CN103961702A - 粘膜给予用wt1肽癌症疫苗组合物 - Google Patents
粘膜给予用wt1肽癌症疫苗组合物 Download PDFInfo
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- CN103961702A CN103961702A CN201410043724.4A CN201410043724A CN103961702A CN 103961702 A CN103961702 A CN 103961702A CN 201410043724 A CN201410043724 A CN 201410043724A CN 103961702 A CN103961702 A CN 103961702A
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Abstract
本发明提供粘膜给予用WT1肽癌症疫苗组合物。本发明的目的在于,通过选择对WT1肽和/或经改变的WT1肽而言最适合的细胞免疫诱导促进剂,提供效能更高的癌症疫苗用组合物。本发明提供包含(i)WT1肽和/或经改变的WT1肽;以及(ii)第一细胞免疫诱导促进剂的用于诱导细胞免疫的粘膜给予用癌症疫苗组合物。
Description
技术领域
本发明涉及包含WT1肽和/或经改变的WT1肽、以及细胞免疫诱导促进剂的粘膜给予用癌症疫苗用组合物。
背景技术
癌症疫苗有为了预防由病毒引发的癌症而防止病毒感染的观点的疫苗,和通过使免疫系统、特别是细胞毒性T细胞(CTL)发挥重要的作用的细胞免疫系统识别肿瘤特异性抗原从而通过免疫体系特异性攻击癌细胞的观点的疫苗。前者对不是病毒引发的癌症完全没有效果,但后者属于将癌细胞自身具有的抗原作为靶的癌症治疗策略,因此,我们认为,通过确定抗原,对具有该抗原的癌症是广泛有效的。尤其是基于后者的观点的癌症疫苗能够治疗通过外科手术难以切除的尺寸的肿瘤,而且与化学疗法、放射线疗法等现有的治疗方法相比较副作用低。
WT1(肾胚细胞瘤(Wilm’s肿瘤))基因在很多的造血器官肿瘤、实体肿瘤、例如急性骨髓性白血病、急性淋巴性白血病、慢性骨髓性白血病、骨髓增生异常综合征、多发性骨髓瘤、非霍奇金氏淋巴瘤、肺癌、乳腺癌、胃癌、大肠·直肠癌、胰腺癌、胆管癌、头颈部扁平上皮癌、甲状腺癌、肾癌、前列腺癌、卵巣癌、子宫癌、骨与软组织肉瘤、恶性黑色素瘤、恶性间皮瘤、睾丸生殖细胞肿瘤及恶性胶质瘤中过量地表达,在癌细胞内产生过量的作为WT1基因生成物的WT1蛋白。WT1蛋白在癌细胞内被片段化,产生由8~12个氨基酸构成的属于部分肽的WT1肽。WT1肽在癌细胞内与MHC I类分子结合而得到的物质转移到癌细胞表面,在癌细胞表面以与MHC I类分子结合的形态作为抗原提呈,成为癌细胞的标记。WT1肽的氨基酸序列成为与细胞的MHC I类分子的类型相符的序列。例如在具有HLA-A*0201型MHC的细胞的情况下,作为WT1肽,产生由9个氨基酸构成的Db126肽等HLA-A*0201型MHC限制性肽,在具有HLA-A*2402型MHC的细胞的情况下,作为WT1肽,产生由9个氨基酸构成的Db235肽等HLA-A*2402型MHC限制性肽。在具有HLA-A26型(WO2005/095598)、HLA-A*3303型(WO2007/097358)、HLA-A*1101型(WO2008/081701)等其它MHC的细胞的情况下,产生各自的MHC限制性的WT1肽。作为抗原,将WT1肽、或者其一部分氨基酸被置换或者经过修饰了的经改变的WT1肽给予到生物体时(这里,将作为抗原给予的WT1肽或经改变的WT1肽称为“WT1抗原肽”),WT1抗原肽在作为抗原提呈细胞的树突状细胞的表面与MHC类分子结合、或暂时进入树突状细胞内而在树突状细胞内与MHC I类分子结合而得到的物质转移到树突状细胞表面,在树突状细胞表面以与MHC I类分子结合的形态作为抗原提呈。具有WT1抗原肽/MHC I类分子复合体的激活了的树突状细胞转移到区域淋巴结,激活用于识别该WT1抗原肽/MHC I类分子复合体的CD8阳性T淋巴细胞,使其分化成细胞毒性T细胞(CTL)而增殖。CTL识别具备与WT1抗原肽具有相同的氨基酸序列的WT1肽(来源于内源性WT1蛋白)和MHC I类分子的复合体的肿瘤细胞、或者具备与WT1抗原肽具有交叉免疫反应性的氨基酸序列的WT1肽(来源于内源性WT1蛋白)和MHC I类分子的复合体的肿瘤细胞,并攻击该肿瘤细胞。因此,Db126肽、Db235肽这样的上述各种MHC限制性的WT1肽、它们的一部分氨基酸被置换或者经过修饰了的经改变的WT1肽作为癌症疫苗是有用的(非专利文献1)。
为了提高WT1肽和/或经改变的WT1肽的作为癌症疫苗的作用,还已知利用佐剂。作为WT1肽和/或经改变的WT1肽的佐剂,例如已知氢氧化铝这样的矿物凝胶;溶血卵磷脂、PLURONIC POLYOL这样的表面活性剂;聚阴离子;肽;或油乳剂(专利文献1);或者GM-CSF、BCG-CWS或MontanideISA51(非专利文献1)。除此以外,还已知各种各样的疫苗佐剂,可以列举出:例如1H-咪唑并〔4,5-c〕喹啉-4-胺、例如咪喹莫特(Imiquimod)(专利文献2)、环状二GMP(c-di-GMP)这样的环状二核苷酸类似物(专利文献3及专利文献4)、TLR2,3,7,8,9配体(专利文献5)。另外还已知,通过在含咪喹莫特的肽透皮免疫中加入Peptide-25,可以进一步增强免疫(非专利文献2)。
作为疫苗的给予途径,皮下或皮内注射是最一般的,除此以外,也尝试了利用各种各样的给予途径例如经皮给予(专利文献5及非专利文献2)、颊部给予、鼻腔给予、舌下给予等粘膜给予(非专利文献3、专利文献6、专利文献7)的免疫诱导。
现有技术文献
专利文献
专利文献1:日本专利第4422903号公报
专利文献2:日本特表平7-505883号公报
专利文献3:日本特表2007-529531号公报
专利文献4:美国专利申请公开US2008/0286296号
专利文献5:美国专利申请公开US2008/0193487号
专利文献6:日本特表2002-531415号公报
专利文献7:美国专利申请公开US2008/0112974号
非专利文献
非专利文献1:Yoshihiro Oka et al.,Current Opinion inImmunology,20:211-220(2008)
非专利文献2:Hosoi Akihiro et al.,Cancer Research,68,3941-3949(2008)
非专利文献3:Zhengrong Cui et al.,Pharmaceutical Research,Vol.19,No.7,947-953(2002)
发明内容
发明要解决的问题
为了提高疫苗的效能而使用佐剂是大家所周知的,但适合的佐剂通常随着抗原的种类、给予途径、想要诱导的免疫(即细胞免疫或体液免疫)等而改变。另外,除佐剂以外,还存在各种各样的用于促进免疫诱导的物质。因此,本发明的目的在于,提供效能更高、便利性更高的癌症疫苗用组合物。
被广泛使用的疫苗是给予微生物或者病毒自身或它们的一部分来进行免疫的物质。通常,微生物、病毒由于其尺寸的原因而可以通过皮肤阻止侵入,因此,不能容易地从皮肤给予,并且,口服给予时,被胃酸及消化酶分解,因此这些给予方法都不容易。从这样的观点考虑,通常使用侵入式地给予到体内的注射剂。但是,注射存在如下的问题:疼痛、恐惧心理、注射伤痕及注射伤痕发展而成的疤痕、只有医务工作者才能进行注射、免疫效果高的皮内注射的给予手艺难、存在医务工作者的针扎感染事故的风险、进行反复给予时需要经常去医院而成为患者的生活负担、产生注射针等需要特殊废弃的医疗废弃物等问题,因此,其并不能说是最佳的给予途径。
WT1肽和/或经改变的WT1肽可以借助MHC I类分子激活CTL(细胞毒性T细胞),即可以诱导细胞免疫。另外,WT1肽和/或经改变的WT1肽为由8~12个氨基酸构成的分子量约700~约1600的分子,虽然说不上是低分子,但比微生物、病毒自身小非常多,因此,也可以考虑通过注射以外的给予途径给予的可能性,但这样的制剂尚未开发出来。其理由多种多样,例如为适合的细胞免疫诱导促进剂尚不明确、是否能将抗原送达至适合于诱导细胞免疫的组织尚不明确等。尤其是在除注射以外的给予途径中为了诱导细胞免疫而给予抗原时能够使用的细胞免疫诱导促进剂尚不明确。
用于解决问题的方案
对利用WT1肽和/或经改变的WT1肽的粘膜给予来进行的细胞免疫诱导所优选的细胞免疫诱导促进剂进行了研究,结果发现,适宜使用的是:Pam3CSK4、Poly(I:C)、脂多糖、咪喹莫特、雷西莫特这样的TLR配体;环状二GMP及环状二AMP这样的环状二核苷酸;左旋咪唑盐酸盐这样的免疫调节低分子药物;依托度酸及洛索洛芬这样的环氧酶抑制剂;EP2受体拮抗剂、EP4受体拮抗剂、DP受体拮抗剂、IP受体拮抗剂这样的前列腺素受体拮抗剂;EP3受体激动剂这样的前列腺素受体激动剂;盐酸小檗碱及柚皮素这样的TSLP产生抑制剂;2’,5’-双脱氧腺苷及烟酸这样的腺苷酸环化酶抑制剂;二十碳五烯酸及二十二碳六烯酸这样的ω-3脂肪酸;PPAR-α激动剂、PPAR-δ激动剂、PPAR-γ激动剂这样的PPAR激动剂;D1受体拮抗剂、D5受体拮抗剂这样的多巴胺受体拮抗剂;D2受体激动剂、D3受体激动剂、D4受体激动剂这样的多巴胺受体激动剂;H1受体拮抗剂、H2受体拮抗剂这样的组胺受体拮抗剂;H1受体激动剂、H3受体激动剂、H4受体激动剂这样的组胺受体激动剂;5-HT2受体拮抗剂、5-HT4受体拮抗剂、5-HT6受体拮抗剂、5-HT7受体拮抗剂这样的血清素受体拮抗剂;5-HT1受体激动剂、5-HT2受体激动剂这样的血清素受体激动剂;V2受体拮抗剂这样的加压素受体拮抗剂;V1受体激动剂这样的加压素受体激动剂;M1受体拮抗剂、M3受体拮抗剂、M5受体拮抗剂这样的毒蕈碱受体拮抗剂;M1受体激动剂、M2受体激动剂、M3受体激动剂、M4受体激动剂、M5受体激动剂这样的毒蕈碱受体激动剂;α1受体拮抗剂、β1受体拮抗剂、β2受体拮抗剂、β3受体拮抗剂这样的肾上腺素受体拮抗剂;α1受体激动剂、α2受体激动剂这样的肾上腺素受体激动剂;AT2受体激动剂这样的血管紧张素受体激动剂;GABAB受体激动剂这样的GABA受体激动剂;PAR-1受体拮抗剂这样的凝血酶受体拮抗剂;PAR-1受体激动剂这样的凝血酶受体激动剂;丁丙诺啡这样的阿片类受体激动剂;CysLT1受体拮抗剂、CysLT2受体拮抗剂这样的白三烯受体拮抗剂;BLT受体激动剂这样的白三烯受体激动剂;腺苷二磷酸这样的ADP受体激动剂;褪黑素这样的褪黑素受体激动剂;奥曲肽这样的生长抑素受体激动剂;屈大麻酚这样的大麻素受体激动剂;芬戈莫德这样的鞘氨醇1-磷酸受体激动剂;mGluR2受体激动剂、mGluR3受体激动剂、mGluR4受体激动剂、mGluR6受体激动剂、mGluR7受体激动剂、mGluR8受体激动剂这样的代谢型谷氨酸受体激动剂;甘草酸这样的磷脂酶A2抑制剂;吡非尼酮这样的TGF-β产生抑制剂;甲磺司特这样的Th2细胞因子抑制剂;癸酸、月桂酸、肉豆蔻酸、异硬脂酸、油酸这样的药理学上容许的酸或其药理学上容许的盐;及Peptide-25这样的辅助肽。
