CN103961699B - 经皮给予用wt1肽癌症疫苗组合物 - Google Patents
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Abstract
本发明提供经皮给予用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)作为第一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的、用于诱导细胞免疫的经皮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经皮给予用癌症疫苗组合物。
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 I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类分子的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Montanide ISA51(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(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 in Immunology,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为了诱导免疫而给予微生物或者病毒自身或它们的一部分的物质。通常,微生物、病毒由于其尺寸的原因,其侵入会被皮肤阻止,因此,疫苗需要侵入式地给予到体内。因而,免疫通常使用注射。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
本发明人发现,通过经皮给予,可以得到良好的细胞免疫诱导效果。本发明人还对适合于利用WT1肽和/或经改变的WT1肽的经皮给予来进行的细胞免疫诱导的物质进行了研究,结果发现,适宜使用的是:药理学上容许的酸或其药理学上容许的盐。进而,还发现,选自由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细胞因子抑制剂的一种以上细胞免疫诱导促进剂和药理学上容许的酸的组合使用是适宜的。在适宜的实施方式中,药理学上容许的酸和TLR配体的组合、或药理学上容许的酸、TLR配体和辅助肽的组合能够特别显著地增强细胞免疫。进而发现,通过在低刺激条件下进行给予,能够得到高的细胞免疫诱导效果。具体而言,通过在选择作为给予经皮给予用癌症疫苗组合物前的皮肤刺激评价用动物模型的皮肤状态的指标的、经皮水分散发量(TEWL)(g/h·m2)为50以下的低刺激状态的基础上,给予经皮给予用癌症疫苗组合物,能够获得高的细胞免疫诱导效果。或者,通过将经皮给予用癌症疫苗组合物的皮肤刺激特性设为给予结束时的皮肤刺激评价用动物模型的皮肤内TSLP水平(pg/mg蛋白质)为10000以下的低刺激特性,也能够获得高的细胞免疫诱导效果。
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)一种经皮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)作为第一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;
(2)根据(1)所述的经皮给予用癌症疫苗组合物,其中,药理学上容许的酸或其药理学上容许的盐为有机酸或其药理学上容许的盐;
(3)根据(2)所述的经皮给予用癌症疫苗组合物,其中,有机酸或其药理学上容许的盐为包含羧基的有机化合物或者包含磺酸基的有机化合物、或其药理学上容许的盐;
(4)根据(2)所述的经皮给予用癌症疫苗组合物,其中,有机酸或其药理学上容许的盐为饱和直链部分的碳数为8~20的饱和或者不饱和的直链或者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、或其药理学上容许的盐;
(5)根据(2)所述的经皮给予用癌症疫苗组合物,其中,有机酸或其药理学上容许的盐为选自由癸酸、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、或其药理学上容许的盐;
(6)根据(1)~(5)中任一项所述的经皮给予用癌症疫苗组合物,其中,还包含第二细胞免疫诱导促进剂,所述第二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;
(7)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为TLR配体;
(8)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为环状二核苷酸;
(9)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为免疫调节低分子药物;
(10)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为环氧酶抑制剂;
(11)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(12)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(13)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为TSLP产生抑制剂;
(14)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为腺苷酸环化酶抑制剂;
(15)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为ω-3脂肪酸;
(16)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(17)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(18)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(19)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(20)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(21)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(22)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(23)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(24)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(25)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(26)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(27)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(28)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(29)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(30)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(31)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(32)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(33)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为阿片类受体激动剂;
(34)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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;
