、蔗糖、果糖、葡萄糖、乳糖、还原麦芽糖糖浆、粉末还原麦芽糖糖浆、葡萄糖果糖液糖、果糖葡萄糖液糖、蜂蜜、赤藻糖醇、阿司帕坦、糖精、糖精钠及明胶等。
本发明涉及的药物含有肽的情况下，作为改善肽等不易经粘膜吸收的难吸收性药物的吸收的促进剂，可使用聚氧乙烯月桂基醚类、十二烷基硫酸钠、皂角苷等表面活性剂；甘氨胆酸、脱氧胆酸、牛磺胆酸等的胆汁酸盐；EDTA、水杨酸类等螯合剂；己酸、癸酸、月桂酸、油酸、亚油酸、混合胶束等脂肪酸类；烯胺衍生物、N-酰基胶原蛋白肽、N-酰基氨基酸、环糊精类、脱乙酰壳多糖类、一氧化氮供体等。
本发明涉及的药物含有肽的情况下，可以将其封入或吸附于聚乳酸·乙醇酸(PLGA)微囊、多孔性羟基磷灰石微粒等中而赋予其缓释性，也可利用脉冲放射型离子导入贴剂而使药物经皮吸收。
对于本发明涉及的药物而言，可以以一种制剂的形式而含有TLR激动剂、和LAG-3蛋白、其突变体或其衍生物，也可以是各自不同的制剂的形式，即，含有TLR激动剂的制剂与含有LAG-3蛋白、其突变体或其衍生物的制剂的组合。
另外，本发明涉及的药物可以以一种制剂的形式而含有诱导对于癌细胞的特异性免疫应答的物质、TLR激动剂、和LAG-3蛋白、其突变体或其衍生物，也可以是各自不同的制剂的形式，即，含有诱导对于癌细胞的特异性免疫应答的物质的制剂，含有TLR激动剂的制剂，和含有LAG-3蛋白、其突变体或其衍生物的制剂的组合。可以将诱导对于癌细胞的特异性免疫应答的物质、TLR激动剂、和LAG-3蛋白、其突变体或其衍生物制成含有2种成分的制剂和含有剩余1种成分的制剂的组合，只要成为3种成分的组合，则也可以是含有任选2种的成分的制剂与含有任选的2种成分的制剂的组合。
另外，本发明涉及的药物也可以是试剂盒。为试剂盒的情况下，试剂盒可包含TLR激动剂、和LAG-3蛋白、其突变体或其衍生物，也可包含诱导对于癌细胞的特异性免疫应答的物质、TLR激动剂、和LAG-3蛋白、其突变体或其衍生物。
将本发明涉及的药物用作癌症疫苗的情况下，也可包含补加的佐剂。作为追加的佐剂的非限定性例子，可举出氢氧化铝、氢氧化钠、磷酸铝、磷酸钙、明矾及羧基乙烯基聚合物等沉降性佐剂，以及弗氏完全佐剂、弗氏不完全佐剂、液体石蜡、羊毛脂、MontanideISA763AV及Montanide ISA51等油性佐剂。
本发明涉及的药物在任一形态下均可与其他的抗癌剂合用，也可与放疗、外科性治疗进行组合。作为其他的抗癌剂，可举出阿霉素、道诺霉素、丝裂霉素、顺铂、长春新碱、表阿霉素、甲氨喋呤、5-氟尿嘧啶、阿克拉霉素、氮芥、环磷酰胺、博来霉素、柔红霉素、多柔比星、长春新碱、长春碱、长春地辛、他莫昔芬及地塞米松等低分子化合物；激活免疫活性细胞的细胞因子(例如人白细胞介素2、人粒细胞巨噬细胞集落刺激因子、人巨噬细胞集落刺激因子及人白细胞介素12)等的蛋白质。
本发明也包括施予治疗有效量的本发明涉及的药物来治疗癌症的方法。治疗有效量可由本领域技术人员根据患者的症状、年龄、性别、体重、敏感性差异、施予方法、施予间隔、制剂的种类等而适宜决定。
本发明中，通过向需要的患者施予TLR激动剂、和LAG-3蛋白、其突变体或其衍生物，能够治疗或预防患者的疾病。另外，本发明中，也提供诱导对于癌细胞的特异性免疫应答的方法，所述方法中，向需要的患者施予TLR激动剂、和LAG-3蛋白、其突变体或其衍生物。
在对患者的疾病进行治疗或预防的情况下，或诱导对于癌细胞的特异性免疫应答的方法中，也可以进一步施予诱导对于癌细胞的特异性免疫应答的物质，优选为源于癌抗原的肽。
通过诱导对于癌细胞的特异性免疫应答，诱导对于癌细胞的特异性免疫应答的物质优选能够使源于癌抗原的肽的药效更强地发挥。
本发明涉及的药物优选联合施予。
