CN110545840A - 免疫应答调节性物质和含有该免疫应答调节性物质的疫苗组合物 - Google Patents
免疫应答调节性物质和含有该免疫应答调节性物质的疫苗组合物 Download PDFInfo
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Abstract
本发明涉及具有新颖结构的免疫应答调节性物质,和含有该免疫应答调节性物质的免疫佐剂组合物,且更具体地,涉及免疫应答调节性物质及其用途,该免疫应答调节性物质是具有降低的毒性的脂多糖(LPS)类似物。本发明的免疫应答调节性物质通过具有极好的固有免疫和诱导对特定病原体的适应性免疫应答的能力表现出免疫增强作用,且通过具有低毒性是非常安全的。此外,含有本发明的免疫应答调节性物质的疫苗含有免疫应答调节性物质和明矾,由此相较于仅使用该免疫应答调节性物质时,改善免疫增强作用。
Description
技术领域
本发明涉及具有新颖结构的免疫调节剂和包含该免疫调节剂的疫苗组合物。更具体地,本发明涉及具有新颖结构的免疫调节剂(即具有降低的毒性的脂多糖(LPS)的类似物),及其用途。
背景领域
脂多糖(LPS)是革兰氏阴性细菌的外膜的主要组分,且促进各种免疫细胞,特别是固有免疫应答。LPS通过分泌细胞因子,表达共刺激分子,和诱导抗原递呈而活化抗原递呈细胞,且使固有免疫应答与适应性免疫应答关联(Akira S,Uematsu S,Takeuchi O,Cell124:783-801(2006);Schnare M,Barton GM,Holt AC,Takeda K,Akira S等Nat Immunol2:947-950(2001))。
LPS由三个域组成,即两亲性域(脂质A)、核心寡糖(OS)、和O-抗原(或O-抗原性)多糖。已知脂质A在LPS的内毒素活性中起作用且通过各种类型的免疫细胞的TLR4(toll样受体4)信号传导表现出免疫刺激性作用(Raetz CR,Whitfield C,Annu Rev Biochem 71:635-700(2002))。已经靶向表现出降低的毒性的脂质A衍生物用于开发人疫苗免疫佐剂。单磷酰脂质A(MPL)是从明尼苏达沙门氏菌(Salmonella minnesota)粗菌株中分离的LPS的无毒性衍生物。此外,铝盐和MPL的组合已被批准作为用于抗HBV(乙型肝炎病毒)和HPV(人乳头瘤病毒)的疫苗的免疫佐剂。
自20世纪50年代以来,已知LPS具有抗癌作用,但由于毒性能够导致因败血症而死亡(即使在纳克(ng)水平的污染的情况下),其尚未适合使用。因此,已经稳步地进行了研究以降低LPS的毒性且已经成功地降低了LPS的毒性,特别是通过去除多糖链或脂质A的脱酰作用(Katz SS等,J Biol Chem.Dec 17;274(51):36579-84 1999)。特别地,通过去除LPS的多糖链获得的、通过脂质A的磷酸化作用获得的MPL已被开发为无LPS毒性的免疫抗癌剂,但已知其作用是不足的。
本申请人已经开发了新颖的LPS类似物,其克服了上述免疫佐剂的缺点(韩国专利号10-1509456)。在整个说明书中提述和引用了很多文章和专利文件。所引用的文章和专利文件的公开内容通过提述以其整体并入本文以更清楚地描述本发明所属的现有技术状态和本发明的内容。
作为努力开发能够表现出极好的免疫刺激活性同时降低毒性(其已经是通过使用常规LPS引起的问题)的LPS类似物的结果,本发明人鉴定出具有降低的毒性的具有新颖结构的EG-免疫调节剂(EG-IM),该降低的毒性通过分离和纯化来自从人肠中发现的大肠杆菌(E.coli)菌株的不具有O-抗原位点的LOS,并使其脱酰而获得,且发现该EG-IM由于其极好的免疫刺激活性可用作免疫佐剂。基于包含该免疫调节剂和铝盐(即明矾)的疫苗组合物表现出优于单独使用该免疫调节剂或该铝盐的情况的免疫刺激活性的发现,本发明人已经完成了本发明。
公开内容
技术问题
因此,本发明的一个目的是提供由下式1表示的具有新颖结构的免疫调节剂和包含该免疫调节剂作为活性成分的免疫佐剂组合物。
式1
其中Glc是葡萄糖,GlcN是葡糖胺,HEP是庚糖,KDO是2-酮-3-脱氧-辛酸,GlcNAc是N-乙酰葡糖胺,且A至F是磷酸盐可结合的位置。
本发明的另一目的是提供疫苗组合物,其包含:(a)抗原;(b)由式1表示的免疫调节剂;和(c)明矾。
技术方案
为了实现上述目的,本发明提供了由下列式1表示的免疫调节剂:
式1
其中Glc是葡萄糖,GlcN是葡糖胺,HEP是庚糖,KDO是2-酮-3-脱氧-辛酸,GlcNAc是N-乙酰葡糖胺,且A至F是磷酸盐可结合的位置。
本发明还提供包含该免疫调节剂作为活性成分的免疫佐剂组合物。
本发明还提供疫苗组合物,其包含:(a)抗原;(b)由式1表示的免疫调节剂;和(c)明矾。
本发明还提供用于预防免疫疾病的方法,其包括用由式1表示的免疫调节剂治疗患者,和该免疫调节剂用于预防免疫疾病的用途。
附图简述
图1A显示通过电泳和银染鉴定经提取的LOS的结果,且图1B显示指示EG-IM的大小降低的结果,基于当用碱处理LOS时通过降解脂质A提取的LOS,其中M表示标记物,泳道1表示脱酰作用前的LOS,且泳道2表示免疫调节剂(EG-IM)。