(35)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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。
(36)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为褪黑素受体激动剂。
(37)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为生长抑素受体激动剂。
(38)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为大麻素受体激动剂。
(39)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为鞘氨醇1-磷酸受体激动剂。
(40)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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。
(41)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为ADP受体激动剂;
(42)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为磷脂酶A2抑制剂;
(43)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为TGF-β产生抑制剂;
(44)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为Th2细胞因子抑制剂;
(45)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二细胞免疫诱导促进剂为辅助肽;
(46)根据(6)所述的经皮给予用癌症疫苗组合物,其中,第二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种以上物质与辅助肽的组合;
(47)根据(1)~(46)中任一项所述的经皮给予用癌症疫苗组合物,其为霜剂的形态;
(48)根据(1)~(46)中任一项所述的经皮给予用癌症疫苗组合物,其为液体制剂的形态;
(49)根据(1)~(48)中任一项所述的经皮给予用癌症疫苗组合物,其中,在低刺激条件下进行给予;
(50)根据(49)所述的经皮给予用癌症疫苗组合物,其中,低刺激条件是皮肤刺激评价用动物模型的给予前的经皮水分散发量(TEWL)为50g/h·m2以下的条件;及
(51)根据(49)或(50)所述的经皮给予用癌症疫苗组合物,其中,低刺激条件是皮肤刺激评价用动物模型的给予结束时的皮肤内TSLP水平为10000pg/mg蛋白质以下的条件。
在其它的实施方式中,本发明的癌症疫苗可以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:
(52)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、及(ii)药理学上容许的酸或其药理学上容许的盐经皮给予给对象;
(53)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、(ii)作为第一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、以及(iii)第二细胞免疫诱导促进剂经皮给予到对象,所述第二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;
(54)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)~(51)中任一项所述的经皮给予用癌症疫苗组合物给予到对象;
(55)药理学上容许的酸或其药理学上容许的盐作为WT1肽和/或经改变的WT1肽的经皮给予用细胞免疫诱导促进剂的应用;
(56)(i)药理学上容许的酸或其药理学上容许的盐与(ii)选自由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细胞因子抑制剂组成的组中的1种以上物质的组合作为WT1肽和/或经改变的WT1肽的经皮给予用细胞免疫诱导促进剂的应用;
(57)一种细胞免疫诱导方法,其包括经皮给予(i)WT1肽和/或经改变的WT1肽、以及(ii)作为第一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;
(58)药理学上容许的酸或其药理学上容许的盐在促进利用WT1肽和/或经改变的WT1肽的经皮给予来进行的细胞免疫诱导中的应用;
(59)(i)药理学上容许的酸或其药理学上容许的盐与(ii)选自由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细胞因子抑制剂组成的组中的1种以上物质的组合在促进利用WT1肽和/或经改变的WT1肽的经皮给予来进行的细胞免疫诱导中的应用;
(60)(i)WT1肽和/或经改变的WT1肽与(ii)作为第一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的组合在利用WT1肽和/或经改变的WT1肽的经皮给予来进行的细胞免疫诱导中的应用;
(61)(i)WT1肽和/或经改变的WT1肽与(ii)药理学上容许的酸或其药理学上容许的盐的组合,其通过经皮给予来进行癌症的治疗或预防在癌症的治疗或预防中的应用、;及
(62)(i)WT1肽和/或经改变的WT1肽、以及(ii)作为第一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在用于诱导细胞免疫的经皮给予用癌症疫苗组合物的制造中的应用。
发明的效果
本发明的癌症疫苗由于能够经皮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。另外,为巴布剂、带状制剂(tapes)等贴剂形态时,具有能够可靠地给予规定的给予量、能够任意地控制药物释放速度、并且给予时不会附着在其它部位的优点。进而,贴剂可以容易地贴附/撕除,因此,还具有在产生副作用时等自应用部位除去贴剂从而患者自己便能立即终止给予的优点。进而,本发明的经皮给予用癌症疫苗组合物还具有与单独给予WT1肽和/或经改变的WT1肽的情况相比效能显著提高的优点。进而,通过使用药理学上容许的酸或其药理学上容许的盐,还具有经皮给予用癌症疫苗组合物的效能进一步提高的优点。进而,本发明的经皮给予用癌症疫苗组合物还具有与注射给予相比诱导更强的细胞免疫的优点。
附图说明
图1是表示利用配合有各种酸的PIB带状制剂的细胞免疫诱导效果的图。
图2是表示各种带状制剂中的添加酸而带来的效果的图。
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 Tyr Leu(序列号1)构成的WT1肽。术语“Db235肽”是指由序列Cys Met Thr Trp 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鍵形成修饰、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。
作为具体例子,Db235肽的一部分改变了的Db235m肽是由序列Cys Tyr Thr TrpAsn 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。作为WO2003/106682中记载的HLA-A24限制性的经改变的WT1肽的具体例,可以列举出序列Arg Tyr Phe Pro Asn Ala Pro Tyr Leu(序列号4)的RYF肽、序列Ala TyrLeu Pro Ala Val Pro Ser Leu(序列号5)的AYL肽。
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,但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、TLR2/6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。本发明的优选的实施方式中,TLR配体为TLR1/2配体、TLR2及Dectin1配体、TLR3配体、TLR4配体、TLR7和/或TLR8配体、和/或TLR9配体。