所谓联合施予本发明涉及的药物，是指向患者施予TLR激动剂、和LAG-3蛋白、其突变体或其衍生物即可，可以分别以任意的组合，同时以及不同时地进行施予。另外，本发明涉及的药物含有诱导对于癌细胞的特异性免疫应答的物质时，可将诱导对于癌细胞的特异性免疫应答的物质、TLR激动剂、和LAG-3蛋白、其突变体或其衍生物分别以任意的组合，同时以及不同时地进行施予。
同时进行施予时，可作为一种制剂而同时进行施予，也可在施予时将TLR激动剂、与LAG-3蛋白、其突变体或其衍生物进行混合、制备成施予制剂后同时进行施予。
不同时地进行施予时，可在施予TLR激动剂后施予LAG-3蛋白、其突变体或其衍生物，也可在施予LAG-3蛋白、其突变体或其衍生物后施予TLR激动剂。
另外，本发明涉及的药物含有诱导对于癌细胞的特异性免疫应答的物质的情况下，同时进行施予时，可作为一种制剂而同时进行施予，也可在施予时将诱导对于癌细胞的特异性免疫应答的物质、TLR激动剂、与LAG-3蛋白、其突变体或其衍生物进行混合、制备成给药制剂后同时进行施予。
不同时地进行施予时，可在施予诱导对于癌细胞的特异性免疫应答的物质后，分别同时或不同时地施予TLR激动剂、和LAG-3蛋白、其突变体或其衍生物，也可在同时或不同时地施予TLR激动剂、和LAG-3蛋白、其突变体或其衍生物后，施予诱导对于癌细胞的特异性免疫应答的物质，另外，也可在施予TLR激动剂、和LAG-3蛋白、其突变体或其衍生物中的一者后，施予诱导对于癌细胞的特异性免疫应答的物质，继而施予TLR激动剂、和LAG-3蛋白、其突变体或其衍生物中的另一者。不同时地进行施予时，可根据各成分的特性，基于各成分的施予间隔，即基于各成分的施予方案(regimen)进行施予。
本说明书中引用的全部专利文献及非专利文献的公开内容均以通过参考而整体并入本说明书中。
[实施例1]
以下，基于实施例具体地说明本发明，但本发明并不限定于这些实施例。本领域技术人员可在不脱离本发明的意义的情况下以各种方式对本发明进行变更，这些变更也包含于本发明的范围内。
1.癌症疫苗
基于图1所示的方案，对使用了源于癌抗原的肽的癌症疫苗中的各种佐剂的效果进行了比较。
材料
作为癌症模型小鼠，向DBA/2小鼠中移植P815细胞(源于DBA/2小鼠的小鼠肥大细胞瘤)而进行使用。
作为源于癌抗原的肽，使用了由作为P815肿瘤的肿瘤抗原的P1A蛋白质的部分序列构成、且已知呈现出MHC的H-2Ld限制性的肽(以下称为“P1A肽”。)。P1A肽的氨基酸序列为LPYLGWLVF(序列号1)。
作为P1A CTL，使用了表达对P1A肽进行识别的T细胞受体的T细胞。实验中，从本申请发明人所拥有的P1A-CTL转基因小鼠采集脾脏，通过TCR Vα8.3(已导入基因的TCR的标记)确认阳性率，基于其结果确定P1A-CTL的细胞数量，进行施予。
作为佐剂，使用了以下的物质。
百日咳菌全菌体(PT)(BioFarma，印度尼西亚万隆市)
Poly I:C(TLR3激动剂)(Invivogen，美国圣地亚哥)
CpG(TLR9激动剂)(Invivogen，美国圣地亚哥)
IFA(弗氏不完全佐剂)(Seppic，法国巴黎)
LAG-3(Adipogen，美国圣地亚)
方法
向每1只DBA/2小鼠皮下接种5×105个细胞的P815肿瘤细胞，以当日作为第0日。在第8日向每1只静脉注射2.5×105个细胞的P1A CTL。在第9日及第16日，向每1只小鼠皮下注射将50μg的P1A肽与佐剂混合在PBS中而得到的制剂。将小鼠分成9组，每组5只，分别使用了以下的佐剂。
1组：PBS(对照)
2组：IFA(50μL/只小鼠)
3组：PT(1×108/只小鼠)
4组：Poly IC(50μg/只小鼠)