发明人等发现,口腔粘膜给予中,尤其适宜使用的是:Pam3CSK4这样的TLR1/2配体;Pam2CSK4、MALP-2及FSL-1这样的TLR2/6配体;脂多糖、脂质A、单磷酰脂这样的TLR4配体;咪喹莫特、雷西莫特、洛索立宾、及TLR7-II这样的TLR7和/或TLR8配体;环状二GMP、环状二AMP这样的环状二核苷酸;左旋咪唑盐酸盐这样的免疫调节低分子药物;辅助肽;环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂、或它们的2种以上的组合。进而还发现,利用下述组合能显著地增强细胞免疫:这些TLR配体和辅助肽的组合、环状二核苷酸和辅助肽的组合、免疫调节低分子药物和辅助肽的组合、环氧酶抑制剂和辅助肽的组合、前列腺素受体拮抗剂和辅助肽的组合、前列腺素受体激动剂和辅助肽的组合、TSLP产生抑制剂和辅助肽的组合、腺苷酸环化酶抑制剂和辅助肽的组合、ω-3脂肪酸和辅助肽的组合、PPAR激动剂和辅助肽的组合、多巴胺受体拮抗剂和辅助肽的组合、多巴胺受体激动剂和辅助肽的组合、组胺受体激动剂和辅助肽的组合、组胺受体拮抗剂和辅助肽的组合、血清素受体激动剂和辅助肽的组合、血清素受体拮抗剂和辅助肽的组合、加压素受体拮抗剂和辅助肽的组合、加压素受体激动剂和辅助肽的组合、毒蕈碱受体拮抗剂和辅助肽的组合、毒蕈碱受体激动剂和辅助肽的组合、肾上腺素受体拮抗剂和辅助肽的组合、肾上腺素受体激动剂和辅助肽的组合、血管紧张素受体激动剂和辅助肽的组合、GABA受体激动剂和辅助肽的组合、凝血酶受体拮抗剂和辅助肽的组合、凝血酶受体激动剂和辅助肽的组合、阿片类受体激动剂和辅助肽的组合、ADP受体激动剂和辅助肽的组合、白三烯受体拮抗剂和辅助肽的组合、白三烯受体激动剂和辅助肽的组合、褪黑素受体激动剂和辅助肽的组合、生长抑素受体激动剂和辅助肽的组合、大麻素受体激动剂和辅助肽的组合、鞘氨醇1-磷酸受体激动剂和辅助肽的组合、代谢型谷氨酸受体激动剂和辅助肽的组合、磷脂酶A2抑制剂和辅助肽的组合、TGF-β产生抑制剂和辅助肽的组合、Th2细胞因子抑制剂和辅助肽的组合、药理学上容许的酸或其药理学上容许的盐和辅助肽的组合。
进而还发现,鼻腔粘膜中,尤其是在上述口腔粘膜给予的细胞免疫诱导促进剂的基础上,酵母多糖这样的TLR2及Dectin1配体;Poly(I:C)这样的TLR3配体;匹多莫德、贝他定这样的免疫调节低分子药物也具有效果。
因此,本发明在第一实施方式中提供以下列举的实施方式:
(1)一种粘膜给予用癌症疫苗组合物,其用于诱导细胞免疫,所述组合物包含:
(i)WT1肽和/或经改变的WT1肽;以及
(ii)第一细胞免疫诱导促进剂,其选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂、及它们的2种以上的组合;
(2)根据(1)所述的粘膜给予用癌症疫苗组合物,其中,还包含作为第二细胞免疫诱导促进剂的药理学上容许的酸或其药理学上容许的盐;
(3)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为TLR配体;
(4)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为环状二核苷酸;
(5)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为免疫调节低分子药物;
(6)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为环氧酶抑制剂;
(7)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为前列腺素受体拮抗剂,进而,前列腺素受体拮抗剂为EP2受体拮抗剂、EP4受体拮抗剂、DP受体拮抗剂、IP受体拮抗剂;
(8)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为前列腺素受体激动剂,进而,前列腺素受体激动剂为EP3受体激动剂;
(9)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为TSLP产生抑制剂;
(10)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为腺苷酸环化酶抑制剂;
(11)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为ω-3脂肪酸;
(12)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为PPAR激动剂,进而,PPAR激动剂为PPAR-α激动剂、PPAR-δ激动剂、PPAR-γ激动剂;
(13)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为多巴胺受体拮抗剂,进而,多巴胺受体拮抗剂为D1受体拮抗剂、D5受体拮抗剂;
(14)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为多巴胺受体激动剂,进而,多巴胺受体激动剂为D2受体激动剂、D3受体激动剂、D4受体激动剂;
(15)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为组胺受体拮抗剂,进而,组胺受体拮抗剂为H1受体拮抗剂、H2受体拮抗剂;
(16)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为组胺受体激动剂,进而,组胺受体激动剂为H1受体激动剂、H3受体激动剂、H4受体激动剂;
(17)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为血清素受体拮抗剂,进而,血清素受体拮抗剂为5-HT2受体拮抗剂、5-HT4受体拮抗剂、5-HT6受体拮抗剂、5-HT7受体拮抗剂;
(18)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为血清素受体激动剂,进而,血清素受体激动剂为5-HT1受体激动剂、5-HT2受体激动剂;
(19)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为加压素受体拮抗剂,进而,加压素受体拮抗剂为V2受体拮抗剂;
(20)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为加压素受体激动剂,进而,加压素受体激动剂为V1受体激动剂;
(21)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为毒蕈碱受体拮抗剂,进而,毒蕈碱受体拮抗剂为M1受体拮抗剂、M3受体拮抗剂、M5受体拮抗剂;
(22)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为毒蕈碱受体激动剂,进而,毒蕈碱受体激动剂为M1受体激动剂、M2受体激动剂、M3受体激动剂、M4受体激动剂、M5受体激动剂;
(23)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为肾上腺素受体拮抗剂,进而,肾上腺素受体拮抗剂为α1受体拮抗剂、β1受体拮抗剂、β2受体拮抗剂、β3受体拮抗剂;
(24)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为肾上腺素受体激动剂,进而,肾上腺素受体激动剂为α1受体激动剂、α2受体激动剂;
(25)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为血管紧张素受体激动剂,进而,血管紧张素受体激动剂为AT2受体激动剂;
(26)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为GABA受体激动剂,进而,GABA受体激动剂为GABAB受体激动剂;
(27)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为凝血酶受体拮抗剂,进而,凝血酶受体拮抗剂为PAR-1受体拮抗剂;
(28)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为凝血酶受体激动剂,进而,凝血酶受体激动剂为PAR-1受体激动剂;
(29)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为阿片类受体激动剂;
(30)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为白三烯受体拮抗剂,进而,白三烯受体拮抗剂为CysLT1受体拮抗剂、CysLT2受体拮抗剂;
(31)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为白三烯受体激动剂,进而,白三烯受体激动剂为BLT受体激动剂。
(32)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为褪黑素受体激动剂。
(33)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为生长抑素受体激动剂。
(34)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为大麻素受体激动剂。
(35)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为鞘氨醇1-磷酸受体激动剂。
(36)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为代谢型谷氨酸受体激动剂,进而,代谢型谷氨酸受体激动剂为mGluR2受体激动剂、mGluR3受体激动剂、mGluR4受体激动剂、mGluR6受体激动剂、mGluR7受体激动剂、mGluR8受体激动剂。
(37)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为ADP受体激动剂;
(38)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为磷脂酶A2抑制剂;
(39)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为TGF-β产生抑制剂;
(40)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为Th2细胞因子抑制剂;
(41)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为辅助肽;
(42)根据(1)或(2)所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为选自由TLR配体、环状二核苷酸、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、及Th2细胞因子抑制剂组成的组中的1种以上的物质与辅助肽的组合;
(43)一种粘膜给予用癌症疫苗膜剂,其包含(1)~(42)中任一项所述的组合物,为膜状制剂的形态;
(44)一种粘膜给予用癌症疫苗液体制剂,其包含(1)~(42)中任一项所述的组合物,为液体制剂的形态;及
(45)一种粘膜给予用癌症疫苗口腔崩解片,其包含(1)~(42)中任一项所述的组合物,为口腔崩解片的形态。
在其它实施方式中,本发明的粘膜给予用癌症疫苗用组合物能够用于癌症的治疗或预防。因此,本发明还提供以下列举的实施方式:
(46)一种癌症的治疗或预防方法,其包括将对治疗有效的量的(i)WT1肽和/或经改变的WT1肽、以及(ii)细胞免疫诱导促进剂粘膜给予到对象,所述细胞免疫诱导促进剂选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂、及它们的2种以上的组合;及