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(glucopyranosyl lipid)、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“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6)的寡聚脱氧核苷酸。
5’―tccatgacgttcctgacgtt-3’
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,例如包括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和/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“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。
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。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(例如包括白介素-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、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TLR8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)、环状二GMP(c-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)、及通用辅助类似物(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、hWT135、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 Ala Val Phe(序列号7)构成的15个氨基酸的肽。hWT135是WO2010/123065“癌抗原辅助肽”中记载的由序列Trp Ala ProVal Leu Asp Phe Ala Pro 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8)。PADRE是由序列D-Ala Lys环己基-Ala Val Ala Ala TrpThr 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9)。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 Phe Lys 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10)。
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。
经改变的辅助肽的一例为Peptide-25B。Peptide-25B是为了提高免疫刺激效果而改变了Peptide-25的一部分氨基酸的经改变的Peptide-25的一例,是由序列Phe Gln AspAla Tyr Asn Ala Val His Ala Ala His Ala Val Phe(序列号11)构成的15个氨基酸的肽。
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,术语“酸”是指布朗斯泰德的酸,包括无机酸及有机酸,优选羧酸,例如脂肪酸及乳酸。在本说明书中使用时,本发明的组合物中可以含有的、作为第一细胞免疫诱导促进剂的“药理学上容许的酸”是指不会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。在本发明的优选的实施方式中,药理学上容许的酸为有机酸,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,更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,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,更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、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肽抗原的经皮给予诱导的免疫应答的增强,因此,在一个实施方式中,在本申请发明中能与药理学上容许的酸或其药理学上容许的盐组合使用的第二细胞免疫诱导促进剂为选自上述物质中的1种以上。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皮肤赋予物理刺激和/或化学刺激、优选不主动对皮肤赋予物理刺激(例如胶带粘贴(tape stripping)、微针)地进行给予。
在本说明书中使用时,术语“低刺激条件”是指,赋予皮肤的刺激比为了提高现有疫苗中所含的抗原的皮肤渗透性而通常对皮肤赋予的刺激低的条件或不对皮肤赋予刺激的条件。将现有的疫苗组合物经皮给予时,给予前或给予时对皮肤赋予物理刺激和/或化学刺激从而提高抗原的皮肤渗透性。在优选的实施方式中,作为低刺激条件,可以列举出物理刺激低的条件及化学刺激低的条件。物理刺激低的条件为例如疫苗给予前的皮肤刺激评价用动物模型的经皮水分散发量(TEWL)(g/h·m2)为50以下、优选45以下、更优选40以下、进一步优选35以下、更进一步优选30以下的条件。对于未经治疗的皮肤,TEWL水平为约2(g/h·m2),因此,给予前的TEWL水平为2(g/h·m2)以上。化学刺激低的条件为例如皮肤刺激评价用动物模型的皮肤内的胸腺基质淋巴细胞生成素(TSLP)水平(pg/mg蛋白质)为10000以下、优选9000以下、更优选8000以下、进一步优选7000以下的条件。对于未经治疗的皮肤,TSLP水平为约1(pg/mg蛋白质),因此,给予结束时,TSLP水平超过1(pg/mg蛋白质),优选超过2(pg/mg蛋白质),更优选超过3(pg/mg蛋白质)。“胸腺基质淋巴细胞生成素(TSLP)”是参与T细胞的分化、募集(recruit)的细胞因子,本发明中,可以用作皮肤刺激的程度的指标(值越大刺激越强)。作为用于达成物理刺激低的条件的手段,例如可以列举出不进行通常进行的给予前的皮肤的预处理、例如胶带粘贴、微针穿刺等。作为用于达成化学刺激低的条件的手段,例如可以列举出不给予特定量以上的具有刺激性的化学成分、例如乙醇、表面活性剂等。向目标对象给予本发明的疫苗组合物时,可以使用皮肤刺激评价用动物模型确定用于达成上述低刺激条件的具体手段,将该手段适用于向目标对象、例如人等给予时。
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经皮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”是指用于评价经皮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MHC1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。为例如包含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肽的经皮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动物模型使用。为了确保经皮给予部位而将毛剪掉时,使用由剪毛导致的皮肤损伤充分恢复了的状态的动物。
在本说明书中使用时,术语“皮肤刺激评价用动物模型”是指用于评价作为皮肤的物理刺激的指标的经皮水分散发量(TEWL)、作为经皮给予用癌症疫苗组合物的皮肤刺激特性的TSLP的动物模型。不管经皮给予用癌症疫苗组合物中所含的抗原的种类如何,作为皮肤刺激评价用动物模型,使用C57BL/6小鼠。为了确保经皮给予部位而将毛剪掉时,使用由剪毛导致的皮肤损伤充分恢复了的状态的动物。
II.经皮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“经皮给予用”组合物为经皮给予中通常使用的任意制剂例如搽剂或者洗剂这样的外用液体制剂、气雾剂这样的外用喷雾剂、软膏剂、硬膏剂、霜剂、凝胶剂或带状制剂或者巴布剂这样的贴剂即可。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。本发明中优选的经皮给予用组合物为霜剂、外用液体制剂或带状制剂的形态。