图2显示根据本发明的EG-免疫调节剂(EG-IM)的结构,其中Glc是葡萄糖,GlcN是葡糖胺,HEP是庚糖,KDO是2-酮-3-脱氧-辛酸,GlcNAc是N-乙酰葡糖胺,且A至F是磷酸可结合的位置。
图3至5显示血清中细胞因子水平的分析结果。在施用3μg的免疫调节剂(EG-IM)或MPL后1和4小时,分析从小鼠(n=3)中收集的心脏血。图3显示IL-6、IL-12p40和TNF-α的分析结果,图4显示IL-5和IL-10的分析结果,且图5显示MCP-1和RANTES的分析结果。
图6显示当使用EG-IM/明矾的组合物时日本脑炎病毒(JEV)抗原特异性抗体滴度的测量结果。
图7显示当施用日本脑炎疫苗时IFN-γ和IL-5细胞因子的分泌水平的测量结果。
图8显示当使用EG-IM/明矾的组合物时流感嗜血杆菌B型(HIB)抗原特异性抗体滴度的测量结果。
图9显示当使用EG-IM/明矾的组合时MERS冠状病毒(MERS-CoV)突起S1抗原特异性抗体滴度的测量结果,图9A显示血清中MERS病毒抗原特异性IgG1抗体滴度,且图9B显示血清中MERS病毒抗原特异性IgG2a抗体滴度。
图10显示当施用使用重组MERS-CoV突起S1 RBD蛋白的MERS疫苗通过用MERS病毒突起S1蛋白刺激测量的IFN-γ、IL-4和IL-5细胞因子的分泌水平。
图11显示当施用使用重组MERS-CoV突起RBD蛋白的MERS疫苗时IFN-γ细胞因子的分泌水平的测量结果。
图12显示当使用EG-IM/明矾的组合时寨卡病毒抗原特异性抗体滴度的测量结果。
图13显示当施用寨卡疫苗时IFN-γ和IL-5细胞因子的分泌水平的测量结果。
图14和15显示当使用EG-IM/明矾的组合时绿脓假单胞菌抗原特异性抗体滴度的测量结果。图14显示用绿脓假单胞菌FT2抗原的免疫,且图15显示用绿脓假单胞菌FT1抗原的免疫。
图16显示当使用EG-IM/明矾的组合时小鼠血清抗绿脓假单胞菌的调理噬菌(opsonophagocytic)活性的结果。图16A显示噬菌刺激诱导的活性,图16B显示取决于血清浓度的噬菌刺激诱导的活性,且图16C显示当缺少补体时和当包括补体时,噬菌刺激活性的比较结果。
发明详述
除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域中的技术人员所理解的相同的含义。通常,本文使用的命名法和以下所述的实验方法是本领域中所熟知的,且是通常使用的。
在本发明的一个实施方案中,通过使用大肠杆菌制备干燥细菌细胞,提取LOS然后使用碱处理去除LOS的毒性来获得EG-免疫调节剂(EG-IM),且MS分析鉴定该免疫调节剂(EG-IM)具有式1的结构。
因此,在一方面中,本发明涉及由下列式1表示的免疫调节剂:
式1
其中Glc是葡萄糖,GlcN是葡糖胺,HEP是庚糖,KDO是2-酮-3-脱氧-辛酸,GlcNAc是N-乙酰葡糖胺,且A至F是磷酸盐可结合的位置。
如本文所用的,术语“LOS(脂低聚糖,lipooligosaccharide)”指LPS(脂多糖)的变体,该变体比天然LPS具有更短的糖链,且因此具有较低分子量。脱酰作用前的LOS优选地具有5,000至10,000Da的分子量,更优选为3,000至4,000Da。术语“脱酰的LOS”指其中经由-C(O)O-键与脂质A的葡糖胺连接的脂肪酸由此去除且相较于LOS毒性大大降低的LOS。该脂肪酸经由-C(O)O-和-C(O)NH-键与脂质A葡糖胺连接。本发明的脱酰的LOS是其中通过使脂质A脱酰去除经由-C(O)O-键连接的脂肪酸的LOS。
该EG-IM可通过多种方法制备,但可依照本发明人的之前的专利中公开的方法制备,即韩国专利号0456681;WO 2004/039413;韩国专利号0740237;和WO 2006/121232。例如,通过用强碱(例如0.2N NaOH)处理使LPS脱酰以从脂质A中去除一些脂肪酸,从而使LPS脱毒。
根据本发明,该EG-IM可与2至6个磷酸基团,优选为3至4个磷酸基团连接,但不限于此。此外,式1中磷酸基团的数目和位置可与下表1中示例的那些相同。
表1
这些磷酸盐在选自下组的位置处结合:式1的AB、AC、AD、AE、AF、BC、BD、BE、BF、CD、CE、CF、DE、DF、EF、ABC、ABD、ABE、ABF、ACD、ACE、ACF、ADE、ADF、AEF、BCD、BCE、BCF、BDE、BDF、BEF、CDE、CDF、CEF、DEF、ABCD、ABCE、ABCF、ABDE、ABDF、ABEF、ACDE、ACDF、ADEF、BCDE、BCDF、BCEF、BDEF、CDEF、ABCDE、ABCEF和ABCDEF。
根据本发明,式1中的糖选自下组:己糖、己糖胺、N-乙酰己糖胺、庚糖和Kdo(2-酮-3-脱氧-辛酸)。
如本文所用的,术语“己糖”意指在分子中包含六个碳原子的单糖,且其实例包括但不限于己酮糖(阿洛酮糖、果糖、山梨糖、塔格糖)、己醛糖(阿洛糖、阿卓糖、葡萄糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖)和脱氧糖(岩藻糖、墨角藻糖、鼠李糖)。