(47)一种癌症的治疗或预防方法,其包括将对治疗有效的量的(1)~(42)中任一项所述的粘膜给予用癌症疫苗组合物、(43)的粘膜给予用癌症疫苗膜剂或(44)的粘膜给予用癌症疫苗液体制剂或(45)的粘膜给予用癌症疫苗口腔崩解片给予到对象。
在其它的实施方式中,本发明还提供作为WT1肽和/或经改变的WT1肽的细胞免疫诱导促进剂的TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂、及它们的2种以上的组合。因此,本发明还提供以下的实施方式:
(48)TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂、或它们的2种以上的组合作为WT1肽和/或经改变的WT1肽的粘膜给予用细胞免疫诱导促进剂的应用。
另外,本发明还提供以下的实施方式:
(49)一种细胞免疫诱导方法,其包括将(i)WT1肽和/或经改变的WT1肽、以及(ii)第一细胞免疫诱导促进剂粘膜给予到对象,所述第一细胞免疫诱导促进剂选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂及它们的2种以上的组合;
(50)TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂、或它们的2种以上的组合在促进利用WT1肽和/或经改变的WT1肽的粘膜给予来进行的细胞免疫诱导中的应用;
(51)(i)WT1肽和/或经改变的WT1肽和(ii)第一细胞免疫诱导促进剂的组合在利用WT1肽和/或经改变的WT1肽的粘膜给予来进行的细胞免疫诱导中的应用,所述第一细胞免疫诱导促进剂选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂及它们的2种以上的组合;
(52)用于癌症的治疗或预防的、(i)WT1肽和/或经改变的WT1肽和(ii)细胞免疫诱导促进剂的组合,其通过粘膜给予来给予到对象,所述细胞免疫诱导促进剂选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂及它们的2种以上的组合;及
(53)(i)WT1肽和/或经改变的WT1肽以及(ii)细胞免疫诱导促进剂在粘膜给予用癌症疫苗组合物的制造中的应用,所述细胞免疫诱导促进剂选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂及它们的2种以上的组合。
发明的效果
本发明的粘膜给予用癌症疫苗用组合物由于能够粘膜给予(尤其是鼻腔给予、包括舌下粘膜的口腔粘膜给予)而具有以下优点:优异的依从性,例如非侵入式给予、无痛、不产生对注射的恐惧、因给予方便而患者可以自行给予、还可以避免医务工作者的针扎感染事故的风险、能够减少反复给予时的去医院的频率而有助于提高患者的生活品质、不产生注射针这样的需要特殊废弃的医疗废弃物。进而,本发明的癌症疫苗还具有与单独给予WT1肽和/或经改变的WT1肽相比较,效能显著提高的优点。此外,与注射给予相比较,本发明的粘膜给予用癌症疫苗用组合物的粘膜给予还具有能诱导更强的细胞免疫的优点。
具体实施方式
为了更容易理解本发明,首先,定义本说明书中使用的术语。未进行定义的术语只要没有上下文不同的启示就表示本领域技术人员、尤其是医学、药学、免疫学、细胞生物学、生物化学、高分子化学等领域的从业者所通常理解的意思。
I.定义
在本说明书中使用时,术语“WT1肽”是指由癌基因WT1(Wilm’s肿瘤)的生成物即WT1蛋白片段化而得到的、由约8~约15个、优选约8~约12个氨基酸构成的部分肽,其中包括Db126肽、Db235肽等。另外,WO-2000/06602中公开的WT1生成物的部分肽、WO2005/095598中记载的来源于WT1的HLA-A26结合性癌抗原肽、WO2007/097358中记载的HLA-A*3303限制性WT1肽、及WO2008/081701中记载的HLA-A*1101限制性WT1肽也包含在本发明的“WT1肽”中。
术语“Db126肽”是指由序列Arg Met Phe Pro Asn Ala Pro TyrLeu(序列号1)构成的WT1肽。术语“Db235肽”是指由序列Cys Met ThrTrp Asn Gln Met Asn Leu(序列号2)构成的WT1肽(专利文献1)。
在本说明书使用时,术语“经改变的WT1肽”是指WT1肽的全部或一部分氨基酸通过置换、修饰等而被改变了的肽。
经改变的WT1肽包括例如:
(a)由在WT1肽的氨基酸序列中置换、缺失或附加1个~数个、例如1个、2个、3个、4个或5个氨基酸而得到的氨基酸序列构成的肽;及
(b)由在WT1肽的氨基酸序列中全部或一部分氨基酸、例如1个或多个、例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个或12个氨基酸经过修饰而得到的氨基酸序列构成的肽。
作为经改变的WT1肽可以具有的氨基酸的“修饰”,并不限定于此,例如可以列举出:乙酰化、甲基化等烷基化、糖基化、羟基化、羧基化、醛化、磷酸化、磺酰化、甲酰化、豆蔻酰化、棕榈酰化、硬脂酰化这样的脂肪链附加修饰、辛酰化、酯化、酰胺化、脱酰胺化、胱氨酸修饰、谷胱甘肽修饰、巯基乙酸修饰这样的二硫键形成修饰、糖化、泛素化、琥珀酰亚胺形成、谷酰化、异戊二烯化等。经改变的WT1肽也可以包含组合1个以上氨基酸的置换、缺失或附加、和1个以上氨基酸的修饰。
作为具体例子,Db235肽的一部分改变了的Db235m肽是由序列Cys TyrThr Trp Asn Gln Met Asn Leu(序列号3)构成的经改变的WT1肽(WO2002/079253),包含在本发明的经改变的WT1肽中。WO2004/026897中记载的WT1置换型肽、WO2007/063903A1中公开的WT1235-243肽衍生物、WO2003/106682中公开的HLA-A24限制性癌抗原肽也包含在本发明的经改变的WT1肽中。
WT1肽和/或经改变的WT1肽可以为游离形态或药理学上容许的任意的盐形态,例如为酸盐(醋酸盐、TFA盐、盐酸盐、硫酸盐、磷酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、草酸盐、氢溴酸盐、琥珀酸盐、硝酸盐、苹果酸盐、柠檬酸盐、油酸盐、棕榈酸盐、丙酸盐、甲酸盐、苯甲酸盐、苦味酸盐、苯磺酸盐、十二烷基硫酸盐、甲磺酸盐、对甲苯磺酸盐、戊二酸盐、各种氨基酸盐等)、金属盐(碱金属盐(例如钠盐、钾盐)、碱土金属盐(例如钙盐、镁盐)、铝盐等)、胺盐(三乙胺盐、苄胺盐、二乙醇胺盐、叔丁胺盐、二环己胺盐、精氨酸盐、二甲基铵盐、铵盐等)的形态。优选的药理学上容许的盐为醋酸盐或TFA盐。WT1肽和/或经改变的WT1肽可以使用利用公知的方法来合成或生产、并进行分离及精制而得到的肽。
在本说明书中使用时,术语“细胞免疫诱导促进剂”是指能够使一同给予的抗原的诱导细胞免疫的效率与没有给予其时的效率相比能够得到改善的所有物质,不受促进细胞免疫诱导的作用机制限定,是指本申请说明书中特定的物质。
在本说明书中使用时,术语“TLR配体”是指Toll样受体(TLR)的配体,例如包括TLR1~9的配体。作为TLR配体,可以列举出TLR1/2配体、TLR2配体、TLR2/6配体、TLR2及Dectin1配体、TLR3配体、TLR4配体、TLR5配体、TLR7和/或TLR8配体、TLR9配体等。在本发明的优选的实施方式中,TLR配体为选自由TLR1/2配体、TLR2配体、TLR2/6配体、TLR2及Dectin1配体、TLR3配体、TLR4配体、TLR7和/或TLR8配体以及TLR9配体组成的组中的1种以上。
在本说明书中使用时,术语“TLR1/2配体”是指Toll样受体(TLR)1及Toll样受体(TLR)2的异质二聚体的配体,例如包括来源于细菌的细胞壁的三酰化脂蛋白及其盐,它们也可以是提取物、生成物或合成品,但并不限定于它们。
本发明的优选的实施方式中,TLR1/2配体为Pam3CSK4。Pam3CSK4具有式
在本说明书中使用时,术语“TLR2配体”是指作用于Toll样受体(TLR)1及Toll样受体(TLR)2的异质二聚体中的TLR2、Toll样受体(TLR)6及Toll样受体(TLR)2的异质二聚体中的TLR2、这两者的配体。TLR2配体包括例如来源于细菌的细胞壁的脂磷壁酸、肽聚糖及其盐,它们可以是提取物、生成物或合成品,但并不限定于它们。本发明的优选的实施方式中,TLR2配体为肽聚糖(PGN)。
在本说明书中使用时,术语“TLR2/6配体”是指Toll样受体(TLR)2及Toll样受体(TLR)6的异质二聚体的配体,包括例如来源于支原体的细胞壁的二酰化脂蛋白及其盐,它们可以是提取物、生成物或合成品,但并不限定于它们。本发明的优选的实施方式中,TLR2/6配体为Pam2CSK4、MALP-2及/或FSL-1。
Pam2CSK4用下式表示。
FSL-1用下式表示。
在本说明书中使用时,术语“TLR2及Dectin1配体”是指Toll样受体(TLR)2及β1,3-葡聚糖受体(Dectin1)的配体,例如包括来源于真菌的细胞壁的β1,3-葡聚糖及其盐,它们也可以是提取物、生成物或合成品,但并不限定于它们。本发明的优选的实施方式中,TLR2及Dectin1配体为来源于酵母细胞壁的酵母多糖。
在本说明书中使用时,术语“TLR3配体”是指Toll样受体(TLR)3的配体,例如包括来源于病毒的双链RNA(dsRNA)及其盐,它们也可以是提取物、生成物或合成品,但并不限定于它们。本发明的优选的实施方式中,TLR3配体为作为合成品的聚肌胞苷酸(Poly(I:C))和/或其盐。
在本说明书中使用时,术语“TLR4配体”是指Toll样受体(TLR)4的配体,包括例如来源于细菌或者植物的脂多糖(LPS)、特别是脂质A衍生物例如单磷酰基脂质A、3-脱酰基单磷酰基脂质A(3D-MPL)、OM174、OM294DP或者OM197MP-Ac DP等、烷基氨基葡糖苷磷酸酯(AGP)、例如WO9850399或者US6303347中公开的AGP或US6764840中公开的AGP的盐,另外,还包括来源于成团泛菌的脂多糖、吡喃葡萄糖基脂(glucopyranosyllipid)、透明质酸钠,但并不限定于这些。
本发明的优选的实施方式中,TLR4配体优选来源于醋酸杆菌属(例如醋化醋酸杆菌、木醋杆菌、东方醋酸菌等)、发酵单胞菌属(例如运动发酵单胞菌等)、黄单胞菌属(例如野油菜黄单胞菌等)、肠杆菌属(例如阴沟肠杆菌等)、泛菌属(例如成团泛菌等)的脂多糖。来源于这些脂多糖的提取物或精制的脂多糖也可以直接使用。另外,例如来源于成团泛菌的脂多糖(IP-PA1)可以自Funakoshi Corporation买入。另外,本发明的优选的实施方式中,TLR4配体为来源于成团泛菌的脂多糖、吡喃葡萄糖基脂、和/或透明质酸钠。
在本说明书中使用时,术语“TLR5配体”是指Toll样受体(TLR)5的配体,例如包括鞭毛蛋白等。本发明中使用的TLR5配体可以是提取物、生成物或合成品,但并不限定于它们。本发明的优选的实施方式中,TLR5配体为鞭毛蛋白。
在本说明书中使用时,术语“TLR7和/或TLR8配体”是指Toll样受体(TLR)7和/或TLR8的配体,包括例如单链RNA、咪喹莫特、雷西莫特(R848)、TLR7-II及其它化合物、例如洛索立宾及溴匹立明,但并不限定于这些。
本发明的优选的实施方式中,TLR7和/或TLR8配体为咪喹莫特。咪喹莫特为式
的1-(2-甲基丙基)-1H-咪唑并[4,5-c]喹啉-4-胺,例如日本特表平7-505883号公报(专利文献2)中记载有其特征及制造方法。