5组：Poly IC(50μg/只小鼠)+CPG(10μg/只小鼠)
6组：LAG-3(1μg/只小鼠)
7组：LAG-3(1μg/只小鼠)+Poly IC(50μg/只小鼠)
结果
将第7日以后的所有小鼠的肿瘤大小(mm3)的变化示于图2～8。
在1～6组中，各组的肿瘤大小均缓缓增大，多数小鼠在中途死亡。就肿瘤大小直至第70日仍然不增大、且存活的小鼠而言，2、3及6组中为0只，1及4组中为1只，5组中为3只，在7组中，全部5只小鼠中均未观察到肿瘤大小的增大，并存活至第115日。
2.免疫细胞向癌组织的浸润
向每1只DBA/2小鼠皮下接种5×105个细胞的P815肿瘤细胞，制备癌症模型小鼠，以当日作为第0日。在第8日向每1只静脉注射2.5×105个细胞的P1A CTL。在第9日及第14日，向每1只小鼠皮下注射将50μg的P1A肽与佐剂混合在PBS中得到的制剂。对各小鼠使用了以下的佐剂。
1组：IFA(50μL/只小鼠)
2组：Poly IC(50μg/只小鼠)
3组：LAG-3(1μg/只小鼠)
4组：LAG-3(1μg/只小鼠)+Poly IC(50μg/只小鼠)
然后，在第21日采集肿瘤组织，制作肿瘤组织切片的标本后，通过苏木精·曙红染色观察组织图像，并且进行细胞核及免疫细胞(CD4细胞及CD8细胞)的荧光染色。
荧光组织染色使用了以下的试剂。
细胞核：ProLongR Gold Antifade Reagent with DAPI(Invitrogen)
CD4细胞一抗：大鼠抗小鼠CD4纯化IgG2b.克隆:GK1.5(eBioscience)
CD4细胞二抗：小鼠单克隆(2B 10A8)抗大鼠IgG2b重链(Alexa FluorR 647)，(abcam)
CD8细胞一抗：大鼠抗小鼠CD8α纯化IgG2a.克隆:53-6.7(eBioscience)
CD8细胞二抗：小鼠单克隆(2A 8F4)抗大鼠IgG2a重链(Alexa FluorR 488)(abcam)
将苏木精·曙红染色图像示于图9A，将细胞核及免疫细胞的荧光染色图像示于图9B。将LAG-3与poly IC组合作为佐剂时，观察到CD4细胞及CD8细胞向肿瘤组织的显著的浸润。
3.在排斥肿瘤的小鼠中的针对同一肿瘤的排斥能力的维持
向每1只DBA/2小鼠皮下接种5×105个细胞的P815肿瘤细胞，制备癌症模型小鼠，以当日作为第0日。在第8日向每1只小鼠静脉注射2.5×105个细胞的P1A CTL。在第9日及第14日，向每1只小鼠皮下注射将50μg的P1A肽与佐剂在PBS中混合得到的制剂。作为佐剂，使用了LAG-3(1μg/只小鼠)+Poly IC(50μg/只小鼠)。
接下来，使用即使接种P815肿瘤细胞也未观察到肿瘤大小的增大、被判断为排斥了肿瘤的DBA/2小鼠，以及未经过任何处理的未处理(naive)DBA/2小鼠，再次皮下接种每1只为1×106个细胞的P815肿瘤细胞、或每1只为1×106个细胞的L1210肿瘤细胞。针对判断为已排斥了肿瘤的DBA/2小鼠，在自最初的P815细胞接种起115日后(第115日)，再次接种肿瘤细胞。
图10左示出了接种L1210细胞后的小鼠的平均肿瘤大小(mm3)的变化，图10右示出了接种P815细胞后的小鼠的平均肿瘤大小(mm3)的变化。两图中○是被判断为排斥了肿瘤的DBA/2小鼠、●是未处理DBA/2小鼠。
未处理DBA/2小鼠中，即使接种P815细胞及L1210细胞中的任一者，也可观察到肿瘤大小的增大。另一方面，被判断为排斥了由P815细胞导致的肿瘤增大的小鼠中，虽然能够观察到伴随作为其他肿瘤细胞的L1210细胞接种而产生的肿瘤大小的增大，但观察不到伴随P815细胞接种而产生的肿瘤大小的增大，从而确认到在小鼠侧维持了针对同一肿瘤的排斥能力。