根据本发明,该己糖是己醛糖,且在具体的实例中,该己醛糖是葡萄糖或半乳糖。
如本文所用的,术语“庚糖”指在分子中含有七个碳原子的单糖,且可根据官能团(醛基和酮基)的位置分类为庚醛糖(位置1)和庚酮糖(位置2)。该庚醛糖是,例如,L-甘油基-D-甘露-庚糖,但不限于此。该庚酮糖是,例如,景天庚酮糖和甘露庚酮糖,但不限于此。
根据本发明,该己糖胺是葡糖胺、半乳糖胺或甘露糖胺,且在具体的实例中,该己糖胺是葡糖胺。
根据本发明,该N-乙酰己糖胺是N-乙酰葡糖胺、N-乙酰半乳糖胺或N-乙酰甘露糖胺,且在具体的实例中,该N-乙酰己糖胺是N-乙酰葡糖胺。
本发明的EG-IM比野生型LPS具有更少的糖。根据本发明的一个实施方案,该EG-IM可包括5至7个糖。在具体的实例中,该EG-IM包括6或7个糖,但不限于此。
本发明的EG-IM不具有O-连接的脂肪酸。
本发明的EG-IM的特征在于其具有显著降低的毒性,因为脂肪酸(例如,C14脂肪酸)从脂质A中去除(脱酰)。该脂肪酸经由-C(O)O-或-C(O)NH-键与脂质A中的葡糖胺连接。在本发明中,脱酰作用意指去除经由-C(O)O-键连接的脂肪酸。
该脱酰作用可通过用碱处理LOS进行,且该碱包括NaOH、KOH、Ba(OH)2、CsOH、Sr(OH)2、Ca(OH)2、LiOH、RbOH、和Mg(OH)2,更优选为NaOH、KOH、Ba(OH)2、Ca(OH)2、LiOH和Mg(OH)2,甚至更优选为NaOH、KOH和Mg(OH)2,且最优选为NaOH。
本发明的EG-IM衍生自大肠杆菌,且该大肠杆菌是大肠杆菌(Escherichia coli)EG0024(登录号:KCTC 12948BP)。该菌株于2015年11月19日以保藏号KCTC 12948BP保藏在韩国生物科学和生物技术研究所的韩国典型培养物保藏中心中。
根据本发明,该EG-IM表现出免疫刺激活性。
如本文所用的,术语“免疫刺激”指诱导对抗原的初始免疫应答或增加对抗原的常规免疫应答至可测量的程度。
在本发明的另一实施方案中,EG-IM施用至小鼠以分析小鼠血清细胞因子的水平。结果,发现该EG-IM诱导细胞因子如TNF-α、IL-5、IL-6、IL-10、IL-12p40、MCP-1和RANTES的分泌。
因此,在另一方面中,本发明涉及包含该EG-IM作为活性成分的免疫佐剂组合物。
本发明的EG-IM尤其适合本发明的疫苗组合物,因为相较于常规免疫佐剂,其表现出极好的免疫刺激作用和降低的毒性。本发明的EG-IM的毒性低于通过脂质A的磷酸化获得的MPL(单磷酰脂质A),本发明的EG-IM通过去除LPS的多糖链以去除该LPS的毒性获得。
本发明的免疫佐剂组合物即使仅用该EG-IM可诱导充分的免疫应答,且针对各种疾病发挥作用。具体地,该免疫佐剂组合物可用于治疗癌症或免疫疾病。
根据本发明,该癌症可以是纤维肉瘤、膀胱癌、垂体腺瘤、胶质瘤、脑肿瘤、鼻咽癌、喉癌、胸腺瘤、间皮瘤、乳腺癌、肺癌、胃癌、食管癌、结肠癌、肝癌、胰腺癌、胰腺内分泌肿瘤、胆囊癌、阴茎癌、输尿管癌、肾细胞癌、前列腺癌、非霍奇金氏淋巴瘤、骨髓增生异常综合征、多发性骨髓瘤、浆细胞瘤、白血病、儿科癌症、皮肤癌、卵巢癌、或宫颈癌,但不限于此。
根据本发明,该免疫疾病可以是特应性皮炎、哮喘、牛皮癣、过敏性结膜炎、过敏性鼻炎、过敏性肉芽肿、过敏性皮炎、胃肠道过敏、过敏性肺炎,食物过敏、荨麻疹、湿疹、类风湿性关节炎、强直性脊柱炎、囊性纤维化、晚期或慢性实体器官移植排斥反应、多发性硬化症、系统性红斑狼疮、斯耶格伦氏综合征、桥本氏甲状腺、多发性肌炎、硬皮病、阿狄森氏病、白癜风、恶性贫血、肾小球肾炎、肺纤维化、炎性肠病、或格雷夫斯病,但不限于此。
此外,任选地,本发明的免疫佐剂组合物可进一步含有另一免疫佐剂成分,例如,组II元素,其选自由Mg、Ca、Sr、Ba和Ra、或其盐组成的组;组IV元素,其选自由Ti、Zr、Hf和Rf、或其铝盐或水合物组成的组;或二甲基十八基溴化铵。所述盐以,例如氧化物、过氧化物、氢氧化物、碳酸盐、磷酸盐、焦磷酸盐、磷酸氢盐、二氢磷酸盐、硫酸盐或硅酸盐形成。
根据本发明,可进一步在本发明的免疫佐剂组合物中含有的免疫佐剂成分选自下组:氢氧化镁、碳酸镁、氢氧化物五水合物、二氧化钛、磷酸钙、碳酸钙、氧化钡、氢氧化钡、过氧化钡、硫酸钡、硫酸钙、焦磷酸钙、碳酸镁、氧化镁、氢氧化铝、磷酸铝和水合硫酸铝钾。
根据本发明,该免疫佐剂组合物可进一步含有氢氧化铝或磷酸钙。
在本发明的另一实施方案中,通过将EG-IM和明矾与日本脑炎病毒(JEV)抗原、流感嗜血杆菌b(HIB)抗原、重组MERS-CoV S1蛋白、重组MERS-CoVS1 RBD蛋白、寨卡病毒包膜蛋白、和绿脓假单胞菌FT2抗原或FT1抗原混合来制备疫苗以鉴定EG-IM和明矾的免疫原性增强作用。每种疫苗施用至小鼠,测量滴度,且分析细胞因子。结果,发现每种疫苗具有极好的抗体介导的免疫功效和/或细胞免疫功效。
在另一方面中,本发明涉及疫苗组合物,该疫苗组合物包含:(a)抗原;(b)由式1表示的免疫调节剂;和(c)明矾。
在另一方面中,本发明涉及用于预防免疫疾病的方法,其包括将式1表示的免疫调节剂施用至有需要的受试者,或本发明的免疫调节剂用于预防免疫疾病的用途。