在其它的优选的实施方式中,TLR7和/或TLR8配体为雷西莫特。雷西莫特为式
的4-氨基-2-(乙氧基甲基)-α,α-二甲基-1H-咪唑并[4,5-c]喹啉-1-乙醇。
在其它的优选的实施方式中,TLR7和/或TLR8配体为TLR7-II。TLR7-II用式
表示。
在其它的优选的实施方式中,TLR7和/或TLR8配体为溴匹立明。溴匹立明用式
表示。
在本说明书中使用时,术语“TLR9配体”是指Toll样受体(TLR)9的配体,例如包括ODN1826等。本发明中使用的TLR9配体可以是提取物、生成物或合成品,但并不限定于它们。本发明的优选的实施方式中,TLR9配体为ODN1826。
ODN1826是包含以下的序列(序列号4)的寡聚脱氧核苷酸。
5’―tccatgacgttcctgacgtt―3’
Toll样受体(TLR)是通过其体内激活而引发特异性细胞因子、趋化因子及生长因子参与的先天性免疫应答的I型跨膜蛋白的家族。所有的TLR都能够激活固定的细胞内信号传递分子、例如核因子κB(NF-κB)及丝裂原激活蛋白激酶(MAP激酶)等,并且,释放出的细胞因子及趋化因子的特异性集合体是各TLR特有的。TLR1/2、TLR2/6、TLR4、TLR5不仅在免疫细胞(树突状细胞及单核细胞等)中广泛表达,就连在粘膜上皮细胞等一般的细胞中也广泛表达。已知它们识别细菌的构成成分、促进促炎细胞因子(TNF-α、IL-1、IL-6)的分泌。关于TLR4,已知其另外还促进I型干扰素(IFNα及IFNβ)的产生。TLR3、7、8、及9包含存在于免疫细胞(树突状细胞及单核细胞等)的内涵体区室或溶酶体区室中的TLR的亚族。具体而言,TLR3由树突状细胞、成纤维细胞等大范围的细胞表达,TLR7由浆细胞样树突状细胞表达,并且较少的程度由单核细胞表达,TLR8由单核细胞以及来源于单核细胞的树突状细胞及髓样树突状细胞表达,TLR9由浆细胞样树突状细胞表达。该亚族介导微生物核酸(单链RNA、双链RNA、单链DNA等)的识别。TLR3、TLR7和/或TLR8、TLR9的激动剂刺激各种促炎细胞因子例如白介素-6、白介素-12、TNF-α、及干扰素-γ的产生。该激动剂还促进协同刺激分子例如CD40、CD80、及CD86等、主要组织相容性复合体分子、及趋化因子受体的表达的增加。I型干扰素(IFNα及IFNβ)在利用TLR7和/或8激动剂激活时由细胞产生。
在本说明书中使用时,术语“环状二核苷酸”是指2个核苷酸的糖部分的2个OH基分别与同一磷酸分子生成酯并环化而得到的分子及其类似物,例如包括环状二AMP(c-di-AMP,环状-di-AMP)、环状二GMP(c-di-GMP、环状-di-GMP)、c-dGpGp、c-dGpdGp、c-GpAp、c-GpCp、c-GpUp等,但并不限定于它们。环状二核苷酸激活树突状细胞或T细胞。环状二核苷酸的进一步的例子、能够将它们作为佐剂使用、及它们的制造方法记载在日本特表2007-529531号公报(专利文献3)中。本发明的优选的实施方式中,环状二核苷酸为环状二GMP和/或环状二AMP。环状二GMP具有下式
在Kawai et al.,Nucleic Acids Research Suppl.3:103-4中记载有其合成方法。
在本说明书中使用时,术语“辅助肽”是指激活辅助性T细胞的所有肽,例如包括来源于结核菌的辅助肽、来源于麻疹病毒的辅助肽、来源于乙型肝炎病毒的辅助肽、来源于丙型肝炎病毒的辅助肽、来源于沙眼衣原体的辅助肽、来源于热带恶性疟原虫子孢子的辅助肽、来源于钥孔虫戚血蓝蛋白的辅助肽、来源于破伤风毒素的辅助肽、来源于百日咳毒素的辅助肽、来源于白喉毒素的辅助肽、来源于癌细胞的辅助肽(例如、WT1_332-347辅助肽(记载在日本专利第4621142号“来源于WT1的HLA-DR结合性抗原肽”中)、hWT135辅助肽、hWT186辅助肽、hWT1294辅助肽(以上3种记载在WO2010123065“癌抗原辅助肽”中)、IMA-MMP-001辅助肽、CEA-006辅助肽、MMP-001辅助肽、TGFBI-004辅助肽、HER-2/neu(aa776-790)辅助肽、AE36辅助肽、AE37辅助肽、MET-005辅助肽、BIR-002辅助肽等)、通用辅助类似物(universal helper analog)(例如PADRE)。本发明的优选的实施方式中,辅助肽是由10~20个氨基酸、优选12~19个氨基酸、更优选13~18个氨基酸构成的。本发明的优选的实施方式中,辅助肽为Peptide-25、或hWT135、或PADRE、或WT1_332-347。Peptide-25是与作为由人型结核菌(结核分枝杆菌)分泌的主要蛋白质之一的Ag85B的氨基酸残基240~254相对应的、由序列Phe Gln Asp Ala Tyr Asn Ala Ala Gly Gly His Asn AlaVal Phe构成的15个氨基酸的肽(序列号5)。hWT135是WO2010/123065“癌抗原辅助肽”中记载的由序列Trp Ala Pro Val Leu Asp Phe AlaPro Pro Gly Ala Ser Ala Tyr Gly Ser Leu构成的18个氨基酸的肽(本申请中,表示为序列号6)。PADRE是由序列D-Ala Lys环己基-AlaVal Ala Ala Trp Thr Leu Lys Ala Ala D-Ala构成的13个氨基酸的肽(本申请中,表示为序列号7)。WT1_332-347是日本专利第4621142号“来源于WT1的HLA-DR结合性抗原肽”中记载的由序列Lys Arg Tyr PheLys Leu Ser His Leu Gln Met His Ser Arg Lys His构成的16个氨基酸的肽(本申请中,表示为序列号8)。
另外,本发明中,也可以代替上述的辅助肽、或与其组合而使用该辅助肽的全部或一部分氨基酸通过置换、修饰等而被改变了的肽(以下称为“经改变的辅助肽”)。
经改变的辅助肽包括例如:
(a)由在原始的辅助肽的氨基酸序列中置换、缺失或附加1个~数个、例如1个、2个、3个、4个或5个氨基酸而得到的氨基酸序列构成的肽;及
(b)由在原始的辅助肽的氨基酸序列中全部或一部分氨基酸、例如1个或多个、例如1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、或18个氨基酸经过修饰而得到的氨基酸序列构成的肽。
作为经改变的辅助肽可以具有的氨基酸的“修饰”,并不限定于此,例如可以列举出:乙酰化、甲基化等烷基化、糖基化、羟基化、羧基化、醛化、磷酸化、磺酰化、甲酰化、豆蔻酰化、棕榈酰化、硬脂酰化这样的脂肪链附加修饰、辛酰化、酯化、酰胺化、脱酰胺化、胱氨酸修饰、谷胱甘肽修饰、巯基乙酸修饰这样的二硫键形成修饰、糖化、泛素化、琥珀酰亚胺形成、谷酰化、异戊二烯化等。另外,经改变的辅助肽也可以组合包含1个以上氨基酸的置换、缺失或附加、和1个以上氨基酸的修饰。
在本说明书中使用时,术语“环氧酶抑制剂“是抑制环氧酶(COX)的功能的物质。以下也称为“COX抑制剂”。COX抑制剂有选择性作用于特定的环氧酶(例如COX-1、COX-2)的抑制剂、不具有选择性的抑制剂。作为本发明中可以使用的COX抑制剂,可以列举出:依托度酸、洛索洛芬、塞来昔布、伐地昔布、帕瑞昔布、罗美昔布、美洛昔康、替诺昔康、双氯芬酸、甲芬那酸、托芬那酸、氟芬那酸、甲氯芬那酸、尼氟灭酸、苄达明、吲哚布芬、三氟醋柳酸、托美丁、非诺洛芬、噻洛芬酸、联苯乙酸、奈帕芬胺、氨芬酸、普拉朵林、扎托布洛芬、舒林酸、萘丁美酮、二氟尼柳、吡罗昔康、布洛芬、萘普生、非诺洛芬、阿司匹林、水杨酸甲酯、水杨酸酰胺、双水杨酸酯、阿洛普令、托美丁、吲哚美辛、丙谷美辛、阿西美辛、氟比洛芬、普拉洛芬、对乙酰氨基酚、夫洛非宁、氯诺昔康、替诺昔康、噻洛芬酸、奥沙普秦、酮洛芬、右酮洛芬、右布洛芬、阿明洛芬、酮咯酸、莫苯唑酸、保泰松、羟基保泰松、酮基保泰松、非普拉宗、Phenbutazone、乙柳酰胺、噻拉米特、替诺立定、依匹唑、依莫法宗及它们的衍生物、以及它们的药理学上容许的盐等。本发明的优选的实施方式中,COX抑制剂为依托度酸和/或洛索洛芬。
洛索洛芬用式
表示。
在本说明书中使用时,术语“前列腺素受体拮抗剂”是指具有妨碍前列腺素作用于受体的功能的物质,例如包括EP2受体拮抗剂、EP4受体拮抗剂、DP受体拮抗剂、IP受体拮抗剂。
在本说明书中使用时,术语“EP2受体拮抗剂”是指具有妨碍前列腺素E2作用于EP2受体的功能的物质。作为EP2受体拮抗剂,可以列举出AH6809及其衍生物、以及它们的药理学上容许的盐等。
AH6809用式
表示。
在本说明书中使用时,术语“EP4受体拮抗剂”是指具有妨碍前列腺素E2作用于EP4受体的功能的物质。作为EP4受体拮抗剂,可以列举出GW627368X及其衍生物、以及它们的药理学上容许的盐等。
GW627368X用式
表示。
在本说明书中使用时,术语“DP受体拮抗剂”是指具有妨碍前列腺素D2作用于DP受体的功能的物质。作为DP受体拮抗剂,可以列举出S-5751、BWA868C及其衍生物、以及它们的药理学上容许的盐等。
BWA868C用式
表示。
在本说明书中使用时,术语“IP受体拮抗剂”是指具有妨碍前列腺素I2作用于IP受体的功能的物质。作为IP受体拮抗剂,可以列举出RO1138452及其衍生物、以及它们的药理学上容许的盐等。
RO1138452用式
表示。
在本说明书中使用时,术语“前列腺素受体激动剂”是指具有该物质自身作用于前列腺素受体的功能的物质,例如包括EP3受体激动剂。
在本说明书中使用时,术语“EP3受体激动剂”是指具有该物质自身作用于EP3受体的功能的物质。作为EP3受体激动剂,可以列举出:噻普酮、GR63799、氯前列醇、ONO-AE-248、卡巴环素、及其衍生物、以及它们的药理学上容许的盐等。
噻普酮用式
表示。
在本说明书中使用时,术语“TSLP产生抑制剂”是指具有抑制TSLP产生的功能的物质。抑制NF-kB的药物制剂被认为也间接地抑制TSLP产生,因此,包括在该范畴内。作为TSLP产生抑制剂,可以列举出:柚皮素、小檗碱、白藜芦醇、木樨草素、芹黄素、金圣草黄素、维露汀(velutin)、芦丁、橙皮苷、槲皮素、大豆甙元、染料木素、那可丁、二吲哚甲烷、呫吨酮、小白菊内酯及它们的衍生物、以及它们的药理学上容许的盐等。
小檗碱用式
表示。
在本说明书中使用时,术语“腺苷酸环化酶抑制剂”是指具有抑制腺苷酸环化酶的活性的功能的物质。作为腺苷酸环化酶抑制剂,可以列举出2’,5’-双脱氧腺苷、烟酸、胰岛素、及它们的衍生物、以及它们的药理学上容许的盐等。
2’,5’-双脱氧腺苷用式
表示。
在本说明书中使用时,术语“ω-3脂肪酸”为不饱和脂肪酸的分类的一种,表示在ω-3位具有碳-碳双键的物质。作为ω-3脂肪酸,可以列举出二十碳五烯酸、α-亚麻酸、二十二碳六烯酸、及它们的衍生物、以及它们的药理学上容许的盐等。
二十碳五烯酸用式
表示。
在本说明书中使用时,术语“PPAR激动剂”是指具有该物质自身作用于过氧化物酶体增殖物激活受体的功能的物质,例如包括PPAR-α激动剂、PPAR-δ激动剂、PPAR-γ激动剂。
在本说明书中使用时,术语“PPAR-α激动剂”是指具有该物质自身作用于α型过氧化物酶体增殖物激活受体的功能的物质。术语“PPAR-δ激动剂”是指具有该物质自身作用于δ型过氧化物酶体增殖物激活受体的功能的物质。术语“PPAR-γ激动剂”是指具有该物质自身作用于γ型过氧化物酶体增殖物激活受体的功能的物质。作为PPAR-α激动剂、和/或PPAR-δ激动剂、和/或PPAR-γ激动剂,可以列举出:氯贝特、非诺贝特、苯扎贝特、环丙贝特、依托贝特、替米沙坦、油基乙醇酰胺、十四烷基巯基乙酸、曲格列酮、吡格列酮、罗格列酮、巴格列酮、来格列酮、环格列酮、达格列酮、依格列宗、耐格列酮(netoglitazone)、英格列扎、替格列扎、莫格他唑、阿格列扎及它们的衍生物、以及它们的药理学上容许的盐等。