4.免疫细胞的增殖能力及细胞上清液中的细胞因子等的测定
向每1只DBA/2小鼠皮下接种5×105个细胞的P815肿瘤细胞，制备癌症模型小鼠，以当日作为第0日。在第8日向每1只静脉注射2.5×105个细胞的P1A CTL。在第9日及第14日，向每1只小鼠皮下注射将50μg的P1A肽与佐剂混合在PBS中而得到的制剂。对各小鼠使用了以下的佐剂。
1组：IFA(50μL/只小鼠)
2组：Poly IC(50μg/只小鼠)
3组：LAG-3(1μg/只小鼠)
4组：LAG-3(1μg/只小鼠)+Poly IC(50μg/只小鼠)
然后，在第21日采集腋窝或鼠蹊部的淋巴结中靠近肿瘤部位的淋巴结，将分离得到的免疫细胞1.5×105个与经100Gy射线照射的P815细胞4×104个共同培养3日。
免疫细胞增殖能力通过下述方法进行测定：向培养上清液中添加3H-胸腺嘧啶核苷(thymidine)(37KBq/孔)，在4小时后测定被细胞摄取的3H-胸腺嘧啶核苷的放射活性。
细胞上清液中的细胞因子量使用Bio-Plex Pro mouse cytokine23-PlexImmunoassay kit(BIO-RAD)进行测定。
将免疫细胞增殖能力的测定结果示于图11A，将细胞因子等的测定结果示于图11B。
在将LAG-3和poly IC组合作为佐剂时，观察到免疫细胞增殖能力的增大。另外，细胞因子等中，将LAG-3和poly IC组合作为佐剂时，可知IFN-gamma、GM-CSF、IL-4、IL-5、IL-17A的产生增加。
5.免疫细胞的细胞表面标记分子的测定
向每1只DBA/2小鼠皮下接种5×105个细胞的P815肿瘤细胞，制备癌症模型小鼠，以当日作为第0日。在第8日向每1只静脉注射2.5×105个细胞的P1A CTL。在第9日及第14日，对每1只小鼠皮下注射将50μg的P1A肽与佐剂混合在PBS中而得到的制剂。对于各小鼠使用了以下的佐剂。
1组：IFA(50μL/只小鼠)
2组：Poly IC(50μg/只小鼠)
3组：LAG-3(1μg/只小鼠)
4组：LAG-3(1μg/只小鼠)+Poly IC(50μg/只小鼠)
然后，在第21日采集腋窝或鼠蹊部的淋巴结中靠近肿瘤部位的淋巴结，回收CD8及Vα8.3表达为阳性的细胞群(杀伤性T细胞)、或CD4及Vα8.3表达为阳性的细胞群(辅助性T细胞)。
对细胞(CD4细胞及CD8细胞)的细胞表面标记分子PD-1、BTLA、TIGIT及LAG-3的表达量进行了测定。作为针对细胞表面标记分子的抗体，使用了以下的抗体。
PD-1：抗小鼠CD279(PD-1)PE.克隆：J43(eBioscience)
BTLA：抗小鼠CD272(BTLA)PE.克隆：8F4(eBioscience)
TIGIT：PE抗小鼠TIGIT(Vstm3)抗议.克隆：1G9(BioLegend)
LAG-3：抗小鼠CD223(Lag-3)PE.克隆：eBioC9B7W(C9B7W)(eBioscience)
CD8细胞的结果示于图12A，CD4细胞的结果示于图12B。
将LAG-3与poly IC组合作为佐剂时，对于PD-1、TIGIT、LAG-3，CD4阳性细胞及CD8阳性细胞均观察到了显著的表达量的减少，但BTLA的表达量的减少较少。
6.使用了B16-F10黑色素瘤接种模型小鼠的细胞因子等的测定
向每1只C57BL/6小鼠皮下接种1×105个的B16-F10黑色素瘤细胞，制备癌症模型小鼠，以当日作为第0日。在第8日，对每1只小鼠皮下注射将50μg的gp100肽与佐剂混合在PBS中而得到的制剂。对各小鼠使用了以下的佐剂。gp100肽的氨基酸序列为KVPRNQDWL(序列号2)。