如本文所用的,术语“抗原”指诱导免疫应答的物质。因此,在本发明中,可使用表现出诱导免疫应答的此类活性的任何物质而无限制。
本发明的抗原可以是肽、蛋白、核酸、糖、病原体、减毒的病原体、灭活的病原体、病毒、病毒样颗粒(VLP)、细胞或细胞片段。
在本发明中,该抗原选自下组:日本脑炎病毒的抗原、流感嗜血杆菌B型(HIB)的抗原、中东呼吸综合征(MERS)病毒的抗原、寨卡病毒的抗原、绿脓假单胞菌的抗原、百日咳的抗原、结核分支杆菌的抗原、炭疽杆菌的抗原、甲型肝炎病毒(HAV)的抗原、乙型肝炎病毒(HBV)的抗原、丙型肝炎病毒(HCV)的抗原、人免疫缺陷病毒病毒(HIV)的抗原、单纯疱疹病毒(HSV)的抗原、脑膜炎萘瑟氏菌的抗原、白喉棒状杆菌的抗原、百日咳博德特氏菌的抗原、破伤风梭菌的抗原、人乳头瘤病毒(HPV)的抗原、水痘病毒的抗原、肠球菌的抗原、金黄色葡萄球菌的抗原、肺炎克雷伯氏菌的抗原、鲍氏不动杆菌的抗原、肠杆菌属的抗原、幽门螺旋杆菌的抗原、疟疾的抗原、登革热病毒的抗原、恙虫病东方体的抗原、严重发热伴血小板减少综合征本雅病毒(SFTS本雅病毒)的抗原、重症急性呼吸综合征-冠状病毒(SARS-CoV)的抗原、流感病毒的抗原、埃博拉病毒的抗原和肺炎双球菌的抗原。
本发明的疫苗组合物可诱导充分的免疫应答,且因此针对特定疾病发挥预防性功效,甚至在其基本组合物的情况下,即仅抗原和EG免疫调节剂(EG-IM)。任选地,本发明的疫苗组合物可进一步含有额外的上述免疫佐剂成分。
此外,根据本发明,该疫苗可以是灭活的疫苗、减毒的疫苗、亚单位疫苗、重组疫苗、蛋白缀合的疫苗、单价疫苗、多价疫苗、或混合的疫苗的形式。
根据本发明的疫苗可以是日本脑炎疫苗、流感嗜血杆菌B型疫苗、MERS疫苗、寨卡疫苗、绿脓假单胞菌疫苗、癌症疫苗、结核疫苗、炭疽疫苗、HAV疫苗、HBV疫苗、HCV疫苗、HIV疫苗、单纯疱疹疫苗、脑膜炎球菌疫苗、白喉疫苗、百日咳疫苗、破伤风疫苗、水痘疫苗、多药物抗性细菌疫苗、肠球菌疫苗、金黄色葡萄球菌疫苗、肺炎克雷伯氏菌疫苗、鲍氏不动杆菌疫苗、肠杆菌属疫苗、幽门螺旋杆菌疫苗、疟疾疫苗、登革热病毒疫苗、恙虫病东方体疫苗、严重发热伴血小板减少综合征本雅病毒(SFTS本雅病毒)疫苗、重症急性呼吸综合征-冠状病毒(SARS-CoV)疫苗、流感病毒疫苗、埃博拉病毒疫苗或肺炎双球菌疫苗,优选日本脑炎疫苗、流感嗜血杆菌B型疫苗、MERS疫苗、寨卡疫苗、或绿脓假单胞菌疫苗。
该癌症疫苗可选自下组:纤维肉瘤、膀胱癌、垂体腺瘤、胶质瘤、脑肿瘤、鼻咽癌、喉癌、胸腺瘤、间皮瘤、乳腺癌、肺癌、胃癌、食管癌、结肠癌、肝癌、胰腺癌、胰腺内分泌肿瘤、胆囊癌、阴茎癌、输尿管癌、肾细胞癌、前列腺癌、非霍奇金氏淋巴瘤、骨髓增生异常综合征、多发性骨髓瘤、浆细胞瘤、白血病、儿科癌症、皮肤癌、卵巢癌、或宫颈癌的疫苗,但不限于此。
根据本发明的疫苗可含有基于该组合物的总重量按重量计1至10%的免疫调节剂。当以少于按重量计1%的量含有免疫调节剂时,不能预期有效的免疫作用。当以超过按重量计30%的量含有免疫调节剂时,免疫耐受可发生。
根据本发明的疫苗可含有基于该组合物的总重量按重量计70至99%的明矾。当以少于按重量计70%的量含有免疫调节剂时,不能预期有效的免疫作用。
本发明的疫苗组合物可含有药物可接受的载剂且含有通常用于配制物的成分,如乳糖、右旋糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟苯甲酯、羟苯丙酯、滑石、硬脂酸镁和矿物油,但不限于此。本发明的疫苗组合物可进一步含有润滑剂、湿润剂、增甜剂、香料、乳化剂、悬浮剂、防腐剂等,除上述成分外。合适的药物可接受的载剂和配制物详细描述于Remington’s Pharmaceutical Sciences(第19版,1995)。
本发明的疫苗组合物可口服或胃肠外施用。在胃肠外施用的情况中,该疫苗组合物可通过静脉内注射、皮下注射、肌肉注射、腹膜内注射、经皮施用等施用。
本发明的疫苗组合物的合适剂量可基于如下因素可变地规定,如配制方法、施用方法、和患者的年龄、体重、性别、病理情况、食物、施用时间、施用途径、排泄速率和响应性。
本发明的疫苗组合物可制备成单剂量形式或可根据本发明所属领域中的普通技术人员可容易地实施的方法使用药物可接受的载剂和/或赋形通过配制来置入多剂量小瓶中。此时,该配制物可为溶液、悬浮液或油性或水性介质中的乳液的形式,或为提取物、粉末、颗粒、片剂或胶囊的形式,且可额外地含有分散剂或稳定剂。
在下文中,将参考下列实施例更详细地描述本发明。然而,对于本领域技术人员显而易见的是,提供这些实施例仅用于说明本发明,而不应解释为限制本发明的范围。
制备实施例:制备免疫调节剂(EG-IM)
1.制备干燥的菌株细胞
在30g/l的TSB(胰酶大豆培养液,Difco)培养基中以80rpm或更低的摇动在37℃培养大肠杆菌20小时,且使用离心机收集该细胞。收集的细胞与乙醇混合,且经离心以获得沉淀物。然后,将丙酮添加至所获得的沉淀物,彻底混合且然后经离心以获得沉淀物。将乙醚添加至所获得的沉淀物,彻底混合且然后经离心以获得沉淀物。所获得的沉淀物在干燥箱中在60℃干燥以制备干燥的细菌细胞。
2.LOS提取