氯贝特用式
表示。
在本说明书中使用时,术语“多巴胺受体拮抗剂”是指具有妨碍多巴胺作用于受体的功能的物质,例如包括D1受体拮抗剂、D5受体拮抗剂。
在本说明书中使用时,术语“D1受体拮抗剂”是指具有妨碍多巴胺作用于D1受体的功能的物质。作为D1受体拮抗剂,可以列举出苯并氮杂卓(benzazepine)、非诺多泮、氯卡色林、SCH23390、SCH39166、LE300及它们的衍生物、以及它们的药理学上容许的盐等。
苯并氮杂卓用式
表示。
在本说明书中使用时,术语“D5受体拮抗剂”是指具有妨碍多巴胺作用于D5受体的功能的物质。作为D5受体拮抗剂,可以列举出SCH39166及它们的衍生物、以及它们的药理学上容许的盐等。
SCH39166用式
表示。
在本说明书中使用时,术语“多巴胺受体激动剂”是指具有该物质自身作用于多巴胺受体的功能的物质,例如包括D2受体激动剂、D3受体激动剂、D4受体激动剂。
在本说明书中使用时,术语“D2受体激动剂”是指具有该物质自身作用于D2受体的功能的物质。作为D2受体激动剂,可以列举出卡麦角林、溴麦角环肽、培高利特、罗匹尼罗、他利克索、阿立哌唑、鲁拉西酮、及它们的衍生物、以及它们的药理学上容许的盐等。
罗匹尼罗用式
表示。
在本说明书中使用时,术语“D3受体激动剂”是指具有该物质自身作用于D3受体的功能的物质。作为D3受体激动剂,可以列举出吡贝地尔、罗替戈汀、PD1289077、OH-DPAT及它们的衍生物、以及它们的药理学上容许的盐等。
罗替戈汀用式
表示。
在本说明书中使用时,术语“D4受体激动剂”是指具有该物质自身作用于D4受体的功能的物质。作为D4受体激动剂,可以列举出氟班色林、ABT724、PD168077、CP226269及它们的衍生物、以及它们的药理学上容许的盐等。
氟班色林用式
表示。
在本说明书中使用时,术语“组胺受体拮抗剂”是指具有妨碍组胺作用于受体的功能的物质,例如包括H1受体拮抗剂、H2受体拮抗剂。
在本说明书中使用时,术语“H1受体拮抗剂”是指具有妨碍组胺作用于H1受体的功能的物质。作为H1受体拮抗剂,可以列举出:酮色林、松齐拉敏、美吡拉敏、曲吡那敏、二甲茚定、氯马斯汀、巴米品、氮异丙嗪、氯苯沙明、二甲替嗪、氯丙嗪、羟嗪、奥匹哌醇、倍他司汀、桂利嗪、左卡巴斯汀、安他唑啉、双苯拉林、卡比沙明、多西拉敏、阿列马嗪、赛克利嗪、美克洛嗪、左西替利嗪、赛庚啶、苯茚胺、曲普利啶、阿扎他啶、阿司咪唑、特非那定、阿伐斯汀、依巴斯汀、地洛他定、卢帕他定、比拉斯汀、咪唑斯汀、诺贝斯汀、柔卡斯啶、替美斯汀、贝他斯汀、苯海拉明、氯苯那敏、酮替芬、异丙嗪、赛庚啶、依匹斯汀、奥洛他定、贝托斯汀、阿司咪唑、依美斯汀、美喹他嗪、奥沙米特、氯雷他定、非索非那定、西替利嗪、氮卓斯汀、及它们的衍生物、以及它们的药理学上容许的盐等。
苯海拉明用式
表示。
在本说明书中使用时,术语“H2受体拮抗剂”是指具有妨碍组胺作用于H2受体的功能的物质。作为H2受体拮抗剂,可以列举出西咪替丁、雷尼替丁、法莫替丁、尼扎替丁、罗沙替丁、拉呋替丁、及它们的衍生物、以及它们的药理学上容许的盐等。
法莫替丁用式
表示。
在本说明书中使用时,术语“组胺受体激动剂”是指具有该物质自身作用于组胺受体的功能的物质,例如包括H1受体激动剂、H3受体激动剂、H4受体激动剂。
在本说明书中使用时,术语“H1受体激动剂”是指具有该物质自身作用于H1受体的功能的物质。作为H1受体激动剂,可以列举出2-吡啶基乙胺、2-噻唑基乙胺及它们的衍生物、以及它们的药理学上容许的盐等。
2-吡啶基乙胺用式
表示。
在本说明书中使用时,术语“H3受体激动剂”是指具有该物质自身作用于H3受体的功能的物质。作为H3受体激动剂,可以列举出Immethridine、Imetit、Immepip、α-甲基组胺、Proxifan、及它们的衍生物、以及它们的药理学上容许的盐等。
Proxifan用式
表示。
在本说明书中使用时,术语“H4受体激动剂”是指具有该物质自身作用于H4受体的功能的物质。作为H4受体激动剂,可以列举出4-甲基组胺、VUF8430、Immepip及它们的衍生物、以及它们的药理学上容许的盐等。
4-甲基组胺用式
表示。
在本说明书中使用时,术语“血清素受体拮抗剂”是指具有妨碍血清素作用于受体的功能的物质,例如包括5-HT2受体拮抗剂、5-HT4受体拮抗剂、5-HT6受体拮抗剂、5-HT7受体拮抗剂。
在本说明书中使用时,术语“5-HT2受体拮抗剂”是指具有妨碍血清素作用于5-HT2受体的功能的物质。作为5-HT2受体拮抗剂,可以列举出苯噻啶、利培酮、奥氮平、喹硫平、阿立哌唑、布南色林、氯氮平、帕潘立酮、利坦色林、育亨宾、美舒麦角、阿戈美拉汀、环苯扎林、沙格雷酯、美西麦角、酮色林及它们的衍生物、以及它们的药理学上容许的盐等。
奥氮平用式
表示。
在本说明书中使用时,术语“5-HT4受体拮抗剂”是指具有妨碍血清素作用于5-HT4受体的功能的物质。作为5-HT4受体拮抗剂,可以列举出哌波色罗(piboserod)、GR113808、GR125487、RS39604、SB204070及它们的衍生物、以及它们的药理学上容许的盐等。
哌波色罗用式
表示。
在本说明书中使用时,术语“5-HT6受体拮抗剂”是指具有妨碍血清素作用于5-HT6受体的功能的物质。作为5-HT6受体拮抗剂,可以列举出Cerlapirdine、氯氮平及它们的衍生物、以及它们的药理学上容许的盐等。
Cerlapirdine用式
表示。
在本说明书中使用时,术语“5-HT7受体拮抗剂”是指具有妨碍血清素作用于5-HT7受体的功能的物质。作为5-HT7受体拮抗剂,可以列举出鲁拉西酮、甲麦角林及它们的衍生物、以及它们的药理学上容许的盐等。
甲麦角林用式
表示。
在本说明书中使用时,术语“血清素受体激动剂”是指具有该物质自身作用于血清素受体的功能的物质,例如包括5-HT1受体激动剂、5-HT2受体激动剂。
在本说明书中使用时,术语“5-HT1受体激动剂”是指具有该物质自身作用于5-HT1受体的功能的物质。作为5-HT1受体激动剂,可以列举出吡氯佐坦(piclozotan)、坦度螺酮、舒马曲坦、佐米曲坦、依立曲坦、利扎曲坦、那拉曲坦、阿莫曲坦、夫罗曲坦、阿维曲坦、麦角胺、麦角生物碱及它们的衍生物、以及它们的药理学上容许的盐等。
佐米曲坦用式
表示。
在本说明书中使用时,术语“5-HT2受体激动剂”是指具有该物质自身作用于5-HT2受体的功能的物质。作为5-HT2受体激动剂,可以列举出α-甲基-5-HT、阿戈美拉汀、去乙芬氟拉明、间氯苯哌嗪及它们的衍生物、以及它们的药理学上容许的盐等。
阿戈美拉汀用式
表示。
在本说明书中使用时,术语“加压素受体拮抗剂”是指具有妨碍加压素作用于受体的功能的物质,例如包括V2受体拮抗剂。
在本说明书中使用时,术语“V2受体拮抗剂”是指具有妨碍加压素作用于V2受体的功能的物质。作为V2受体拮抗剂,可以列举出托伐普坦(tolvaptan)、莫扎伐普坦、考尼伐坦、利希普坦、及它们的衍生物、以及它们的药理学上容许的盐等。
莫扎伐普坦用式
表示。
在本说明书中使用时,术语“加压素受体激动剂”是指具有该物质自身作用于加压素受体的功能的物质,例如包括V1受体激动剂。
在本说明书中使用时,术语“V1受体激动剂”是指具有该物质自身作用于V1受体的功能的物质。作为V1受体激动剂,可以列举出加压素、苯赖加压素、去氨加压素、赖氨加压素、特利加压素、鸟氨酸加压素、精氨酸加压素、及它们的衍生物、以及它们的药理学上容许的盐等。
去氨加压素用式
表示。
在本说明书中使用时,术语“毒蕈碱受体拮抗剂”是指具有妨碍乙酰胆碱作用于毒蕈碱受体的功能的物质,例如包括M1受体拮抗剂、M3受体拮抗剂、M5受体拮抗剂。
在本说明书中使用时,术语“M1受体拮抗剂”是指具有妨碍乙酰胆碱作用于M1受体的功能的物质。术语“M3受体拮抗剂”是指具有妨碍乙酰胆碱作用于M3受体的功能的物质。术语“M5受体拮抗剂”是指具有妨碍乙酰胆碱作用于M5受体的功能的物质。作为M1受体拮抗剂、和/或M3受体拮抗剂、和/或M5受体拮抗剂,可以列举出哌仑西平、阿托品、曲美布汀、哌立度酯、奥昔布宁、托吡卡胺、丙哌维林、托特罗定、索非那新、达非那新、咪达那新、羟苄利明、噻托溴铵、艾司奥昔布宁、替喹溴铵、及它们的衍生物、以及它们的药理学上容许的盐等。
奥昔布宁用式
表示。
在本说明书中使用时,术语“毒蕈碱受体激动剂”是指具有该物质自身作用于毒蕈碱受体的功能的物质,例如包括M1受体激动剂、M2受体激动剂、M3受体激动剂、M4受体激动剂、M5受体激动剂。
在本说明书中使用时,术语“M1受体激动剂”是指具有该物质自身作用于M1受体的功能的物质。术语“M2受体激动剂”是指具有该物质自身作用于M2受体的功能的物质。术语“M3受体激动剂”是指具有该物质自身作用于M3受体的功能的物质。术语“M4受体激动剂”是指具有该物质自身作用于M4受体的功能的物质。术语“M5受体激动剂”是指具有该物质自身作用于M5受体的功能的物质。作为M1受体激动剂、和/或M2受体激动剂、和/或M3受体激动剂、和/或M4受体激动剂、和/或M5受体激动剂,可以列举出乙酰胆碱、醋克利定、阿伐美林(alvameline)、他沙利定、呫诺美林、毛果芸香碱、西维美林、氨甲酰甲胆碱、马扎替可、毒蕈碱及它们的衍生物、以及它们的药理学上容许的盐等。
氨甲酰甲胆碱用式
表示。
在本说明书中使用时,术语“肾上腺素受体拮抗剂”是指具有妨碍肾上腺素作用于受体的功能的物质,例如包括α1受体拮抗剂、β1受体拮抗剂、β2受体拮抗剂、β3受体拮抗剂。
在本说明书中使用时,术语“α1受体拮抗剂”是指具有妨碍肾上腺素作用于α1受体的功能的物质。作为α1受体拮抗剂,可以列举出哌唑嗪、多沙唑嗪、布那唑嗪、曲马唑嗪、阿夫唑嗪、西洛多辛、特拉唑嗪、坦索罗辛、及它们的衍生物、以及它们的药理学上容许的盐等。
坦索罗辛用式
表示。
在本说明书中使用时,术语“β1受体拮抗剂”是指具有妨碍肾上腺素作用于β1受体的功能的物质。术语“β2受体拮抗剂”是指具有妨碍肾上腺素作用于β2受体的功能的物质。术语“β3受体拮抗剂”是指具有妨碍肾上腺素作用于β3受体的功能的物质。作为β1受体拮抗剂、和/或β2受体拮抗剂、和/或β3受体拮抗剂,可以列举出波吲洛尔、吲哚洛尔、噻吗洛尔、二氯异丙肾上腺素、阿普洛尔、卡替洛尔、茚诺洛尔、布尼洛尔、喷布洛尔、普萘洛尔、纳多洛尔、尼普洛尔、替利洛尔、醋丁洛尔、塞利洛尔、美托洛尔、阿替洛尔、比索洛尔、倍他洛尔、普拉洛尔、贝凡洛尔、布托沙明、卡维地洛、氨磺洛尔、阿罗洛尔、拉贝洛尔、及它们的衍生物、以及它们的药理学上容许的盐等。
普萘洛尔用式
表示。
在本说明书中使用时,术语“血管紧张素受体激动剂”是指具有该物质自身作用于血管紧张素受体的功能的物质,例如包括AT2受体激动剂。
在本说明书中使用时,术语“肾上腺素受体激动剂”是指具有该物质自身作用于肾上腺素受体的功能的物质,例如包括α1受体激动剂、α2受体激动剂。
在本说明书中使用时,术语“α1受体激动剂”是指具有该物质自身作用于α1受体的功能的物质。术语“α2受体激动剂”是指具有该物质自身作用于α2受体的功能的物质。作为α1受体激动剂、和/或α2受体激动剂,可以列举出:去甲肾上腺素、去甲苯福林、依替福林、萘甲唑林、苯肾上腺素、米多君、甲氧胺、辛弗林、间羟胺、阿布他明、麻黄碱、羟甲唑啉、四氢唑林、赛洛唑啉、曲马唑啉、伪麻黄碱、地匹福林、阿米福林、甲基麻黄碱、利美尼定、溴莫尼定、美托咪定、甲苯噻嗪、替扎尼定、胍法辛、甲基多巴、胍那苄、及它们的衍生物、以及它们的药理学上容许的盐等。
甲苯噻嗪用式
表示。