例如,作为搽剂用基质,可以列举出水;醇,例如乙醇和丙二醇;脂肪油,例如固体石蜡、软石蜡、液体石蜡、甘油、石蜡油、蜜蜡、金属皂;粘液(mucilage);天然油[例如:杏仁油、玉米油、花生油、蓖麻油、橄榄油、或它们的衍生物(例如聚氧乙烯醚蓖麻油(PolyoxylCastor Oil))];羊脂或其衍生物、脂肪酸和/或酯(例如:硬脂酸、油酸、肉豆蔻酸异丙酯)、以及它们的混合物。
洗剂是将活性成分微细地均匀分散在水性液体中而得到的制剂,有悬浮性洗剂和乳浊性洗剂。作为悬浮剂,例如可以列举出阿拉伯胶、海藻酸钠、羧甲基纤维素钠、甲基纤维素、膨润土等。作为乳化剂,例如可以列举出月桂基硫酸钠、山梨糖醇酐脂肪酸酯等。
例如,作为软膏基质,可以使用通常作为疏水性基质的油脂类、蜡、烃化合物等。具体而言,作为软膏基质,可以列举出黄色凡士林、白色凡士林、石蜡、液体石蜡、液体石蜡和聚乙烯的复合软膏基质(plastibase)、有机硅等矿物性基质、蜜蜡、动植物性油脂等动植物性基质等。
例如,作为霜剂用基质,可以列举出亲水性软膏、雪花膏(vanishing cream)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)、亲水性液体石蜡和聚乙烯的复合软膏基质(plastibase)等油/水型基质。
例如,作为凝胶基质,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、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、明胶、聚乙二醇等。
例如,作为巴布剂用基质,可以列举出明胶、羧甲基纤维素钠、甲基纤维素、聚丙烯酸钠、高岭土、聚乙烯醇、聚乙烯基吡咯烷酮、甘油、丙二醇、水等。
例如,带状制剂包含粘合剂层和用于支撑粘合剂层的支撑体,所述粘合剂层包含丙烯酸系粘合剂、天然橡胶系粘合剂、合成橡胶系粘合剂(包括合成异戊二烯橡胶、聚异丁烯(PIB)、丁苯橡胶、苯乙烯-异戊二烯-苯乙烯(SIS)橡胶等橡胶系弹性体)、有机硅系粘合剂、乙烯基酯系粘合剂、乙烯基醚系粘合剂等。根据需要,可以进一步含有在使用前使粘合剂层不会露出、而在使用时能够容易地从粘合剂层剥离的剥离衬垫。
本发明的经皮给予用癌症疫苗组合物中的WT1肽和/或经改变的WT1肽、药理学上容许的酸或其药理学上容许的盐、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,本发明的经皮给予用癌症疫苗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,本发明的经皮给予用癌症疫苗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%的药理学上容许的酸或其药理学上容许的盐。本发明的经皮给予用癌症疫苗组合物包含细胞免疫诱导促进剂时,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。
本发明的经皮给予用癌症疫苗组合物为带状制剂的形态时,该带状制剂(以下也称为“本发明的带状制剂”)的粘合剂层包含抗原,根据需要还包含细胞免疫诱导促进剂。在一个实施方式中,本发明的带状制剂的粘合剂层包含以粘合剂层的总重量为基准优选0.01~40重量%、更优选0.1~30重量%的抗原。本发明的带状制剂的粘合剂层包含细胞免疫诱导促进剂时,包含以粘合剂层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。
用于形成本发明的带状制剂的粘合剂层的粘合剂没有特别限定,例如为由丙烯酸系聚合物形成的丙烯酸系粘合剂;包含苯乙烯-二烯-苯乙烯嵌段共聚物(例如苯乙烯-异戊二烯-苯乙烯嵌段共聚物、苯乙烯-丁二烯-苯乙烯嵌段共聚物等)、聚异戊二烯、聚异丁烯、丁基橡胶、聚丁二烯等橡胶系弹性体的橡胶系粘合剂;有机硅橡胶、二甲基硅氧烷基料、二苯基硅氧烷基料等有机硅系粘合剂;聚乙烯基甲基醚、聚乙烯基乙基醚、聚乙烯基异丁基醚等乙烯基醚系粘合剂;醋酸乙烯酯-乙烯共聚物等乙烯基酯系粘合剂;由对苯二甲酸二甲酯、间苯二甲酸二甲酯、邻苯二甲酸二甲酯等羧酸成分与乙二醇等多元醇成分形成的聚酯系粘合剂等。特别优选的粘合剂为丙烯酸系粘合剂、橡胶系粘合剂、有机硅系粘合剂。这些粘合剂以其固体成分计,以粘合剂层的总重量为基准,以优选10~90重量%、更优选20~80重量%的量包含在粘合剂层中。
作为丙烯酸系粘合剂的例子,可以列举出将以包含(甲基)丙烯酸C2~18烷基酯为第1单体的聚合物作为主成分的丙烯酸酯系粘合剂。作为上述(甲基)丙烯酸烷基酯(第1单体)的例子,可以列举出为烷基的碳数1~18的直链状、支链状或环状烷基(例如甲基、乙基、丙基、丁基、戊基、己基、环己基、庚基、辛基、2-乙基己基、壬基、癸基、十一烷基、十二烷基、十三烷基等)的(甲基)丙烯酸烷基酯等,优选为烷基的碳数4~18的直链状、支链状或环状烷基(例如丁基、戊基、己基、环己基、庚基、辛基、2-乙基己基、壬基、癸基、十一烷基、十二烷基、十三烷基等)的(甲基)丙烯酸烷基酯。进而,为了在常温下赋予粘合性,更优选使用使聚合物的玻璃化转变温度降低的单体成分,因此,更优选为烷基的碳数4~8的直链状、支链状或环状烷基(例如丁基、戊基、己基、环己基、庚基、辛基、2-乙基己基等,优选丁基、2-乙基己基、环己基,特别优选2-乙基己基)的(甲基)丙烯酸烷基酯。具体而言,更优选丙烯酸丁酯、丙烯酸2-乙基己酯、甲基丙烯酸2-乙基己酯、丙烯酸环己酯、甲基丙烯酸环己酯等,其中,最优选丙烯酸2-乙基己酯。这些(甲基)丙烯酸烷基酯(第1单体成分)可以使用1种或组合使用2种以上。
另外,丙烯酸系粘合剂可以含有能与上述(甲基)丙烯酸烷基酯共聚的第2单体,作为这样的第2单体,可以列举出具有能成为使用交联剂时的交联点的官能团的单体。作为能够参与交联反应的官能团,可以列举出羟基、羧基、乙烯基等,优选羟基及羧基。作为该单体(第2单体成分)的具体例,可以列举出(甲基)丙烯酸羟乙酯、(甲基)丙烯酸羟丙酯、N-羟烷基(甲基)丙烯酰胺、(甲基)丙烯酸、衣康酸、马来酸、马来酸酐、中康酸、柠康酸、戊烯二酸等。其中,从获得的容易性的观点考虑,优选丙烯酸、甲基丙烯酸、丙烯酸羟乙酯(尤其是丙烯酸2-羟乙酯),最优选丙烯酸。这些单体(第2单体成分)可以使用1种或组合使用2种以上。
进而,丙烯酸系粘合剂根据需要可以含有第2单体以外的第3单体。作为第3单体(第3单体成分),例如可以列举出醋酸乙烯酯、丙酸乙烯酯等乙烯基酯类;甲基乙烯基醚、乙基乙烯基醚等乙烯基醚类;N-乙烯基-2-吡咯烷酮、N-乙烯基己内酰胺等乙烯基酰胺类;(甲基)丙烯酸甲氧基乙酯、(甲基)丙烯酸乙氧基乙酯、(甲基)丙烯酸四氢糠基酯等(甲基)丙烯酸烷氧基酯;(甲基)丙烯酸羟丙酯、丙烯酸α-羟甲酯等含羟基单体(由于是作为第3单体成分使用,因此,不作为交联点);(甲基)丙烯酰胺、二甲基(甲基)丙烯酰胺、N-丁基(甲基)丙烯酰胺、N-羟甲基(甲基)丙烯酰胺等具有酰胺基的(甲基)丙烯酸衍生物;(甲基)丙烯酸氨基乙酯、(甲基)丙烯酸二甲氨基乙酯、(甲基)丙烯酸叔丁氨基乙酯等(甲基)丙烯酸氨基烷基酯;(甲基)丙烯酸甲氧基乙二醇酯、(甲基)丙烯酸甲氧基二乙二醇酯、(甲基)丙烯酸甲氧基聚乙二醇酯、(甲基)丙烯酸甲氧基聚丙二醇酯等(甲基)丙烯酸烷氧基亚烷基二醇酯;(甲基)丙烯腈;苯乙烯磺酸、烯丙基磺酸、(甲基)丙烯酸磺丙基酯、(甲基)丙烯酰氧基萘磺酸酯、丙烯酰胺甲基磺酸等具有磺酸的单体;乙烯基哌啶酮、乙烯基嘧啶、乙烯基哌嗪、乙烯基吡咯、乙烯基咪唑、乙烯基噁唑、乙烯基吗啉等含乙烯基单体等。其中,优选乙烯基酯类、乙烯基酰胺类,乙烯基酯类优选醋酸乙烯酯,乙烯基酰胺类优选N-乙烯基-2-吡咯烷酮。这些单体(第3单体成分)可以使用1种或组合使用2种以上。
该丙烯酸系粘合剂为(甲基)丙烯酸烷基酯(第1单体成分)与具有能参与交联反应的官能团的乙烯基单体(第2单体成分)的共聚物时,优选(甲基)丙烯酸烷基酯与具有能参与交联反应的官能团的乙烯基单体以(甲基)丙烯酸烷基酯:具有能参与交联反应的官能团的乙烯基单体=99~85:1~15的重量比进行配合并共聚,更优选为99~90:1~10的重量比。
另外,该丙烯酸系粘合剂为(甲基)丙烯酸烷基酯(第1单体成分)、具有能参与交联反应的官能团的乙烯基单体(第2单体成分)、与这两种单体以外的其它单体(第3单体成分)的共聚物时,优选(甲基)丙烯酸烷基酯、具有能参与交联反应的官能团的乙烯基单体、与这两种单体以外的其它单体以(甲基)丙烯酸烷基酯:具有能参与交联反应的官能团的乙烯基单体:这两种单体以外的其它单体=40~94:1~15:5~50的重量比进行配合并共聚,更优选为50~89:1~10:10~40的重量比。
聚合反应使用自身公知的方法进行即可,没有特别限定,例如可以列举出添加聚合引发剂(例如过氧化苯甲酰、偶氮二异丁腈等),在溶剂(例如醋酸乙酯等)中使上述单体在50~70℃下反应5~48小时的方法。