在测量该干燥的细菌细胞的重量后,每1g的重量添加7.5mL的PCP(苯酚、氯仿、石油醚)提取溶液以从该细菌细胞中分离LOS。通过使用旋转蒸发仪的方法在高温从该LOS提取物中去除有机溶剂。剩下的提取物在高温经离心以获得沉淀物,且用乙醚洗涤该沉淀物。然后将纯化的水添加至此以形成沉淀物。该形成的沉淀物经离心,且从上清液中分离,且用乙醇洗涤剩下的沉淀物,从而收集该沉淀物。该沉淀物在高温干燥箱中彻底干燥,且将该沉淀物溶解在纯化的水中以提取LOS。
3.去除LOS毒性
在测定该LOS提取物的含量后,将该LOS提取物的浓度调整至3mg/mL,且将该LOS提取物与0.2N NaOH以1:1的体积比混合。使反应在60℃的恒温水浴中进行120分钟,并使用涡旋振荡每10分钟搅拌5秒。然后,将1N乙酸添加至此,其量为0.2N NaOH的初始量的约1/5。然后,通过乙醇沉淀获得免疫调节剂EG-IM。
4.定量且鉴定LOS和EG-IM
通过使用2-硫代巴比土酸的KDO(2-酮-3-二氧辛酸)测定法测量LOS和EG-IM的含量,测量其浓度,且通过SDS-PAGE基于大小分离LOS和EG-IM并通过银染鉴定,且示于图1中。图1A显示通过电泳和银染鉴定提取的LOS的结果。图1B显示基于当用碱处理LOS时通过脂质A的降解提取的LOS而指示EG-IM的大小降低的结果,其中M表示标记物(参见Plus 2预染标准物,Invitrogen,LC5952),泳道1表示脱酰作用前提取的LOS,且泳道2表示EG-IM(脱酰的LOS)。
实施例1:免疫调节剂(EG-IM)的结构分析
经纯化的样品适当地用纯化的水稀释。CU18反相柱(ACQUITY BEH300 C18 1.7um2.1X 150mm)安装于该仪器(UPLC,Water)上,然后使用流动相A(50mM甲酸铵pH 4.5)和流动相B(100%乙腈)以35至95%的浓度梯度分离该样品。用质谱仪(VELOS PRO,Thermo)进行MS分析和MS/MS分析。分析具有100至3,000m/z的分子量的分子。在MS分析后,再次分析经鉴定的具有50至2,000m/z的分子量的分子。将具有2,372m/z的分子量的分子鉴定为主要成分,且通过分析每个峰获得的结构示意图示于图2中。
实施例2:免疫调节剂(EG-IM)的免疫应答分析
1.免疫和取血
将3μg的根据本发明的EG-IM或MPL施用至6周龄小鼠(BALB/c,雌性,中心实验室动物/SLC日本)后肢的股骨区的三角肌,该小鼠在5周龄时进入且纯化(rarefied)一周(n=3)。将盐水施用至对照组的小鼠。施用后一和四小时,经腹膜内施用罗普/氯胺酮麻醉溶液以麻醉小鼠,且从心脏收集血液。使血液在冷藏条件静置约4小时,且血清通过在4℃和3,000rpm离心10分钟来分离,转移至新管并保存在-70℃。
2.分析小鼠血清中的细胞因子水平
进行多重细胞因子测定法(Millipore MAP测定法试剂盒,Millipore,Billerica,MA,USA)以测量细胞因子和趋化因子的水平。靶细胞因子是TNF-α、IL-5、IL-6、IL-10、IL-12p40、MCP-1和RANTES,且测试结果使用测定仪器[Luminex 200(Millipore)]和测定程序[MILLIPLEX Analyst(Millipore)]来分析,并示于图3至5中。图3显示IL-6、IL-12p40和TNF-α的分析结果,图4显示IL-5和IL-10的分析结果,且图5显示MCP-1和RANTES的分析结果。
如从图3至5中可见,当施用EG-IM时,其诱导作为诱导炎症的细胞因子的TNF-α和IL-6、作为Th1型细胞因子的IL-12p40、和作为趋化因子的IP-10、MIG-1、MCP-1和RANTES的分泌。此外,该免疫调节剂诱导的细胞因子的水平高于通过MPL诱导的情况。这意味着EG-IM(免疫调节剂)的体内免疫刺激活性优于MPL。
实施例3:分析灭活的疫苗中EG-IM/明矾的功效
1.日本脑炎疫苗的免疫
使用日本脑炎病毒(JEV)抗原以鉴定灭活的疫苗中EG-IM/明矾的免疫原性增强作用。灭活的日本脑炎疫苗,或日本脑炎疫苗和明矾(氢氧化铝;Brenntag,德国)的组合物以两周的间隔两次施用至6周龄BALB/c小鼠(Koatec,Korea)。制备该组合物使得该灭活的日本脑炎疫苗以0.5μg/小鼠或1μg/小鼠的量使用,明矾以25μg/小鼠的量使用且EG-IM以0.5μg/小鼠的量使用以产生100μl的最终体积。对阴性对照组施用PBS(磷酸盐缓冲的盐水,pH7.3)。
2.JEV抗原特异性抗体滴度的测量