1组：IFA(50μL/只小鼠)
2组：Poly IC(50μg/只小鼠)
3组：LAG-3(1μg/只小鼠)
4组：LAG-3(1μg/只小鼠)+Poly IC(50μg/只小鼠)
然后，在第14天，采集腋窝或鼠蹊部的淋巴结中靠近肿瘤部位的淋巴结(或这两个部位的淋巴结)，将分离得到的免疫细胞以每1孔为3×105个、在10、5、2.5或0μg/mL的gp100肽的存在下进行培养。
免疫细胞增殖能力通过下述方法测定：向培养上清液中添加3H-胸腺嘧啶核苷(37KBq/孔)，对在为期3日的培养中的最后10小时期间内被细胞摄取的3H-胸腺嘧啶核苷的放射活性进行测定。
在10μg/mL的gp100肽的存在下培养3日后得到的细胞上清液中的IFN-gamma产生量使用Bio-Plex Pro mouse cytokine 23-Plex Immunoassay kit(BIO-RAD)进行测定。
将免疫细胞增殖能力的测定结果示于图13A，将IFN-gamma产生量的测定结果示于图13B。图13A中，●表示1组的结果，□表示2组的结果，■表示3组的结果，○表示4组的结果。
即使在使用了B16-F10黑色素瘤接种模型小鼠体系的情况下，将LAG-3和poly IC组合作为佐剂时，仍然观察到了gp100肿瘤抗原特异性免疫细胞增殖能力的增大及IFN-gamma产生量的增加。
在将LAG-3与poly IC组合作为佐剂时，与肿瘤模型体系及成为免疫抗原的肽的种类无关，均确认到了发挥显著的免疫系统的活性效果的结果。
7.由免疫佐剂组合带来的肿瘤增殖抑制效果
作为佐剂使用了以下的物质。
Poly I:C(TLR3激动剂)(Invivogen，美国圣地亚哥)
RIBOXXOL(TLR3激动剂)(Riboxx，德国拉德博伊尔)
MPL(TLR4激动剂)(Invivogen，美国圣地亚哥)
咪喹莫特(TLR7/8激动剂)(Invivogen，美国圣地亚哥)
CpG(TLR9激动剂)(Invivogen，美国圣地亚哥)
LAG-3(Adipogen，美国圣地亚哥)
向每1只DBA/2小鼠皮下接种5×105个细胞的P815肿瘤细胞，制备癌症模型小鼠，以当日作为第0日。在第7日，向每1只静脉注射2.5×105个细胞的P1A CTL。在第8日及第15日，对每1只小鼠皮下注射将50μg的P1A肽与佐剂混合在PBS中而得到的制剂。将小鼠分成9组，每组4只或每5只，分别使用了以下的佐剂。
1组：仅P1A肽(对照)
2组：Poly IC(50μg/只小鼠)
3组：Poly IC(50μg/只小鼠)+LAG-3(1μg/只小鼠)
4组：无P1A肽、仅Poly IC(50μg/只小鼠)+LAG-3(1μg/只小鼠)
5组：RIBOXXOL(100μg/只小鼠)
6组：RIBOXXOL(100μg/只小鼠)+LAG-3(1μg/只小鼠)
7组：MPL(10μg/只小鼠)+LAG-3(1μg/只小鼠)
8组：咪喹莫特(50μg/只小鼠)+LAG-3(1μg/只小鼠)
9组：CpG(10μg/只小鼠)+LAG-3(1μg/只小鼠)
将第7日以后的所有小鼠的肿瘤大小(mm3)的变化示于图14～20所示。
1组中，直到第40日为止，5只中的5只全部死亡，但2组中，5只中存活4只，3组中，5只中存活5只，4组中，5只中存活2只，5～7组中，5只中存活1只，此外，3组中，5只中3只存活至第66日为止。通过将2组～4组、5组、和6组进行比较，显示出了佐剂的合用效果。另外，在不施予P1A肽的4组中，到第43日为止，全部小鼠均死亡，这表明同时施予佐剂和P1A肽的方案是优选的。
8.使用了B16-F10黑色素瘤接种模型小鼠的免疫佐剂组合带来的肿瘤增殖抑制效