作为本发明中特别优选的丙烯酸系粘合剂,例如为丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮的共聚物、丙烯酸2-乙基己酯/N-(2-羟乙基)丙烯酰胺/N-乙烯基-2-吡咯烷酮的共聚物、丙烯酸2-乙基己酯/丙烯酸2-羟乙酯/醋酸乙烯酯的共聚物、丙烯酸2-乙基己酯/丙烯酸的共聚物等,更优选为丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮的共聚物。
根据需要,可以对这些丙烯酸系粘合剂实施利用紫外线照射、电子射线照射等辐射线照射进行的物理交联,使用三官能性异氰酸酯等异氰酸酯系化合物、有机过氧化物、有机金属盐、金属醇盐、金属螯合化合物、多官能性化合物(多官能性外部交联剂,二丙烯酸酯、二甲基丙烯酸酯等多官能性内部交联用单体)等各种交联剂的化学交联处理。
作为橡胶系粘合剂,可以列举出配合有作为橡胶系弹性体的例如聚异丁烯·聚丁烯系、苯乙烯·二烯·苯乙烯嵌段共聚物、苯乙烯·丁二烯系、腈系、氯丁二烯系、乙烯基吡啶系、聚异丁烯系、丁基系、异戊二烯·异丁烯系等弹性体的橡胶系粘合剂。其中,从对肽及其细胞免疫诱导促进剂的溶解性及皮肤粘接性的方面考虑,优选使用聚异丁烯(PIB)、苯乙烯·二烯·苯乙烯嵌段共聚物〔例如苯乙烯·丁二烯·苯乙烯嵌段共聚物(SBS)、苯乙烯·异戊二烯·苯乙烯嵌段共聚物(SIS)等〕等,这些可以混合使用。
另外,为了达到适度的粘合力及药剂溶解性,橡胶系粘合剂可以混合为相同成分或不同成分且平均分子量不同的橡胶系弹性体来使用。例如,以聚异丁烯为例进行说明时,优选为平均分子量150,000~5,500,000的高分子量的聚异丁烯与平均分子量10,000~150,000的中分子量的聚异丁烯和/或平均分子量500~4,000的低分子量的聚异丁烯的混合物。这里,适宜的是,以高分子量:中分子量:低分子量=10~80、优选20~70:0~90、更优选10~80:0~80、进一步优选10~60的重量比配合高分子量、中分子量及低分子量的聚异丁烯。
本发明的平均分子量是指利用Flory的粘度式计算的粘均分子量,其是由20℃下的乌氏粘度计的毛细管1的流动时间利用Schulz-Blaschke式算出斯托丁格指数(Staudinger Index)(J0),使用该J0值通过下述式求出的。
[数学式1]
(式)
J0=ηsp/c(1+0.31ηsp)(Schulz-Blaschke式)
ηsp=t/t0-1
t:溶液的流动时间(利用Hagenbach-couette校正公式)
t0:溶剂的流动时间(利用Hagenbach-couette校正公式)
c:溶液的浓度(g/cm3)
粘均分子量
在该橡胶系粘合剂中,为了赋予适合的粘合性,可以配合例如松香系树脂、聚萜烯树脂、香豆酮-茚树脂、石油系树脂、萜烯-酚醛树脂、二甲苯树脂、脂环族饱和烃树脂等赋粘剂。赋粘剂可以以橡胶系粘合剂的总重量为基准,以50重量%以下、优选5~40重量%的比例配合上述赋粘剂中的1种或2种以上。
作为有机硅系粘合剂,可以列举出由聚有机硅氧烷系、聚二甲基硅氧烷系、或聚二甲基二苯基硅氧烷系等形成的有机硅系粘合剂。其中,优选使用来自Dow CorningCorporation的BIO PSA这样的商业上能获得的有机硅系粘合剂等。
作为支撑粘合剂层的支撑体,没有特别限定,优选实质上使肽、细胞免疫诱导促进剂不透过的支撑体,即不会发生粘合剂层中所含的肽、细胞免疫诱导促进剂、添加剂等通过支撑体中而自背面流失从而含量降低的支撑体。
作为支撑体,例如可以使用聚酯、聚酰胺、聚偏氯乙烯、聚乙烯、聚丙烯、聚氯乙烯、乙烯-丙烯酸乙酯共聚物、聚四氟乙烯、离聚物树脂、金属箔等单独的薄膜或它们的层叠薄膜等。其中,为了使支撑体和粘合剂层的粘接性(锚固性)良好,优选将支撑体设为由上述材质形成的无孔的塑料薄膜和多孔薄膜的层叠薄膜。该情况下,理想的是,粘合剂层形成于多孔薄膜侧。作为这样的多孔薄膜,采用与粘合剂层的锚固性提高的多孔薄膜,具体而言,可以列举出纸、织布、无纺布、编织布、实施了机械穿孔处理的片等。其中,从操作性等观点考虑,特别优选纸、织布、无纺布。多孔薄膜从锚固性提高、带状制剂的柔软性及贴附操作性等方面考虑,采用厚度1~200μm的范围的多孔薄膜。另外,作为多孔薄膜,使用织布、无纺布时,将单位面积重量设为优选5~30g/m2、更优选6~15g/m2即可。
作为最适合的支撑体,可以列举出厚度1.5~6μm的聚酯薄膜(优选聚对苯二甲酸乙二醇酯薄膜)和单位面积重量6~15g/m2的聚酯(优选聚对苯二甲酸乙二醇酯)制无纺布的层叠薄膜。
为了保护粘合剂层的粘合面直至使用为止,理想的是,在本发明的带状制剂粘合面层叠剥离衬垫。作为剥离衬垫,只要能够进行剥离处理、并确保足够轻的剥离力就没有特别限定,例如可以使用通过在与粘合剂层的接触面涂布有机硅树脂、氟树脂等而实施了剥离处理的聚酯、聚氯乙烯、聚偏氯乙烯、聚对苯二甲酸乙二醇酯等薄膜、优质纸、玻璃纸等纸、或优质纸或者玻璃纸等与聚烯烃的层压薄膜等。剥离衬垫的厚度优选为10~200μm、更优选为25~100μm。作为剥离衬垫,从阻隔性、价格等方面考虑,优选由聚酯(尤其是聚对苯二甲酸乙二醇酯)树脂形成的衬垫。
进而,该情况下,从操作性方面考虑,优选具有25~100μm左右的厚度的衬垫。
本发明的组合物优选在低刺激条件下给予给对象。低刺激条件下的给予例如可以通过如下方式来达成,(i)在用皮肤刺激评价用动物模型进行评价时的经皮水分散发量(TEWL)(g/h·m2)为50以下的给予条件下将本发明的组合物给予给对象,(ii)将用皮肤刺激评价用动物模型进行评价时的皮肤内TSLP水平(pg/mg蛋白质)为10000以下的组合物给予给对象等方式。
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。另外,本发明的组合物为带状制剂的形态时,该带状制剂可以含有皮肤渗透性增强剂作为添加剂。
在本说明书中使用时,术语“皮肤渗透性增强剂”是指经皮给予的抗原渗透皮肤的效率与未给予皮肤渗透性增强剂的效率相比能够得到改善的所有物质。作为皮肤渗透性增强剂,只要是在室温(25℃)为液态即具有流动性、或混合使用2种以上时混合物在室温(25℃)下最终变为液态、并具有促进吸收的效果的物质就没有特别限定。作为该有机液态成分,从与粘合剂层的相容性的观点考虑,优选疏水性液态成分。
作为该皮肤渗透性增强剂,例如可以列举出油醇、辛基十二烷醇等高级醇;甘油、乙二醇、聚丙二醇等多元醇;油酸、辛酸等高级脂肪酸;肉豆蔻酸异丙酯、棕榈酸异丙酯、油酸乙酯等脂肪酸酯;癸二酸二乙酯、己二酸二异丙酯等多元酸酯;三异硬脂酸二甘油酯、单油酸山梨糖醇酐、二辛酸丙二醇、单月桂酸聚乙二醇、四油酸聚氧乙烯山梨糖醇等多元醇脂肪酸酯;聚氧乙烯月桂基醚等聚氧乙烯烷基醚;角鲨烷、液体石蜡等烃;橄榄油、蓖麻油等植物油;硅油;N-甲基吡咯烷酮、N-十二烷基吡咯烷酮这样的吡咯烷酮类;癸基甲基亚砜这样的亚砜等,这些增强剂可以使用1种或混合使用2种以上。
使用橡胶系或丙烯酸系的粘合剂时,可以使用第二皮肤渗透性增强剂。具体的第二皮肤渗透性增强剂例如包括聚乙烯吡咯烷酮、交联聚维酮、聚丙二醇、聚乙烯醇、羧基乙烯基聚合物、羟丙基纤维素等或它们的混合物,但并不限定于此,在优选的实施方式中,本发明的第二皮肤渗透性增强剂为聚乙烯吡咯烷酮、交联聚维酮和/或聚丙二醇。
从WT1肽和/或经改变的WT1肽的皮肤渗透性增强的观点考虑,作为皮肤渗透性增强剂,优选使用高级醇、更具体而言为碳数8~18(优选8~14)的高级醇,脂肪酸酯、更具体而言为碳数8~18(优选12~16)的脂肪酸和碳数1~18的一元醇的脂肪酸酯、多元醇脂肪酸酯等,尤其优选使用脂肪酸酯、特别是肉豆蔻酸异丙酯、棕榈酸异丙酯、或癸二酸二乙酯。该皮肤渗透性增强剂的量以粘合剂层的总重量为基准优选为0.1重量%~70重量%、更优选为1重量%~65重量%、进一步优选为5重量%~60重量%。皮肤渗透性增强剂的比例为0.1重量%以上时,得到高的经皮吸收促进效果。为70重量%以下时,能够抑制粘合剂层整体的粘合力、内聚力的降低,并得到高的经皮吸收性,因此是有利的。
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。药理学上容许的酸或其药理学上容许的盐与抗原同时或逐次给予,优选同时给予。药理学上容许的酸或其药理学上容许的盐的有效量根据所使用的具体的酸或盐、组合使用的细胞免疫诱导促进剂的有无等而可以大范围地变化,1日用量0.01μg~1g/kg体重能够得到令人满意的结果。组合使用细胞免疫诱导促进剂时,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,1日用量0.01μg~1g/kg体重能够得到令人满意的结果。辅助肽的有效量根据所使用的具体的其它成分、它们的分量等而可以大范围地变化,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。每次的连续给予时间在1分钟~7天的区间内适当选择。给予间隔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每天~1年1次(例如1日1次、2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。