在最后施用后两周,麻醉小鼠并从其中收集心脏血以制备血液样品。使用终点稀释酶联免疫吸附测定方法以测量免疫后血清中对JEV抗原特异性的抗体的滴度。将JEV稀释至浓度为1μg/ml,在96孔板上以100μl/孔包覆(在4℃过夜)并用300μl的1%BSA(牛血清白蛋白)封闭(室温,1小时)。封闭后,用含有0.05%吐温20的PBS洗涤三次,且将免疫后获得的血清通过10倍系列稀释进行稀释且使100μl的每个稀释的血清反应(37℃,2小时)。为了鉴定该JEV抗原特异性抗体,使辣根过氧化物酶缀合的抗小鼠IgG抗体(Jackson,115-035-003)、IgG1抗体(Serotec,STAR132P)和IgG2a抗体(Serotec,STAR133P)反应,然后向其添加TMB(四甲基联苯胺,BD Bio science,55555214),且用1N H2SO4终止该反应。测试结果通过测量450nm处的吸光度和测量免疫后收集的血液中的IgG、IgG1和IgG2a抗体的滴度来获得。结果,在使用EG-IM/明矾的测试组中,相较于仅使用EG-IM或仅使用明矾的测试组,JEV病毒抗原特异性IgG抗体的产生分别增加为13倍和3倍。此外,相较于仅使用EG-IM或仅使用明矾的测试组,使用EG-IM/明矾的测试组的JEV病毒抗原特异性IgG1抗体的产生分别增加为12倍和3倍,而且在使用EG-IM/明矾的测试组中JEV病毒抗原特异性IgG2a抗体的产生也是增加的(图6)。
因此,含有作为免疫调节剂的EG-IM以及作为免疫佐剂的明矾的本发明的日本脑炎疫苗显示极好的免疫性,即疫苗功效。
3.细胞因子分析
在最后施用后两周,麻醉小鼠,且提取脾脏组织并分离成单个细胞,用5μg/ml的灭活的JEV抗原或重组JEV gE蛋白刺激,并培养72小时。然后,通过夹心ELISA(R&D系统,DY485;DY405)分析IFN-γ和IL-5细胞因子的分泌。
结果,相较于仅使用明矾(其发挥改善体液免疫性的功能)的测试组,使用EG-IM/明矾的测试组增强了IFN-γ分泌,但不增强IL-5分泌(图7)。
因此,可以发现,含有EG-IM和明矾的日本脑炎病毒疫苗具有极好的诱导TH1型细胞免疫性以及抗体介导的免疫应答的能力。
实施例4:分析缀合疫苗中EG-IM/明矾的功效
1.B型流感嗜血杆菌疫苗的免疫
将HIB(嗜血杆菌b)抗原用于鉴定缀合疫苗中EG-IM/明矾的免疫原性增强作用。将ActHIB(嗜血杆菌b缀合疫苗、破伤风类毒素缀合物,赛诺菲巴斯德SA)和EG-IM/明矾的混合物以两周的间隔三次肌肉内施用至6周龄BALB/c小鼠(SLC,日本)。关于施用的量,将2μg/小鼠的ActHIB、25μg/小鼠的明矾或0.5μg/小鼠的EG-IM混合。
2.测量HIB抗原特异性抗体滴度
在最后施用后两周,麻醉小鼠,从其中收集心脏血以制备血液样品,且使用小鼠抗流感嗜血杆菌b型IgG ELISA试剂盒(XpressBio,USA)测量血液中IgG抗体的滴度以测量HIB抗原特异性抗体的滴度。
结果,相较于可商购的疫苗,使用EG-IM/明矾的测试组在HIB抗原特异性IgG抗体的产生中显示2倍增加(图8)。
因此,可见含有作为免疫调节剂的EG-IM以及作为免疫佐剂的明矾二者的B型流感嗜血杆菌疫苗诱导抗体介导的免疫应答且具有极好的免疫性功效,即疫苗功效。
实施例5:分析重组疫苗中EG-IM/明矾的功效
<MERS疫苗>
I.使用重组MERS-CoV突起S1蛋白的情况
1.MERS疫苗的免疫
将重组MERS-CoV突起S1蛋白(eEnzyme,MERS-S1-005P)用于鉴定重组疫苗中EG-IM/明矾的免疫原性增强作用。重组MERS-CoV突起S1蛋白和明矾和/或EG-IM的混合物以两周的间隔三次肌肉内施用至6周龄BALB/c小鼠(SLC,日本)。关于施用的量,将0.5或1μg/小鼠的S1蛋白,25μg/小鼠的明矾或0.5μg/小鼠的EG-IM混合。
2.测量MERS病毒抗原特异性抗体滴度
在最后施用后四周,麻醉小鼠,从其中收集心脏血以制备血液样品,且使用ELISA试剂盒测量血液中IgG1和IgG2a抗体的滴度以测量MERS病毒抗原特异性抗体的滴度。
结果,相较于仅使用明矾的测试组,使用EG-IM/明矾的测试组浓度依赖性地增加了MERS病毒抗原特异性IgG1和IgG2抗体的产生,且相较于仅使用明矾的测试组,IgG2a的增量高于IgG1的增量(图9)。因此,可见含有作为免疫调节剂的EG-IM以及作为免疫佐剂的明矾的MERS疫苗具有极好的免疫性功效,即疫苗功效。
3.细胞因子分析
在最后施用后四周,麻醉小鼠,提取脾脏组织并分离成单个细胞,且该细胞用S1蛋白刺激,并培养72小时。然后,通过夹心ELISA(R&D系统,DY485;DY404;DY405)分析IFN-γ、IL-4和IL-5细胞因子的分泌。
结果,相较于仅使用明矾(其发挥改善体液免疫的功能)的测试组,使用EG-IM/明矾的测试组浓度依赖性地增强了IFN-γ分泌,但降低了IL-4和IL-5的分泌(图10)。
II.使用重组MERS-CoV S1 RBD蛋白的情况
1.MERS疫苗的免疫
将重组MERS-CoV S1 RBD蛋白用于鉴定重组疫苗中EG-IM/明矾的免疫原性增强作用。重组MERS-CoV S1 RBD蛋白和明矾和/或EG-IM的混合物以两周的间隔三次肌肉内施用至6周龄BALB/c小鼠(SLC,日本)。关于施用的量,将1μg/小鼠的RBD蛋白、25μg/小鼠的明矾、12.5μg/小鼠的Addavax或0.5μg/小鼠的EG-IM混合。
2.细胞因子分析
在最后施用后两周,麻醉小鼠,提取脾脏组织并分离成单个细胞,且该细胞用RBD蛋白刺激并培养72小时。然后,为了分析有助于IFN-γ细胞因子的分泌的T细胞亚型,当用该抗原刺激时,每个测试组用CD4封闭的抗体或CD8封闭的抗体处理。72小时后,收集该细胞培养溶液且通过夹心ELISA(R&D系统,DY485)分析IFN-γ细胞因子的分泌。AddaVax(Invivogen)用作对照免疫佐剂。