果
向每1只C57BL/6小鼠皮下接种1×105个B16-F10黑色素瘤细胞，制备癌症模型小鼠，以当日作为第0日。在第5日及第12日共2次，向每1只小鼠皮下注射将50μg的gp100肽与佐剂在PBS中进行混合而得到的制剂。对各小鼠使用了以下的佐剂。
1组：IFA(50μL/只小鼠)
2组：Poly IC(50μg/只小鼠)
3组：LAG-3(1μg/只小鼠)
4组：LAG-3(1μg/只小鼠)+Poly IC(50μg/只小鼠)
在第5日以后的全部小鼠的肿瘤大小(mm3)的变化示于图21～24。对于各组5只小鼠而言，1组中在第31日5只全部死亡，2组中在第35日5只全部死亡，3组中在第37日5只全部死亡，另一方面，4组在第57日5只全部死亡。与1组相比，在2组及3组中无法确认到显著的存活时间的延长，但在4组中，相对于1、2及3组这3组而言，确认到了显著的存活时间的延长。
序列表自由文本
序列号1示出了P1A肽的氨基酸序列。
序列号2示出了gp100肽的氨基酸序列。
Claims (11)
1.药物，所述药物含有：
PolyI:C或其盐；和
LAG-3蛋白与IgG的融合蛋白。
2.如权利要求1所述的药物，所述药物用于联合施予下述成分：
PolyI:C或其盐；和
LAG-3蛋白与IgG的融合蛋白。
3.如权利要求1所述的药物，所述药物还含有至少1种诱导对于癌细胞的特异性免疫应答的物质。
4.如权利要求3所述的药物，所述药物用于联合施予下述成分：
PolyI:C或其盐；
LAG-3蛋白与IgG的融合蛋白；和
至少1种诱导对于癌细胞的特异性免疫应答的物质。
5.如权利要求3所述的药物，其中，所述诱导对于癌细胞的特异性免疫应答的物质为源于癌抗原的肽。
6.如权利要求5所述的药物，所述药物含有2种以上源于癌抗原的肽。
7.如权利要求1所述的药物，所述药物用于癌症疫苗疗法。
8.如权利要求7所述的药物，所述药物为抗癌剂。
9.佐剂，其用于诱导对于癌细胞的特异性免疫应答，所述佐剂含有：
PolyI:C或其盐；和
LAG-3蛋白与IgG的融合蛋白。
10.如权利要求3所述的药物，其用于癌症疫苗疗法。
11.如权利要求10所述的药物，所述药物为抗癌剂。
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| ES2805829T3 (es) | 2015-03-09 | 2021-02-15 | Cytlimic Inc | Péptido derivado de GPC3, composición farmacéutica para el tratamiento o la prevención de cáncer usando el mismo, inductor de inmunidad y método para producir células presentadoras de antígeno |
| EP3281641B1 (en) | 2015-04-07 | 2020-12-16 | Cytlimic Inc. | Adjuvant for cancer vaccines |
| EP3527216B1 (en) | 2016-10-11 | 2024-02-14 | NEC Corporation | A medicine comprising a toll-like receptor agonist, lag-3 protein, a hsp70-derived peptide and a gpc3-derived peptide |
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