在本说明书中使用时,术语“血管紧张素受体激动剂”是指具有该物质自身作用于血管紧张素受体的功能的物质,例如包括AT2受体激动剂。
在本说明书中使用时,术语“AT2受体激动剂”是指具有该物质自身作用于AT2受体的功能的物质。作为AT2受体激动剂,可以列举出Novokinin、血管紧张素及它们的衍生物、以及它们的药理学上容许的盐等。
血管紧张素用式
表示。
在本说明书中使用时,术语“GABA受体激动剂”是指具有该物质自身作用于GABA受体的功能的物质,例如包括GABAB受体激动剂。
在本说明书中使用时,术语“GABAB受体激动剂”是指具有该物质自身作用于GABAB受体的功能的物质。作为GABAB受体激动剂,可以列举出巴氯芬、γ-氨基丁酸、阿巴氯芬(Arbaclofen)及它们的衍生物、以及它们的药理学上容许的盐等。
巴氯芬用式
表示。
在本说明书中使用时,术语“凝血酶受体拮抗剂”是指具有妨碍凝血酶作用于受体的功能的物质,例如包括PAR-1受体拮抗剂。
在本说明书中使用时,术语“PAR-1受体拮抗剂”是指具有妨碍凝血酶作用于PAR-1受体的功能的物质。作为PAR-1受体拮抗剂,可以列举出Vorapaxar、Atopaxar、FR171113、RWJ56110、达比加群、达比加群酯、美拉加群、希美加群、水蛭素、哈艾劳格(hirolog)、阿加曲班及它们的衍生物、以及它们的药理学上容许的盐等。
Vorapaxar用式
表示。
在本说明书中使用时,术语“凝血酶受体激动剂”是指具有该物质自身作用于凝血酶受体的功能的物质,例如包括PAR-1受体激动剂。
在本说明书中使用时,术语“PAR-1受体激动剂”是指具有该物质自身作用于PAR-1受体的功能的物质。作为PAR-1受体激动剂,可以列举出TRAP-6、TRAP-14、NAT6-NH2及它们的衍生物、以及它们的药理学上容许的盐等。
TRAP-6用式
表示。
在本说明书中使用时,术语“阿片类受体激动剂”是指具有该物质自身作用于阿片类受体的功能的物质。作为阿片类受体激动剂,可以列举出曲美布汀、爱维莫潘、吗啡、羟考酮、二氢可待因、海洛因、哌替啶、喷他佐辛、丁丙诺啡、布托啡诺、纳布啡、替利定、地佐辛、美普他酚、他喷他多、纳曲酮、美沙酮、乙基吗啡、氢可酮、乙酰基二氢可待因、烯丙吗啡、洛哌丁胺、瑞莫必利、奥匹哌醇、及它们的衍生物、以及它们的药理学上容许的盐等。
丁丙诺啡用式
表示。
在本说明书中使用时,术语“白三烯受体拮抗剂”是指具有妨碍白三烯作用于受体的功能的物质,例如包括CysLT1受体拮抗剂、CysLT2受体拮抗剂。
在本说明书中使用时,术语“CysLT1受体拮抗剂”是指具有妨碍白三烯作用于CysLT1受体的功能的物质。术语“CysLT2受体拮抗剂”是指具有妨碍白三烯作用于CysLT2受体的功能的物质。作为CysLT1受体拮抗剂、和/或CysLT2受体拮抗剂,可以列举出孟鲁司特、扎鲁司特、普仑司特、及它们的衍生物、以及它们的药理学上容许的盐等。例如,作为孟鲁司特的药理学上容许的盐,可以列举出孟鲁司特钠等。
孟鲁司特钠用式
表示。
在本说明书中使用时,术语“白三烯受体激动剂”是指具有该物质自身作用于白三烯受体的功能的物质,例如包括BLT受体激动剂。
在本说明书中使用时,术语“BLT受体激动剂”是指具有该物质自身作用于BLT受体的功能的物质。作为BLT受体激动剂,可以列举出白三烯B4、CAY10583及它们的衍生物、以及它们的药理学上容许的盐等。
白三烯B4用式
表示。
在本说明书中使用时,术语“ADP受体激动剂”是指具有该物质自身作用于ADP受体的功能的物质。作为ADP受体激动剂,可以列举出腺苷二磷酸、及它们的衍生物、以及它们的药理学上容许的盐等。
腺苷二磷酸用式
表示。
在本说明书中使用时,术语“褪黑素受体激动剂”是指具有该物质自身作用于褪黑素受体的功能的物质。作为褪黑素受体激动剂,可以列举出褪黑素、哌拉平、他司美琼、及它们的衍生物、以及它们的药理学上容许的盐等。
褪黑素用式
表示。
在本说明书中使用时,术语“生长抑素受体激动剂”是指具有该物质自身作用于生长抑素受体的功能的物质。作为生长抑素受体激动剂,可以列举出生长抑素、生长抑素-14、奥曲肽、及它们的衍生物、以及它们的药理学上容许的盐等。
奥曲肽用式
表示。
在本说明书中使用时,术语“大麻素受体激动剂”是指具有该物质自身作用于大麻素受体的功能的物质。作为大麻素受体激动剂,可以列举出屈大麻酚、大麻隆、左南曲朵、奥特那班(otenabant)、GW833972A、GW405833、及它们的衍生物、以及它们的药理学上容许的盐等。
屈大麻酚用式
表示。
在本说明书中使用时,术语“鞘氨醇1-磷酸受体激动剂”是指具有该物质自身作用于鞘氨醇1-磷酸受体的功能的物质。作为鞘氨醇1-磷酸受体激动剂,可以列举出芬戈莫德、ponesimod、RPC-1063、ONO-4641、SEW2871、鞘氨醇1-磷酸及它们的衍生物、以及它们的药理学上容许的盐等。
芬戈莫德用式
表示。
在本说明书中使用时,术语“代谢型谷氨酸受体激动剂”是指具有该物质自身作用于代谢型谷氨酸受体的功能的物质,例如包括mGluR2受体激动剂、mGluR3受体激动剂、mGluR4受体激动剂、mGluR6受体激动剂、mGluR7受体激动剂、mGluR8受体激动剂。
在本说明书中使用时,术语“mGluR2受体激动剂”是指具有该物质自身作用于mGluR2受体的功能的物质。术语“mGluR3受体激动剂”是指具有该物质自身作用于mGluR3受体的功能的物质。术语“mGluR4受体激动剂”是指具有该物质自身作用于mGluR4受体的功能的物质。术语“mGluR6受体激动剂”是指具有该物质自身作用于mGluR6受体的功能的物质。术语“mGluR7受体激动剂”是指具有该物质自身作用于mGluR7受体的功能的物质。术语“mGluR8受体激动剂”是指具有该物质自身作用于mGluR8受体的功能的物质。作为mGluR2受体激动剂、和/或mGluR3受体激动剂、和/或mGluR4受体激动剂、和/或mGluR6受体激动剂、和/或mGluR7受体激动剂、和/或mGluR8受体激动剂,可以列举出VU0361737、VU0155041、联苯茚酮A、PBDA、L-AP4、及它们的衍生物、以及它们的药理学上容许的盐等。
VU0361737用式
表示。
在本说明书中使用时,术语“磷脂酶A2抑制剂”是指具有抑制磷脂酶A2的活性的功能的物质。作为磷脂酶A2抑制剂,可以列举出甘草酸、甘草次酸、及它们的衍生物、以及它们的药理学上容许的盐等。
甘草次酸用式
表示。
在本说明书中使用时,术语“TGF-β产生抑制剂”是指具有抑制TGF-β产生的功能的物质。作为TGF-β产生抑制剂,可以列举出吡非尼酮、曲尼司特、及其衍生物、以及它们的药理学上容许的盐等。
吡非尼酮用式
表示。
在本说明书中使用时,术语“Th2细胞因子抑制剂”是指具有抑制IL-4、IL-5这样的Th2细胞因子产生的功能的物质。作为Th2细胞因子抑制剂,可以列举出suplatast及其衍生物、以及它们的药理学上容许的盐等。作为suplatast的药理学上容许的盐,例如可以列举出甲磺司特。本发明的优选的实施方式中,Th2细胞因子抑制剂为甲磺司特。
甲磺司特用式
表示。
在本说明书中使用时,本发明的组合物中可以含有的作为第二细胞免疫诱导促进剂的“药理学上容许的酸”是指不对给予对象产生有害的作用、且不会使该组合物中的成分的药理活性消失的酸。本发明的优选的实施方式中,药理学上容许的酸为有机酸,更优选为包含羧基的有机化合物或包含磺酸基的有机化合物,进一步优选为饱和直链部分的碳数为8~20的饱和或不饱和的直链或支链脂肪酸或乳酸或苹果酸或水杨酸或马来酸或柠檬酸、或包含磺酸基的有机化合物,更进一步优选为饱和直链部分的碳数为8~16的饱和或不饱和的直链或支链脂肪酸或乳酸或苹果酸或水杨酸或马来酸或柠檬酸、或包含磺酸基的有机化合物,再进一步优选为选自由癸酸、月桂酸、肉豆蔻酸、异硬脂酸及油酸组成的组中的脂肪酸、或乳酸或水杨酸或柠檬酸或甲磺酸。
在本说明书中使用时,本发明的组合物中可以含有的“药理学上容许的盐”是指不对给予对象产生有害的作用、且不会使该组合物中的成分的药理活性消失的盐,包括无机酸盐(例如盐酸盐、磷酸盐)、有机酸盐(例如醋酸盐、邻苯二甲酸盐、TFA盐)、金属盐(碱金属盐(例如钠盐、钾盐)、碱土金属盐(例如钙盐、镁盐)、铝盐等)、胺盐(三乙胺盐、苄胺盐、二乙醇胺盐、叔丁胺盐、二环己胺盐、精氨酸盐、二甲基铵盐、铵盐等),但并不限定于此。
在本说明书中使用时,术语“免疫调节低分子药物”是指激活或抑制T细胞、NK细胞、巨噬细胞等免疫细胞的物质中不属于上述TLR配体、环状二核苷酸、辅助肽、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、及Th2细胞因子抑制剂中的任一种的药物。作为免疫调节低分子药物,例如可以列举出贝他定、匹多莫德、左旋咪唑、戈洛莫德、福芬诺尔、及它们的衍生物、以及它们的药理学上容许的盐等。例如,作为左旋咪唑的药理学上容许的盐,可以列举出左旋咪唑盐酸盐等。
贝他定用式
表示。
匹多莫德用式
表示。
左旋咪唑盐酸盐用式
表示。
本发明中,免疫调节低分子药物通常为分子量不足1000、优选不足500的化合物。本发明的优选的实施方式中,免疫调节低分子药物为选自由贝他定、匹多莫德及左旋咪唑盐酸盐组成的组中的1种以上化合物。
本发明如上所述发现,各种细胞免疫诱导促进剂中,TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、及Th2细胞因子抑制剂特别适合于由WT1肽抗原和/或经改变的WT1肽抗原的粘膜给予诱导的免疫应答的增强,因此,在一个实施方式中,本申请发明的细胞免疫诱导促进剂为选自上述中的1种以上物质。在本申请发明的特别优选的实施方式中,细胞免疫诱导促进剂为选自TLR配体、环状二核苷酸、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、及Th2细胞因子抑制剂中的1种以上物质与辅助肽的组合。作为定量测定细胞免疫的诱导的方法,开发了很多方法,可以使用其中的任1种或1种以上、例如实施例中记载的ELISPOT法。
在本说明书中使用时,非侵入式给予是指不主动对粘膜赋予物理刺激和/或化学刺激、优选不主动对粘膜赋予物理刺激(例如粘膜剥离处理、粘膜损伤处理、粘膜穿孔处理)地进行给予。
在本说明书中使用时,术语“癌症”是指伴随WT1基因的异常表达、例如过表达的癌症,例如造血器官肿瘤、实体肿瘤。伴随WT1基因的异常表达的造血器官肿瘤包括例如急性骨髓性白血病、急性淋巴性白血病及慢性骨髓性白血病这样的白血病、骨髓增生异常综合征、多发性骨髓瘤以及非霍奇金氏淋巴瘤这样的恶性淋巴瘤,但并不限定于此。伴随WT1基因的异常表达的实体肿瘤包括例如肺癌、乳腺癌、胃癌、大肠·直肠癌、胚细胞癌、肝癌、皮肤癌、胰腺癌、胆管癌、头颈部扁平上皮癌、甲状腺癌、肾癌、膀胱癌、前列腺癌、卵巣癌、子宫癌、子宫颈癌、骨与软组织肉瘤、恶性黑色素瘤、恶性间皮瘤、睾丸生殖细胞肿瘤及恶性胶质瘤,但并不限定于此。
在本说明书中使用时,术语“基因的异常表达”是指某个细胞的基因的表达水平与相同组织的其它细胞相比显著升高或降低例如2倍以上、例如4倍以上。术语“过表达”是指异常表达为表达水平之上。基因的表达水平可以使用该技术领域公知的任意方法来容易地测定。
在本说明书中使用时,术语“对象”是指在实际应用阶段给予粘膜给予用癌症疫苗组合物而能够诱导免疫应答的动物,是指具有WT1基因的任意动物,典型的为包括人在内的哺乳类、例如小鼠、大鼠、狗、猫、兔子、马、牛、绵羊、猪、山羊、猴、黑猩猩等。特别优选的对象为人。