结果,相较于仅使用明矾(其发挥改善体液免疫的功能)的测试组或使用addavax的测试组,使用EG-IM/明矾的测试组增强了IFN-γ分泌(图11)。
因此,可以发现,含有EG-IM和明矾的MERS疫苗具有极好的诱导TH1型细胞免疫性以及抗体介导的免疫应答的能力。
寨卡疫苗
1.寨卡疫苗的免疫
将重组寨卡病毒包膜蛋白用于鉴定重组疫苗中EG-IM/明矾的免疫原性增强作用。将重组寨卡病毒包膜蛋白和明矾和/或EG-IM的混合物以两周的间隔两次肌肉内施用至6周龄BALB/c小鼠(SLC,日本)。关于施用的量,将2μg/小鼠的寨卡病毒包膜蛋白与25μg/小鼠的明矾或0.5μg/小鼠的EG-IM混合。
2.测量寨卡病毒抗原特异性抗体滴度
在最后施用后两周,麻醉小鼠,从其中收集心脏血以制备血液样品,且使用ELISA试剂盒测量血液中的IgG1和IgG2a抗体的滴度以测量重组寨卡病毒包膜蛋白特异性抗体的滴度。
结果,相较于仅使用EG-IM或仅使用明矾的测试组,使用EG-IM/明矾的测试组改善了寨卡病毒抗原特异性IgG1和IgG2a抗体的产生,且相较于使用仅使用明矾的测试组,IgG2a的增量高于IgG1的增量(图12)。因此,可见含有作为免疫调节剂的EG-IM以及作为免疫佐剂的明矾二者的寨卡疫苗具有极好的免疫性功效,即疫苗功效。
3.细胞因子分析
在最后施用后两周,麻醉小鼠,提取脾脏组织并分离成单个细胞,且该细胞用寨卡病毒包膜蛋白刺激并培养72小时。然后,通过夹心ELISA(R&D系统,DY485;DY405)分析IFN-γ和IL-5细胞因子的分泌。
结果,相较于仅使用明矾(其发挥改善体液免疫的功能)的测试组,使用EG-IM/明矾的测试组浓度依赖性地增强了IFN-γ分泌,但降低了IL-5分泌(图13)。
因此,可以发现,含有EG-IM和明矾的寨卡疫苗具有极好的诱导TH1型细胞免疫性以及抗体介导的免疫应答的能力。
实施例6:分析提取的蛋白疫苗中EG-IM/明矾的功效
1.绿脓假单胞菌疫苗的免疫
将绿脓假单胞菌FT2抗原或FT1抗原用于鉴定提取的蛋白疫苗中EG-IM/明矾的免疫原性增强作用。该FT2抗原或FT1抗原和明矾和/或EG-IM的混合物以一周的间隔两次肌肉内施用至6周龄BALB/c小鼠。该抗原以5或6.5μg/小鼠的量使用。施用PBS的组用作阴性对照组。
2.测量绿脓假单胞菌抗原特异性抗体滴度
在最后施用后两周,麻醉小鼠,从其中收集心脏血以制备血液样品,且使用ELISA试剂盒测量血液中的(总)IgG、IgG1和IgG2a抗体的滴度以测量绿脓假单胞菌抗原特异性抗体的滴度。
结果,当使用绿脓假单胞菌FT2抗原免疫时,相较于仅使用EG-IM或仅使用明矾的测试组,使用EG-IM/明矾的测试组改进了绿脓假单胞菌特异性IgG抗体的产生(图14)。此外,当使用绿脓假单胞菌FT1抗原时,同样地,相较于仅使用EG-IM或仅使用明矾的测试组,使用EG-IM/明矾的测试组改进了抗原特异性IgG、IgG1和IgG2a抗体的产生,以及绿脓假单胞菌GN3(FT1菌株)特异性IgG、IgG1和IgG2a抗体的产生(图15)。这指示用作免疫佐剂的EG-IM/明矾改进了对用于绿脓假单胞菌疫苗的抗原的反应性以及对实际感染性细菌细胞的反应性。
3.测量通过绿脓假单胞菌疫苗的免疫形成的小鼠血清的调理噬菌活性
为了测定通过绿脓假单胞菌疫苗的免疫形成的小鼠血清的调理噬菌活性,将6.5μg的绿脓假单胞菌FT2抗原单独或将该抗原与明矾和/或EG-IM的混合物以两周的间隔施用两次。在最后免疫后两周,收集心脏血液,收集血清并测量针对绿脓假单胞菌PA103(FT2菌株)的调理噬菌活性。具体地,绿脓假单胞菌FT2生长至指数期,收集,在56℃热灭活30分钟,且在4℃与100μg/ml FITC-异构体I反应1小时以用荧光标记该菌株。将该荧光标记的菌株用PBS洗涤几次并使用缓冲溶液稀释至OD600为0.9用于测试调理噬菌活性(HBSS中5%确定的FBS和0.1%明胶)。对该荧光标记的菌株计数,且将其5x106CFU与免疫的血清混合,与灭活的兔补体混合并在缺少光照的情况下以摇动培养30分钟。然后,该菌株混合物与HL-60细胞以20:1(菌株:HL-6细胞)的比例混合并培养30分钟。培养后,该细胞用含有0.1%BSA的PBS洗涤,收集并使用流式细胞术(FACSCanto IITM系统,BD Biosciences)和FlowJo软件(Treestar,USA)分析。调理噬菌活性表示为HL-60细胞中标记的平均荧光强度(MFI)。
结果,相较于仅施用EG-IM/明矾的阴性对照组或施用该抗原和明矾的组合的测试组,吞噬作用通过施用抗原和EG-IM/明矾的组合的小鼠的血清来活化(图16A)。吞噬作用取决于血清浓度和补体(图16B和16C)。由此,可看出由该EG-IM/明矾组合物诱导的对绿脓假单胞菌疫苗特异性的抗体增强了针对绿脓假单胞菌的调理噬菌,使得该抗体的功能可被改进。
4.测量绿脓假单胞菌抗原的保护功效