本发明中,物理刺激是指以擦伤、摩擦为代表的使角质损伤的所有的物理刺激。例如,利用粘合带等除去角质的胶带粘贴的操作、利用切割刀使皮肤受伤的操作、或用微小的针在角质上开孔的使用微针的操作也包含在该物理刺激中。
经皮水分散发量是指每小时从1m2角质散发的水分量(g)。经皮水分散发量可以利用水分散发量测定装置容易地在短时间内进行测定,其通常被广泛用作评价皮肤的损伤程度的指标。本发明中,其也用作物理刺激水平的指标。
TSLP(胸腺基质淋巴细胞生成素)是由皮肤的角化细胞、胸腺、粘膜上皮细胞产生的IL-7样细胞因子的1种,已知其参与树突状细胞的成熟化、T细胞分化。本发明中,其用作作为源自药物的刺激的化学刺激水平的指标。
以下列举出实施例对本发明进行更详细且具体的说明。本说明书中作为实施例记载的组合物均相当于本发明的疫苗组合物的优选方案,但本发明不限定于实施例的范围。
实施例
霜剂
制造具有下述表2的组成的霜剂。具体而言,以表2中记载的配合量配合Db126肽(HLA-A*02型MHC限制性肽)或者RYF肽(HLA-A*24型MHC限制性肽)或者AYL肽(HLA-A*24型MHC限制性肽)、辅助肽以外的细胞免疫诱导促进剂、辅助肽、药理学上容许的酸、以及根据需要添加的添加剂,进而配合15重量份的DMSO,在其中加入基质(基底霜),使全部含量为100重量份,得到霜剂。对于在表2中记载了配合量的实施例或比较例的霜剂,各成分的配合量如表中所记载。
表2中的基底霜是以下述表1记载的组成配合材料并混合而制得的。
[表1]
表1
基底霜 | |
白色凡士林 | 69.0重量% |
单硬脂酸山梨糖醇酐 | 0.8重量% |
苄醇 | 2.7重量% |
十六醇 | 2.7重量% |
硬脂醇 | 4.0重量% |
聚山梨酸酯60 | 4.0重量% |
浓甘油 | 2.7重量% |
水 | 14.1重量% |
白色凡士林、单硬脂酸山梨糖醇、苄醇、硬脂醇、聚山梨酸酯60、浓甘油、二甲基亚砜(DMSO)从和光纯药工业购入。Db126抗原肽的TFA盐、RYF肽的TFA盐、AYL肽的TFA盐、Db126抗原肽的醋酸盐、Peptide-25(Pep25)及Peptide-25B(Pep25B)使用化学合成并进行了HPLC精制的物质。十六醇、咪喹莫特(IMQ)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。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、Pam3CSK4使用InvivoGen制造的物质、吡喃葡萄糖基脂使用InvivoGen制造的物质(MPLAs)、酵母多糖使用nacalai tesque制造的物质、Poly(I:C)使用InvivoGen制造的物质、溴匹立明使用TOCRIS bioscience制造的物质、R848使用InvivoGen制造的物质、透明质酸钠使用Kikkoman Biochemifa Company制造的物质(microhyaluronic acid FCH)、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MPBiomedical制造的物质、甲磺司特使用TOCRIS bioscience制造的物质、依托度酸使用和光纯药制造的物质、洛索洛芬Na使用阳进堂制造的物质。
使用咪喹莫特:东京化成工业制造、氯贝特:LKT Laboratories制造、非诺贝特:和光纯药制造、槲皮素:Cayman Chemical制造、小檗碱(盐酸小檗碱n水合物):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、吲哚美辛:和光纯药制造、阿司匹林:Sigma-Aldrich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、伐地昔布: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、罗匹尼罗(盐酸罗匹尼罗):Ragactives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:CaymanChemical制造、白三烯B4:Cayman Chemical制造、孟鲁司特(孟鲁司特钠):LG LifeSciences、齐留通:Toronto Research Chemicals、烟酸:和光纯药制造、甘草酸(甘草酸二钾):和光纯药制造、吡非尼酮:TOCRIS bioscience制造、曲尼司特:和光纯药制造、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、Immepip(Immepip二氢溴酸盐):TOCRIS bioscience制造、Proxifan:TOCRIS bioscience制造、氮卓斯汀(氮卓斯汀盐酸盐):LKT Labs、西咪替丁:和光纯药、4-甲基组胺:TOCRIS bioscience制造、奥氮平:和光纯药制造、育亨宾(育亨宾盐酸盐):和光纯药制造、乙酰胆碱(氯化乙酰胆碱):和光纯药制造、甲麦角林(甲麦角林苯基甲基酯):TOCRIS bioscience制造、氯氮平:和光纯药制造、舒马曲坦:MYUNG IN PHARM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、奥昔布宁(奥昔布宁盐酸盐):SIGMA制造、毛果芸香碱(盐酸毛果芸香碱):和光纯药制造、坦索罗辛(坦索罗辛盐酸盐):Cipla制造、米多君(盐酸米多君):和光纯药制造、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、联苯茚酮A:Sigma-Aldrich制造、L-AP4(L-2-氨基-4-膦酰基丁酸):和光纯药制造。
准备以PET薄膜侧为带侧将PET薄膜/PET无纺布层叠品(面积0.7cm2)贴合在固定用粘合带的中央部而得到的复合基质。将在该复合基质的无纺布部分涂布4mg霜剂而得到的材料作为免疫试验的给予样品。
小鼠免疫试验1(霜剂)
对上述霜剂,使用免疫评价用动物模型进行小鼠免疫试验。免疫诱导水平的评价利用ELISPOT法进行。具体而言,将小鼠背部的毛剪掉,设置用于使因剪毛而导致的皮肤损伤恢复的饲养时间,然后,对小鼠的背部皮肤给予规定时间的样品并除去,进行规定天数的饲养,评价抗原特异性细胞免疫的诱导水平。自给予起经过规定天数后,摘除脾脏,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,利用ELISPOT法评价IFN-γ产生细胞斑点数(斑点数/3×106细胞)。霜剂的给予量均为4mg、给予次数为(24hr/周)×1次、脾脏摘除为自给予起6天后。
实施例3中,使用Dunplon Tape(Nitto Denko Cs System Corporation、No.375)向进行了10次胶带粘贴(TS)的皮肤给予,在实施例4及5中,分别向通过微细切割刀(MICROFEATHER No.7330G、FEATHER制造)及微针(针长750μm、Micro Needle Roller SystemMR75、Ostar Beauty制造)赋予了损伤的皮肤给予。
另外,对于一部分霜剂,还按照以下记载的方法进行给予后的小鼠的皮肤内TSLP水平、给予前的小鼠的经皮水分散发量、以及Db126抗原肽及咪喹莫特的皮肤渗透性的测定。TSLP水平、经皮水分散发量、及皮肤渗透性的评价中使用的小鼠为C57BL/6小鼠。
(TSLP水平的测定方法)
在制剂给予结束时,摘除小鼠背部皮肤,在提取溶剂中(包含蛋白酶抑制剂(Protease Inhibitor Cocktail for general use,SIGMA―ALDRICH)和10μM吲哚美辛(和光纯药制造)的PBS溶液)使用均质器(Physcotron、Micro Tech Nichion Inc.制造)将皮肤粉碎。使粉碎的皮肤以4℃、9000g进行10分钟离心分离后,回收上清液。用ELISA(MouseTSLP Quantikine ELISA Kit、R&D Systems)测定上清液中的TSLP量。另外,用BCA法(Pierce BCA Protein Assay Kit、Thermo SCIENTIFIC)测定上清液中的总蛋白质量,用TSLP量除以总蛋白质量,进行标准化。