在本说明书中使用时,术语“免疫评价用动物模型”是指用于评价粘膜给予用癌症疫苗组合物的免疫诱导特性的动物模型,具体而言是指用于评价细胞免疫诱导水平的动物模型。作为免疫评价用动物模型,考虑疫苗组合物中的抗原和动物的MHC 1类分子的相容性,使用能够评价利用疫苗组合物中的抗原的细胞免疫诱导的动物。为包含HLA-A*24型MHC限制性1类肽的疫苗组合物的情况下,用BALB/c小鼠进行评价。为包含HLA-A*02型MHC限制性肽的疫苗组合物的情况下,用能评价利用HLA-A*02型MHC限制性肽的免疫诱导的转基因小鼠进行评价。为包含其它的HLA型的MHC限制性肽的疫苗组合物的情况下,用能评价利用该HLA型的MHC限制性肽的免疫诱导的动物进行评价。为包含蛋白抗原的疫苗组合物的情况下,用具备与蛋白抗原的氨基酸序列中所含的1类表位中想要进行免疫诱导的1类表位具有相容性的MHC的动物进行评价。需要说明的是,为使用Db126肽的粘膜给予用癌症疫苗组合物的情况下,Db126肽不仅适合于HLA-A*02型也适合于MHC-H-2Db型,因此,不仅是能评价利用HLA-A*0201型MHC限制性肽的免疫诱导的转基因小鼠、具有MHC-H-2Db型的动物C57BL/6小鼠也可以作为免疫评价用小鼠模型使用。
II.粘膜给予用癌症疫苗组合物
WT1肽和/或经改变的WT1肽作为癌症疫苗有用是已知的事实(例如专利文献1)。
在本说明书中使用时,术语“粘膜给予用”组合物是指粘膜给予例如舌下、鼻腔、颊部、直肠或阴道给予中通常使用的任意制剂,例如可以为凝胶剂(胶浆剂)、霜剂、软膏剂、硬膏剂等半固体制剂、液体制剂、散剂、细粒剂、颗粒剂、膜剂、片剂、口腔崩解片等固体制剂、气雾剂剂这样的粘膜用喷雾剂、吸引剂等。这些组合物的区分、定义、性质、制法等在本技术领域是公知的,可以参考例如日本药典第16版。
例如,作为液体制剂用溶剂,可以使用适量的水或乙醇、甘油、丙二醇等溶剂,可以使成分分散或溶解在该溶剂中而制备液体制剂。
例如,作为凝胶剂(胶浆剂)用基质,可以使用作为水凝胶基质的羧基乙烯基聚合物、凝胶基质(gelbase)、无脂肪性软膏、聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、海藻酸钠、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、醋酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、塔拉胶(tara gum)、罗望子胶、车前子胶、琼脂、结冷胶、葡甘露聚糖、刺槐豆胶、瓜尔豆胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚醣、Eudragit、酪蛋白、海藻酸烷基酯、明胶、聚乙二醇等。将这些基质溶解在溶剂中能够制备具有流动性的凝胶剂、具有成型性的凝胶剂。作为溶剂,优选为水,还可以使用甘油、丙二醇。
例如,作为霜剂用基质,可列举出亲水性软膏、雪花膏等水/油型基质;亲水性凡士林、精制羊毛脂、阿夸弗尔(aquaphor)、优塞林(Eucerin)、Neoeserine、含水羊毛脂、冷霜(cold cream)、亲水性液体石腊和聚乙烯的复合软膏基质(plastibase)等油/水型基质。通过将这些基质投入到油脂系溶剂或水中,利用均质器等进行高速搅拌,能够制备霜剂。
例如,作为膜剂用基质,可列举出聚乙烯基吡咯烷酮、聚乙烯醇、聚丙烯酸钠、羧甲基纤维素、淀粉、黄原胶、刺梧桐胶、海藻酸钠、甲基纤维素、羧基乙烯基聚合物、琼脂、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、醋酸邻苯二甲酸纤维素(CAP)、羧甲基乙基纤维素(CMEC)、乙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧基乙烯基聚合物、黄蓍胶、阿拉伯胶、刺槐豆胶、瓜尔豆胶、角叉菜胶、糊精、葡聚糖、直链淀粉、羧甲基纤维素钾、羧甲基纤维素钠、羧甲基纤维素钙、普鲁兰多糖、壳聚糖、羧甲基淀粉钠、车前属种皮、半乳甘露聚醣、甲基丙烯酸氨基烷基酯共聚物E、甲基丙烯酸氨基烷基酯共聚物RS、甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、丙烯酸甲酯·甲基丙烯酸·甲基丙烯酸甲酯共聚物、丙烯酸乙酯·甲基丙烯酸甲酯共聚物、聚乙烯醇缩醛二乙基氨基乙酸酯、酪蛋白、海藻酸烷基酯等。通过将这些基质溶解在水或乙醇等极性有机溶剂中,进行薄膜涂布后使其干燥,能够制备膜剂。在一个优选的实施方式中,本发明的粘膜给予用疫苗组合物为膜状制剂的形态。
例如,作为散剂、细粒剂、颗粒剂、片剂用添加剂,可以使用乳糖、玉米淀粉、结晶纤维素之类的赋形剂;羟丙基纤维素、阿拉伯胶等结合剂;以及适量的水或乙醇等溶剂,进行混合搅拌后,造粒、干燥、压片,组合这些工序进行制备。根据需要还可以添加硬脂酸镁之类的润滑剂、羟丙基纤维素、蔗糖等包衣剂。
例如,作为口腔崩解片(冷冻干燥型)用基质,可列举出明胶、普鲁兰多糖等多糖类。另外,作为成型剂,可以使用甘露糖醇、海藻糖、山梨糖醇、甘氨酸等。通过将这些添加剂溶解在水中,分注后使其冷冻干燥,能够制备口腔崩解片(冷冻干燥型)。在一个优选的实施方式中,本发明的粘膜给予用疫苗组合物为口腔崩解片的形态。
例如,作为气雾剂,作为内容物可列举出液体制剂、流动性高的凝胶剂、霜剂、散剂等微粉。通过使用喷雾设备使它们在气体中分散成固体或液体的微粒,能够高效地给予至口腔粘膜、鼻腔粘膜之类的给予部位。
本发明的组合物中的WT1肽和/或经改变的WT1肽以及细胞免疫诱导促进剂的比例没有特别限定。在一个实施方式中,本发明的组合物包含以组合物的总重量为基准优选0.01~40重量%、更优选0.1~30重量%的WT1肽和/或经改变的WT1肽。在一个实施方式中,本发明的组合物包含以组合物的总重量为基准优选0.001~30重量%、更优选0.01~20重量%的细胞免疫诱导促进剂。
另外,本发明的组合物根据需要可以含有添加剂。添加剂根据与基质的主成分、WT1肽和/或经改变的WT1肽、及其细胞免疫诱导促进剂的相容性、想要实施的给予方案等而自例如等渗剂、防腐·杀菌剂、抗氧化剂、溶解剂、助溶剂、悬浮剂、填充剂、pH调节剂、稳定剂、吸收促进剂、释放速度控制剂、着色剂、增塑剂、交联剂、粘合剂等、或者它们的2种以上的组合中选择。
WT1肽和/或经改变的WT1肽的对治疗有效的量根据疾病的严重程度、对象的年龄及相对的健康以及其它的已知的因素而可以大范围地变化,通常,1日用量约0.1μg~1g/kg体重能够得到令人满意的结果。细胞免疫诱导促进剂与WT1肽和/或经改变的WT1肽同时或逐次给予,优选同时给予。细胞免疫诱导促进剂的有效量根据所使用的具体的细胞免疫诱导促进剂、其它细胞免疫诱导促进剂的有无等而可以大范围地变化,但1日用量0.01μg~1g/kg体重能够得到令人满意的结果。1日用量可以1次给予,也可以分2次以上例如2次、3次、4次或5次等多次来给予。给予间隔是任意的,可以根据患者的状态、癌症的严重程度、是治疗目的还是预防目的等从例如1日1次、3日1次、1周1次、2周1次、1个月1次、3个月1次、6个月1次、1年1次或比该范围更长的给予间隔中适当选择。通常,出于实际具有重度癌症的患者的治疗的目的,以更高频率、高用量给予WT1肽和/或经改变的WT1肽,出于不患有癌症的患者的预防的目的,以更低频率、低用量给予WT1肽和/或经改变的WT1肽。
以下列举出实施例对本发明进行更详细且具体的说明,但本发明不限定于实施例的范围。
实施例
舌下给予液体制剂
制造具有下述表1的组成的液体制剂,作为小鼠免疫试验的给予样品。具体而言,在表1记载的配合量的Db126肽(醋酸盐)及细胞免疫诱导促进剂以及根据需要添加的药理学上容许的酸中添加4重量份的添加剂(DMSO)及作为基质的生理盐水,使总量为100重量份,进行混合,制备舌下给予液体制剂。
Db126肽(醋酸盐)、Peptide-25使用化学合成并进行HPLC精制而成的物质。咪喹莫特从东京化成工业购入。环状二GMP(c-di-GMP)及环状二AMP(c-di-AMP)从Biolog Life Science Institute公司购入。Pam3CSK4使用InvivoGen制造的物质、酵母多糖使用nacalai tesque制造的物质、Poly(I:C)使用InvivoGen制造的物质、来源于成团泛菌的脂多糖使用自然免疫应用技研制造的物质、吡喃葡萄糖基脂使用InvivoGen制造的物质(MPLAs)、雷西莫特(R848)及ODN1826使用InvivoGen制造的物质、匹多莫德使用Santa CruzBiotechnology制造的物质、贝他定使用和光纯药制造的物质、左旋咪唑盐酸盐使用MP Biomedical制造的物质、肽聚糖、Pam2CSK4、鞭毛蛋白使用InvivoGen制造的物质、TLR7-II使用CALBIOCHEM制造的物质。
使用咪喹莫特:东京化成工业制造、氯贝特:LKT Laboratories制造、槲皮素:Cayman Chemical制造、白藜芦醇(白藜芦醇(合成品)):和光纯药制造、那可丁:和光纯药制造、3,3’-二吲哚甲烷:和光纯药制造、呫吨酮:和光纯药制造、小白菊内酯:和光纯药制造、依托度酸:和光纯药制造、洛索洛芬(洛索洛芬Na):阳进堂制造、双氯芬酸(双氯芬酸钠):和光纯药制造、酮洛芬:和光纯药制造、塞来昔布:TOCRIS bioscience制造、、二十二碳六烯酸:Cayman Chemical制造、2’,5’-双脱氧腺苷:BIOMOLInternational、SCH23390:和光纯药制造、罗替戈汀:STARNASCENS制造、GW627368X:Cayman Chemical制造、噻普酮:Cayman Chemical制造、氯前列醇:和光纯药制造、BWA868C:Cayman Chemical制造、RO1138452:Cayman Chemical制造、白三烯B4:Cayman Chemical制造、孟鲁司特(孟鲁司特钠):LG Life Sciences、齐留通:Toronto Research Chemicals、甘草酸(甘草酸二钾):和光纯药制造、吡非尼酮:TOCRIS bioscience制造、苯海拉明(苯海拉明盐酸盐):和光纯药制造、法莫替丁:和光纯药制造、Proxifan:TOCRIS bioscience制造、氮卓斯汀(氮卓斯汀盐酸盐):LKT Labs、4-甲基组胺:TOCRIS bioscience制造、奥氮平:和光纯药制造、佐米曲坦:Cipla制造、托伐普坦:Sigma-Aldrich制造、去氨加压素:Sigma-Aldrich制造、毛果芸香碱(盐酸毛果芸香碱):和光纯药制造、奥昔布宁(奥昔布宁盐酸盐):Cipla制造、普萘洛尔(盐酸普萘洛尔):和光纯药制造、甲苯噻嗪:和光纯药制造、Novokinin:Sigma-Aldrich制造、巴氯芬:东京化成制造、TRAP-6:Bachem制造、腺苷二磷酸:MP Biomedicals制造、生长抑素-14:Bachem制造、GW405833:Sigma-Aldrich制造、SEW2871:Cayman Chemical制造、曲美布汀(马来酸曲美布汀):东京化成制造、洛哌丁胺(洛哌丁胺盐酸盐):和光纯药制造、褪黑素:LKT Labs制造、L-AP4(L-2-氨基-4-膦酰基丁酸):和光纯药制造、甲磺司特:TOCRIS bioscience制造。
膜剂
制造具有下述表1的组成的膜剂。具体而言,添加D-甘露醇(Roquette制造)46重量份及聚乙二醇400(和光纯药制造)2.6重量份、纯化水150重量份,进行超声波搅拌。在其中添加羟丙基纤维素(日本曹达制造、HPC-SSL)41重量份、Db126肽(化学合成·HPLC精制品)10重量份、Peptide-25(化学合成·HPLC精制品)0.3重量份、及辅助肽以外的细胞免疫诱导促进剂0.1重量份,充分搅拌混合。将该溶液的1/100量(2.5重量份)滴加在聚对苯二甲酸乙二醇酯制剥离薄膜上,进行风干及减压干燥,得到1重量份的膜状制剂。在后述的小鼠免疫试验中,以每只小鼠1张(10mg)/次的量给予各膜状制剂。细胞免疫诱导促进剂的获得来源与上述舌下给予液体制剂的情况同样。