为了鉴定EG-IM/明矾对绿脓假单胞菌抗原的保护性功效,将FT2抗原和明矾和/或EG-IM的5μg的混合物以一周的间隔两次施用至6周龄BALB/c小鼠。施用PBS的组用作阴性对照组。在最后施用后两周,收集血液样品且在一周后,用10LD50的绿脓假单胞菌FT2菌株PA103对小鼠进行致死性挑战,且对其存活观察8天。
表2
免疫 | 保护性功效(%) |
PBS | 0 |
Ag | 20 |
Ag+EG-IM | 0 |
Ag+明矾 | 20 |
Ag+EG-IM/明矾 | 80 |
如从上表2中可见,使用EG-IM/明矾的测试组被诱导以具有约80%的保护性功效。然而仅使用EG-IM或仅使用明矾的测试组几乎不被诱导而具有保护性功效。
因此,已知的是通过将作为该抗原的从绿脓假单胞菌中提取的水溶性蛋白混合物、作为免疫调节剂的EG-IM、和作为免疫佐剂的明矾混合而制备的绿脓假单胞菌疫苗能够显著诱导抗体介导的免疫应答以及保护性功效。
工业实用性
由于诱导对特定病原体的固有免疫性和适应性免疫反应的极好的能力,本发明的免疫调节剂具有极好的免疫增强功效,且安全性极佳,因为它几乎没有毒性。此外,相较于仅使用该免疫调剂时的情况,含有本发明的免疫调节剂的疫苗包含该免疫调节剂和明矾二者,由此表现出增强的免疫增强作用。
Claims (12)
1.一种由下列式1表示的免疫调节剂:
式1
其中Glc是葡萄糖,GlcN是葡糖胺,HEP是庚糖,KDO是2-酮-3-脱氧-辛酸,GlcNAc是N-乙酰葡糖胺,且A至F是磷酸盐可结合的位置。
2.根据权利要求1的免疫调节剂,其中该免疫调节剂通过经由用碱处理脂低聚糖(LOS)使脂质A脱酰来解毒。
3.根据权利要求1的免疫调节剂,其中该磷酸盐的数目是2至6。
4.根据权利要求1的免疫调节剂,其中每个磷酸盐在选自下组的位置处结合:式1的AB、AC、AD、AE、AF、BC、BD、BE、BF、CD、CE、CF、DE、DF、EF、ABC、ABD、ABE、ABF、ACD、ACE、ACF、ADE、ADF、AEF、BCD、BCE、BCF、BDE、BDF、BEF、CDE、CDF、CEF、DEF、ABCD、ABCE、ABCF、ABDE、ABDF、ABEF、ACDE、ACDF、ADEF、BCDE、BCDF、BCEF、BDEF、CDEF、ABCDE、ABCEF和ABCDEF。
5.根据权利要求1的免疫调节剂,其中该免疫调节剂不具有O-连接的脂肪酸。
6.根据权利要求1的免疫调节剂,其中该免疫调节剂具有免疫刺激活性。
7.一种免疫佐剂组合物,其包含根据权利要求1的免疫调节剂作为活性成分。
8.根据权利要求7的免疫佐剂组合物,其进一步包含选自下组的免疫佐剂成分:组II元素,其选自由Mg、Ca、Sr、Ba和Ra组成的组;组IV元素,其选自由Ti、Zr、Hf和Rf组成的组;铝盐或其水合物;和二甲基十八基溴化铵。
9.一种疫苗组合物,其包含:
(a)抗原;
(b)根据权利要求1的免疫调节剂;和
(c)明矾。
10.根据权利要求9的疫苗组合物,其中该抗原选自下组:肽、蛋白、核酸、糖、病原体、减毒的病原体、灭活的病原体、病毒、病毒样颗粒(VLP)、细胞或细胞片段。
11.根据权利要求9的疫苗组合物,其中该抗原选自下组:日本脑炎病毒的抗原、流感嗜血杆菌(Haemophilus influenzae)B型(HIB)的抗原、中东呼吸综合征(MERS)病毒的抗原、寨卡病毒的抗原、绿脓假单胞菌(Pseudomonas aeruginosa)的抗原、百日咳的抗原、结核分支杆菌(Mycobacterium tuberculosis)的抗原、炭疽芽孢杆菌的抗原、甲型肝炎病毒(HAV)的抗原、乙型肝炎病毒(HBV)的抗原、丙型肝炎病毒(HCV)的抗原、人免疫缺陷病毒(HIV)的抗原、单纯疱疹病毒(HSV)的抗原、脑膜炎萘瑟氏菌(Neisseria meningitides)的抗原、白喉棒状杆菌(Corynebacterium diphtheria)的抗原、百日咳博德特氏菌(Bordetellapertussis)的抗原、破伤风梭菌(Clostridium tetani)的抗原、人乳头瘤病毒(HPV)的抗原、水痘病毒的抗原、肠球菌(Enterococci)的抗原、金黄色葡萄球菌(Staphylococcusaureus)的抗原、肺炎克雷伯氏菌(Klebsiella pneumoniae)的抗原、鲍氏不动杆菌(Acinetobacter baumannii)的抗原、肠杆菌(Enterobacter)的抗原、幽门螺旋杆菌(Helicobacter pylori)的抗原、疟原虫的抗原、登革热病毒的抗原、恙虫病东方体(Orientia tsutsugamushi)的抗原、严重发热伴血小板减少综合征本雅病毒(SFTS本雅病毒)的抗原、重症急性呼吸综合征-冠状病毒(SARS-CoV)的抗原、流感病毒的抗原、埃博拉病毒的抗原和肺炎双球菌(Diplococcus pneumonia)的抗原。
12.根据权利要求9的疫苗组合物,其中该疫苗是灭活的疫苗、减毒的疫苗、亚单位疫苗、重组疫苗、蛋白缀合的疫苗、单价疫苗、多价疫苗、或混合的疫苗。
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