(经皮水分散发量测定)
使用便携式密闭室方式水分散发量测定装置(ASAHIBIOMED制造、VAPO SCAN AS-VT100RS),使该设备接触小鼠皮肤5~15秒左右,从而进行测定。将在对小鼠皮肤进行预处理的10分钟后测定的值作为经皮水分散发量(TEWL)(g/h·m2)。
(小鼠皮肤渗透性试验)
使用Franz扩散池,进行Db126抗原肽以及咪喹莫特的皮肤渗透试验。将从预先剪毛了的小鼠的背部摘除的皮肤安装在循环有37℃的磷酸缓冲液(pH7.4等渗缓冲液)的Franz扩散池(适用面积4.91cm2)中。在该安装的皮肤上贴附0.7cm2的制剂,在24小时后取池内的试样。将采取的试样供给至高效液相色谱·串联型质谱仪,由预先制定的标准曲线算出24小时后渗透皮肤的Db126抗原肽的量(Db126抗原肽渗透量、μg/cm2/24hr)以及咪喹莫特的量(咪喹莫特渗透量、μg/cm2/24hr)。
将免疫试验的结果以及TSLP水平及经皮水分散发量的测定结果与所使用的小鼠一同示于下述表2中。表2中的“转基因小鼠”是能评价利用HLA-A*0201型MHC限制性肽来进行的细胞免疫诱导的转基因小鼠。另外,将皮肤渗透性的测定结果示于表3。此外,为了进行比较,将使用后述的注射剂的免疫的结果(比较例4~8)记载在表的最后。
[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
[表2-10]
表2续
[表2-11]
表2续
[表2-12]
表2续
[表2-13]
表2续
[表2-14]
表2续
[表2-15]
表2续
[表2-16]
表2续
[表2-17]
表2续
[表2-18]
表2续
[表2-19]
表2续
[表2-20]
表2续
[表2-21]
表2续
[表2-22]
表2续
IMQ:咪喹莫特(TLR7和/或TLR8配体)
c-di-GMP:环状二GMP(环状二核苷酸)
c-di-AMP:环状二AMP(环状二核苷酸)
PEP:Peptide-25(序列号7)(辅助肽)
PEPB:Peptide-25B(序列号11)(辅助肽)
poly(I:C):聚肌胞苷酸(TLR3配体)
R848:雷西莫特(TLR7和/或TLR8配体)
SDS:十二烷基硫酸钠
TS:胶带粘贴
Db126肽为醋酸盐的形态。
RYF肽及AYL肽为TFA盐的形态。
括号内的数值为各成分的配合比例(重量份)(在以下的表中也同样)。
[表3]
表3
带状制剂
使带状制剂中使用的粘合剂聚合(丙烯酸系粘合剂A、B)、或调配(PIB橡胶系粘合剂、SIS系粘合剂A、SIS-PIB系粘合剂A)。
(丙烯酸系粘合剂A的聚合)
在非活性气体氛围下,使丙烯酸2-乙基己酯75份、N-乙烯基-2-吡咯烷酮22份、丙烯酸3份及偶氮二异丁腈0.2份在醋酸乙酯中在60℃下溶液聚合,得到丙烯酸系粘合剂A溶液。
(丙烯酸系粘合剂B的聚合)
在非活性气体氛围下,使丙烯酸2-乙基己酯70份、N-乙烯基-2-吡咯烷酮25份、N-(2-羟乙基)丙烯酰胺5份及偶氮二异丁腈0.2份在醋酸乙酯中在60℃下溶液聚合,得到丙烯酸系粘合剂B溶液。
(PIB橡胶系粘合剂的调配)
将聚异丁烯(Opanol B200、BASF公司制造)24份、聚异丁烯(Opanol B12、BASF公司制造)36份及脂环族系石油树脂(ALCON P-100、荒川化学公司制造)40份溶解在甲苯中,得到PIB橡胶系粘合剂溶液。
(SIS系粘合剂A的调配)
将苯乙烯-异戊二烯-苯乙烯嵌段共聚物(SIS5002、JSR公司制造)60份、及脂环族系石油树脂(ALCON P-100、荒川化学公司制造)40份溶解在甲苯中,得到SIS系粘合剂A溶液。
(SIS-PIB系粘合剂A的调配)
将苯乙烯-异戊二烯-苯乙烯嵌段共聚物(SIS5002、JSR公司制造)30份、聚异丁烯(Opanol B100、BASF公司制造)30份及脂环族系石油树脂(ALCON P-100、荒川化学公司制造)40份溶解在甲苯中,得到SIS-PIB系粘合剂A溶液。
制造具有下述表4的组成的带状制剂。具体而言,配合表4记载的配合量的Db126抗原肽、细胞免疫诱导促进剂、药理学上容许的酸、及根据需要添加的皮肤渗透性增强剂、和粘合剂溶液及有机溶剂(醋酸乙酯、乙醇、甲苯等)并混合,以干燥后的厚度为约80μm的方式延展在剥离衬垫上,通过干燥,除去有机溶剂,贴合支撑体,制备带状制剂。粘合剂溶液以有机溶剂干燥后的各成分与粘合剂的总计为100重量份的方式配合。支撑体使用聚对苯二甲酸乙二醇酯(PET)薄膜(厚度25μm)。剥离衬垫使用实施了有机硅剥离处理的聚对苯二甲酸乙二醇酯(PET)制衬垫(厚度75μm)。将该带状制剂以面积为0.7cm2的方式切割而成的带状制剂作为免疫试验的给予样品。在给予时剥下剥离衬垫并给予。
Db126抗原肽、细胞免疫诱导促进剂及药理学上容许的酸的获得来源与上述霜剂的情况相同。肉豆蔻酸异丙酯(IPM)从Croda Japan KK购入。WT135(hWT135辅助肽)、PADRE(通用辅助肽)、WT1332(WT1332-347辅助肽)均使用化学合成、并进行了HPLC精制的物质。
小鼠免疫试验2(带状制剂)
使用如上操作制造的带状制剂,利用与上述小鼠免疫试验1同样的方法进行小鼠免疫试验。给予次数为(24hr/周)×1次、脾脏摘除为自给予起6天后。所使用的小鼠为能评价利用HLA-A*0201型MHC限制性肽来进行的细胞免疫诱导的转基因小鼠。
在实施例100中,向用微细切割刀(MICRO FEATHER No.7330G、FEATHER制)赋予了损伤的皮肤给予。
对于一部分带状制剂,利用与上述霜剂同样的方法,进行给予后的小鼠的皮肤内TSLP水平、给予前的小鼠的经皮水分散发量、以及Db126抗原肽及咪喹莫特的皮肤渗透性的测定。TSLP水平、经皮水分散发量、及皮肤渗透性的评价中使用的小鼠为C57BL/6小鼠。
将免疫试验的结果、以及TSLP水平及经皮水分散发量的测定结果示于下述表4。另外,将皮肤渗透性的测定结果示于表5。
[表4-1]
表4
[表4-2]
表4续
[表4-3]
表4续
[表4-4]
表4续
[表4-5]
表4续
[表4-6]
表4续
[表4-7]
表4续
[表4-8]
表4续
[表4-9]
表4续
[表4-10]
表4续
[表4-11]
表4续
丙烯酸系A:丙烯酸系粘合剂A
丙烯酸系B:丙烯酸系粘合剂B
PIB:PIB橡胶系粘合剂
SIS:SIS系粘合剂A
SIS-PIB:SIS-PIB系粘合剂A
WT135:hWT135辅助肽(序列号8)(辅助肽)
PADRE:通用辅助肽(序列号9)(辅助肽)
WT1332:WT1332-347辅助肽(序列号10)(辅助肽)
IPM:肉豆蔻酸异丙酯、Croda Japan KK制造
IPP:肉豆蔻酸异丙酯、和光纯药工业社制造
MA:肉豆蔻酸
BL-4.2:聚氧乙烯(4,2)月桂基醚、Nikko Chemicals Co.,Ltd.制造
Db126肽均为醋酸盐的形态。
括号内的数值为各成分的配合比例(重量份)。
[表5]
表5
外用液体制剂
制造具有下述表6的组成的外用液体制剂。以表6中记载的配合量配合Db126抗原肽、细胞免疫诱导促进剂及药理学上容许的酸、以及15重量份的DMSO,在其中加入基质,使总含量为100重量份,进行混合,得到外用液体制剂。作为基质,使用以重量比计为98:2或者90:10的比例的量配合丙二醇(PG)和油醇(OA)并混合而制得的基质。准备将纤维素无纺布(面积0.8cm2)贴合在固定用粘合带的中央部而得到的复合基质。将使该复合基质的无纺布部分含浸制得的外用液体制剂67μL而成的物质作为免疫试验的给予样品。
Db126抗原肽、细胞免疫诱导促进剂及药理学上容许的酸的获得来源与上述霜剂的情况同样。乳酸从和光纯药工业购入。
小鼠免疫试验3(外用液体制剂)
使用如上操作制造的外用液体制剂,利用与上述小鼠免疫试验1同样的方法进行小鼠免疫试验。给予量如上所述为67μL、给予次数为(24hr/周)×1次、脾脏摘除为自给予起6天后。所使用的小鼠为C57BL/6。
对于一部分外用液体制剂,使用作为皮肤刺激评价用动物模型的C57BL/6小鼠,利用与上述霜剂同样的方法,进行给予后的小鼠的皮肤内TSLP水平、及给予前的小鼠的经皮水分散发量的测定。
将免疫试验的结果、以及TSLP水平及经皮水分散发量的测定结果与所使用的小鼠一同示于下述表6。
[表6]
表6
PG/OA:丙二醇和油醇(均为和光纯药工业)的混合物。[]内的数值表示PG和OA的量比。
Db126肽均为醋酸盐的形态。()内的数值为各成分的配合比例(重量份)。
注射剂