口腔崩解片
制造具有下述表1的组成的口腔崩解片。具体而言,取D-甘露醇(Roquette制造)48.6重量份及水溶性的来源于鱼的明胶41重量份,添加到纯化水400重量份中,在35℃下溶解。向其中添加Db126肽(化学合成·HPLC精制品)10重量份、Peptide-25(化学合成·HPLC精制品)0.3重量份、及辅助肽以外的细胞免疫诱导促进剂0.1重量份,充分搅拌混合。将该溶液的1/100量(5重量份)滴加在铝箔上,进行冷冻干燥处理,得到1重量份的口腔崩解片。在后述的小鼠免疫试验中,以每只小鼠1片(10mg)/次的量给予各口腔崩解片。细胞免疫诱导促进剂的获得来源与上述舌下给予液体制剂的情况同样。
小鼠免疫试验1(舌下给予)
对上述舌下给予液体制剂、膜剂及口腔崩解片进行小鼠免疫试验。试验用ELISPOT法进行。具体而言,给予1次的情况下,将小鼠麻醉后,向舌下部给予液体制剂、膜剂或口腔崩解片,维持原样2分钟后,饲养6天。给予2次的情况下,自第1次的给予起6天后,同样地重复上述操作。从最后给予那一天起6天后,摘除脾脏,按照以下记载的ELISPOT法评价抗原特异性细胞免疫诱导水平。
(ELISPOT法)
由摘除的脾脏制备脾细胞悬浮液。在固定有抗小鼠IFN-γ抗体的ELISPOT板的孔中,与培养液一起加入脾细胞(3×106细胞/孔)和抗原肽(100μM),在37℃、5%CO2的培养条件下共培养20小时,评价IFN-γ产生细胞斑点数(斑点数/3×106细胞)。
将免疫试验的结果与给予量及给予次数一同示于下述表1。所使用的小鼠为能评价利用HLA-A*0201型MHC拘束性肽来进行的免疫诱导的转基因小鼠。另外,为了进行比较,将使用后述的注射剂的免疫的结果(比较例2~6)示于表1的最后。
[表1-1]
表1
[表1-2]
表1续
[表1-3]
表1续
[表1-4]
表1续
[表1-5]
表1续
[表1-6]
表1续
[表1-7]
表1续
[表1-8]
表1续
[表1-9]
表1续
[表1-10]
表1续
[表1-11]
表1续
[表1-12]
表1续
[表1-13]
表1续
[表1-14]
表1续
()内的数值为各成分的配合比例(重量份)(以下的表中也同样)。
HPC:羟丙基纤维素
PEG:聚乙二醇4
PGN:肽聚糖
poly(I:C):聚肌胞苷酸
syn-MPL:合成单磷酰脂A(吡喃葡萄糖基脂)
c-di-GMP:环状二GMP
c-di-AMP:环状二AMP
左旋咪唑HCl:左旋咪唑盐酸盐
PEP:Peptide-25(序列号5)(辅助肽)
WT1_35:hWT135(序列号6)(辅助肽)
WT1_332:WT1_332-347(序列号8)(辅助肽)
PADRE:PADRE(序列号7)(辅助肽)
MA:肉豆蔻酸
鼻腔给予液体制剂
制造具有下述表2的组成的液体制剂,作为小鼠免疫试验的给予样品。具体而言,在表2记载的配合量的Db126肽(醋酸盐)及细胞免疫诱导促进剂中添加4重量份的添加剂(DMSO)及作为基质的生理盐水,使总量为100重量份,进行混合,制备鼻腔给予液体制剂。Db126肽及细胞免疫诱导促进剂的获得来源与上述舌下给予液体制剂的情况同样。
小鼠免疫试验2(鼻腔给予)
对上述鼻腔给予液体制剂进行小鼠免疫试验。试验用ELISPOT法进行。具体而言,给予1次的情况下,将小鼠麻醉后,使其从鼻腔吸入液体制剂,饲养6天。给予2次的情况下,自第1次给予起6天后,同样地重复上述操作。自最后给予那一天起6天后,摘除脾脏,用ELISPOT法评价抗原特异性细胞免疫诱导水平。ELISPOT法用与上述小鼠免疫试验1同样的方法进行。
将免疫试验的结果与给予量及给予次数一同示于下述表2。所使用的小鼠为能评价利用HLA-A*0201型MHC拘束性肽来进行的免疫诱导的转基因小鼠。另外,为了进行比较,将使用后述的注射剂的免疫的结果(比较例2~6)记载在表2的最后。
[表2-1]
表2
[表2-2]
表2续
[表2-3]
表2续
[表2-4]
表2续
[表2-5]
表2续
[表2-6]
表2续
[表2-7]
表2续
[表2-8]
表2续
[表2-9]
表2续
皮内注射剂
制备具有下述表3的组成的皮内注射剂,作为免疫试验的给予样品。具体而言,在表3记载的配合量的Db126肽(醋酸盐)及作为佐剂的MontanideISA51VG(Freund Corp.)中添加0.5重量份的添加剂(DMSO)及作为基质的生理盐水,使总量为100重量份,进行混合,制备注射剂。Db126肽的获得来源与上述舌下给予液体制剂的情况同样。
小鼠免疫试验3(皮内注射)
对上述皮内注射剂进行小鼠免疫试验。试验用ELISPOT法进行。具体而言,向小鼠背部皮内注射给予200μL后,饲养6天。自给予日起6天后,摘除脾脏,用ELISPOT法评价抗原特异性细胞免疫诱导水平。给予次数为1次。所使用的小鼠为能评价利用HLA-A*0201型MHC拘束性肽来进行的免疫诱导的转基因小鼠。ELISPOT法用与上述小鼠免疫试验1同样的方法进行。将免疫试验的结果示于下述表3。
[表3]
表3
对包含WT1肽和/或经改变的WT1肽;以及第一细胞免疫诱导促进剂的粘膜给予用癌症疫苗组合物,向舌下(表1)或者鼻腔(表2)给予,评价有效的第一细胞免疫诱导促进剂。
其结果,选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂及它们的2种以上的组合的细胞免疫诱导促进剂是优选的。
优选的是,选自TLR配体、环状二核苷酸、免疫调节低分子药物、环氧酶抑制剂、TSLP产生抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、PPAR激动剂、TGF-β产生抑制剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、毒蕈碱受体拮抗剂、肾上腺素受体拮抗剂、阿片类受体激动剂、褪黑素受体激动剂、代谢型谷氨酸受体激动剂及它们的2种以上的组合的第一细胞免疫诱导促进剂、以及辅助肽以外的这些第一细胞免疫诱导促进剂和辅助肽的组合是有效的。
对于舌下,进一步优选的是,选自TLR4配体、TLR1/2配体、TLR2/6配体、TLR7和/或TLR8配体、环状二核苷酸、免疫调节低分子药物、环氧酶抑制剂、TSLP产生抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、PPAR激动剂、TGF-β产生抑制剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、毒蕈碱受体拮抗剂、肾上腺素受体拮抗剂、阿片类受体激动剂、褪黑素受体激动剂、代谢型谷氨酸受体激动剂及它们的2种以上的组合的第一细胞免疫诱导促进剂、以及辅助肽以外的这些第一细胞免疫诱导促进剂和辅助肽的组合是有效的。
对于鼻腔,进一步优选的是,选自TLR4配体、TLR1/2配体、TLR2及Dectin1配体、TLR3配体、TLR7和/或TLR8配体、环状二核苷酸、免疫调节低分子药物、环氧酶抑制剂、TSLP产生抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、PPAR激动剂、TGF-β产生抑制剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、毒蕈碱受体拮抗剂、肾上腺素受体拮抗剂、阿片类受体激动剂、褪黑素受体激动剂、代谢型谷氨酸受体激动剂及它们的2种以上的组合的第一细胞免疫诱导促进剂、以及辅助肽以外的这些第一细胞免疫诱导促进剂和辅助肽的组合是有效的。
进而还确认了,通过添加作为第二细胞免疫诱导促进剂的药理学上容许的酸或其药理学上容许的盐,促进了免疫诱导。
另外还确认了,从安全性的观点考虑,相比于鼻腔给予,更优选舌下给予,但作为从给予简便性、保存稳定性的观点考虑优选的剂型的、膜剂、口腔崩解片也具有强的免疫诱导。
如表1及2所示,通过粘膜给予,可以获得与注射同等或其以上的免疫诱导效果。根据临床研究相关的论文(Current Opinion in immunology2008,20:211-220),WT1疫苗在人的注射免疫中确认到了作为癌症疫苗的效果。本发明的粘膜给予用癌症疫苗组合物在作为免疫评价用动物模型的小鼠体系中表现出与注射免疫同等以上的免疫诱导效果,因此,能够充分期待给予给人类时诱导与注射同等以上的免疫、发挥作为癌症疫苗的效果。
Claims (7)
1.一种粘膜给予用癌症疫苗组合物,其用于诱导细胞免疫,所述组合物包含:
(i)WT1肽和/或经改变的WT1肽;以及
(ii)第一细胞免疫诱导促进剂,其选自TLR配体、环状二核苷酸、辅助肽、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、Th2细胞因子抑制剂、及它们的2种以上的组合。
2.根据权利要求1所述的粘膜给予用癌症疫苗组合物,其中,还包含作为第二细胞免疫诱导促进剂的药理学上容许的酸或其药理学上容许的盐。
3.根据权利要求1或2所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为辅助肽。
4.根据权利要求1或2所述的粘膜给予用癌症疫苗组合物,其中,第一细胞免疫诱导促进剂为选自由TLR配体、环状二核苷酸、免疫调节低分子药物、环氧酶抑制剂、前列腺素受体拮抗剂、前列腺素受体激动剂、TSLP产生抑制剂、腺苷酸环化酶抑制剂、ω-3脂肪酸、PPAR激动剂、多巴胺受体拮抗剂、多巴胺受体激动剂、组胺受体激动剂、组胺受体拮抗剂、血清素受体激动剂、血清素受体拮抗剂、加压素受体拮抗剂、加压素受体激动剂、毒蕈碱受体拮抗剂、毒蕈碱受体激动剂、肾上腺素受体拮抗剂、肾上腺素受体激动剂、血管紧张素受体激动剂、GABA受体激动剂、凝血酶受体拮抗剂、凝血酶受体激动剂、阿片类受体激动剂、ADP受体激动剂、白三烯受体拮抗剂、白三烯受体激动剂、褪黑素受体激动剂、生长抑素受体激动剂、大麻素受体激动剂、鞘氨醇1-磷酸受体激动剂、代谢型谷氨酸受体激动剂、磷脂酶A2抑制剂、TGF-β产生抑制剂、及Th2细胞因子抑制剂组成的组中的1种以上的物质与辅助肽的组合。
5.一种粘膜给予用癌症疫苗膜剂,其包含权利要求1~4中任一项所述的组合物,为膜状制剂的形态。
6.一种粘膜给予用癌症疫苗液体制剂,其包含权利要求1~4中任一项所述的组合物,为液体制剂的形态。
7.一种粘膜给予用癌症疫苗口腔崩解片,其包含权利要求1~4中任一项所述的组合物,为口腔崩解片的形态。
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US10206985B2 (en) | 2019-02-19 |
CN103961702B (zh) | 2019-04-09 |
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JP2014169282A (ja) | 2014-09-18 |
CA2840988A1 (en) | 2014-08-05 |
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KR102045029B1 (ko) | 2019-11-14 |
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