制造具有下述表7的组成的皮内注射剂。具体而言,在表7记载的配合量的Db126抗原肽及作为佐剂的Montanide ISA51VG(Freund Corp.)中添加作为基质的生理盐水,使总量为100重量份,用均质器进行混合,制备注射剂。
小鼠免疫试验4(注射剂)
使用如上操作制造的注射剂,用与上述小鼠免疫试验1同样的方法进行小鼠免疫试验。给予量为30μL、给予次数为1次、脾脏摘除为自给予起6天后。所使用的小鼠为能评价利用HLA-A*0201型MHC限制性肽来进行的细胞免疫诱导的转基因小鼠。将免疫试验的结果示于下述表7。
[表7]
表7
Db126肽均为醋酸盐的形态。
括号内的数值为各成分的配合比例(重量份)。
体内CTL杀伤试验
自最终免疫给予起7天后,按照下述要领移植脾脏细胞(靶细胞或者对照细胞(control cell)),在移植完18小时后取脾脏,进行FACS测定,从而求出%特异性溶解。
步骤1.首次接受试验的小鼠的脾脏细胞采取
自首次接受试验的小鼠(与免疫试验中使用的小鼠相同种类的免疫评价用动物模型)摘除脾脏,在加入了RPMI1640培养基的培养皿中,使用载玻片磨碎。回收至50mL管后,进行10℃、1100rpm、5分钟离心分离,然后,丢弃上清液,加入20mL裂解缓冲液,在室温下孵育5分钟。加入20mL培养基后,进行离心分离,然后,加入培养基,通过细胞筛网。
步骤2.脾脏细胞的抗原标记
将步骤1中制备的脾脏细胞进行10℃、1100rpm、5分钟离心分离,然后,丢弃上清液,加入HBSS缓冲液,成为2×107细胞/mL。将该细胞液分注入2根50mL管中,在一个管的细胞液中以最终浓度为10μM的方式加入100μM抗原溶液(抗原为各免疫给予物中配合的抗原),作为靶细胞。另一个管的细胞为对照细胞。将两种细胞在37℃下孵育1小时,然后,进行离心分离,丢弃上清液,加入培养基。
步骤3.脾脏细胞的CFSE标记
将步骤2中进行了抗原标记的细胞离心分离,以为1×107细胞/mL的方式加入0.1%BSA-PBS。在靶细胞液中以最终浓度为10μM的方式加入5mM CFSE溶液,在对照细胞液中以最终浓度为1μM的方式加入5mM CFSE溶液,涡流混合后在37℃下孵育10分钟。其后进行离心分离,丢弃上清液,加入培养基。
步骤4.脾脏细胞移植
将步骤3中进行了CFSE标记的细胞离心分离,丢弃上清液,使用HBSS缓冲液,以为5×107细胞/mL的方式进行制备。将靶细胞液和对照细胞液等量混合,自眼窝静脉向免疫了的小鼠每次给予200μL(移植细胞数:1×107细胞/只)。
步骤5.免疫小鼠的脾脏细胞制备和FACS测定
脾脏细胞移植18小时后,摘除脾脏,与步骤1同样地制备脾脏细胞。其后,利用FACS检测CFSE阳性细胞,由CFSE高的细胞(靶细胞)和CFSE低的细胞(对照细胞)的比率,利用以下的式子评价细胞毒性。利用该指标评价抗原特异性诱导的免疫在生物体内特异性攻击抗原提呈细胞的能力,结果确认本发明的给予物质的效果高。
r=(%CFSE低的细胞)/(%CFSE高的细胞)
%特异性溶解=(1-(r非免疫/r免疫))×100
由比较例1和实施例1的比较、比较例2和实施例7的比较、比较例3和实施例8的比较、比较例12和实施例95的比较、比较例14和实施例105的比较、比较例15和实施例106的比较、比较例16和实施例127的比较、比较例17和实施例148~153的比较、比较例18和实施例154的比较可知,通过添加酸,能促进细胞免疫的诱导。
另外还可知,配合有酸的各种带状制剂能够诱导细胞免疫(参照表4及图1、2)。还可知,通过配合优选辛酸、异硬脂酸、癸酸、月桂酸、肉豆蔻酸、异硬脂酸、油酸、硬脂酸、乳酸,特别是癸酸、月桂酸、肉豆蔻酸、异硬脂酸、油酸、及乳酸,可以诱导强的细胞免疫。其中,月桂酸、肉豆蔻酸、异硬脂酸、油酸、及乳酸特别优异。
利用液体制剂的经皮免疫通过添加酸也能促进免疫诱导。乳酸、水杨酸、苹果酸、甲磺酸、马来酸、柠檬酸是有效的,乳酸、水杨酸、柠檬酸、甲磺酸特别有效。
进而,还可知能够诱导比注射更强的细胞免疫(参照表4及7)。
由以上结果可以确认,包含(i)WT1肽和/或经改变的WT1肽;以及(ii)作为第一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的、用于诱导细胞免疫的经皮给予用癌症疫苗组合物对细胞免疫的诱导是有效的。
另外,由表2、表4、及表6可知,利用胶带粘贴、皮肤切伤这样的预处理对皮肤赋予物理性损伤,利用表面活性剂、基质种类赋予化学刺激时,细胞免疫变弱。
对于有机脂肪酸的种类不同的带状制剂,未发现皮肤渗透量与免疫诱导水平有明确的对应关系。另外,确认了,通过皮肤的预处理,Db126及咪喹莫特的皮肤渗透量增大。
与免疫试验的结果对照可知,通过提高PG/OA液体制剂的OA比、或者在带中添加表面活性剂,作为皮肤刺激的指标的TSLP升高,细胞免疫诱导水平减弱。由该结果可知,在低刺激条件下进行细胞免疫诱导是很重要的。
可知,由于皮肤的预处理,TEWL值升高,由于物理刺激,皮肤屏障发生破坏。该结果与皮肤渗透试验中由于皮肤的预处理而Db126及咪喹莫特的皮肤渗透量大幅增加相对应。然而,虽然渗透量增加,但细胞免疫并没有增加,反而减弱。由该结果可知,与增加抗原及佐剂的皮肤渗透量相比,在低刺激条件下给予对细胞免疫诱导是更重要的。
Claims (7)
1.一种经皮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;
(ii)作为第一细胞免疫诱导促进剂的药理学上容许的有机酸或其药理学上容许的盐;以及
(iii)第二细胞免疫诱导促进剂;
其中,所述WT1肽为如SEQ ID NO:1所示的肽;
所述有机酸或其药理学上容许的盐选自肉豆蔻酸或其药理学上容许的盐;
所述第二细胞免疫诱导促进剂选自PEP和IMQ的组合或WT135和IMQ的组合。
2.根据权利要求1所述的经皮给予用癌症疫苗组合物,其为霜剂的形态。
3.根据权利要求1所述的经皮给予用癌症疫苗组合物,其为液体制剂的形态。
4.根据权利要求1~3中任一项所述的经皮给予用癌症疫苗组合物,其在低刺激条件下进行给予。
5.根据权利要求4所述的经皮给予用癌症疫苗组合物,其中,低刺激条件是皮肤刺激评价用动物模型的所述组合物给予前的经皮水分散发量即TEWL为50g/h·m2以下的条件。
6.根据权利要求4所述的经皮给予用癌症疫苗组合物,其中,低刺激条件是皮肤刺激评价用动物模型的所述组合物给予结束时的皮肤内胸腺基质淋巴细胞生成素即TSLP水平为10000pg/mg蛋白质以下的条件。
7.根据权利要求5所述的经皮给予用癌症疫苗组合物,其中,低刺激条件是皮肤刺激评价用动物模型的所述组合物给予结束时的皮肤内胸腺基质淋巴细胞生成素即TSLP水平为10000pg/mg蛋白质以下的条件。
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- 2014-01-29 JP JP2014014800A patent/JP6512567B2/ja active Active
- 2014-01-29 US US14/166,950 patent/US10071051B2/en active Active
- 2014-01-29 KR KR1020140011627A patent/KR20140100416A/ko active IP Right Grant
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- 2014-01-29 CN CN201410042896.XA patent/CN103961699B/zh not_active Expired - Fee Related
- 2014-01-29 EP EP14000317.9A patent/EP2762152A1/en not_active Withdrawn
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EP2762152A1 (en) | 2014-08-06 |
CN103961699A (zh) | 2014-08-06 |
RU2014102940A (ru) | 2015-08-10 |
KR20140100416A (ko) | 2014-08-14 |
RU2685933C2 (ru) | 2019-04-23 |
JP2014169276A (ja) | 2014-09-18 |
JP6512567B2 (ja) | 2019-05-15 |
CA2840941A1 (en) | 2014-08-05 |
US10071051B2 (en) | 2018-09-11 |
US20140220057A1 (en) | 2014-08-07 |
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