CN101917985B - 糖基神经酰胺增强对抗原的免疫反应的用途 - Google Patents
糖基神经酰胺增强对抗原的免疫反应的用途 Download PDFInfo
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Abstract
在此提供了一种含有式I化合物的组合物。还提供了一种通过给药抗原和所述组合物来增强受试者对抗原的免疫应答的方法。增强了的免疫应答可以是体液免疫应答、CD4+T细胞应答、CD8+T细胞应答、或者导致抗原呈递细胞的激活。还提供了通过肌内注射抗原和含有式I所述化合物的组合物来增强免疫应答的方法。
Description
相关应用的交叉参考
本申请要求于2007年12月5日提交的美国临时专利申请No.60/992,460的优先权,将其整体合并于本申请用于参考。
技术领域
本发明提供了糖基神经酰胺在增强对抗原的免疫应答中的应用。
背景技术
疫苗的基本目的是提供抗病理条件的持续免疫性。理论上,疫苗提供功能活化的抗体、引起细胞介导的免疫、并且激活具有高度特异反应性和“记忆力”的T淋巴细胞和B淋巴细胞,来提供对抗更多抗原入侵的保护作用。
佐剂是非特异地放大免疫应答的疫苗添加剂。佐剂增强免疫系统的机制各不相同。佐剂可以归类为“免疫调节”或“抗原递送”系统。免疫调节佐剂通过改变淋巴因子产生而调节免疫细胞的行为,来准备启动免疫系统。另一方面,抗原递送系统行使向适宜的免疫细胞递送抗原的功能。此外,佐剂可以增加应答的速度和持续期、调节抗体亲和力、特异性、同型或亚类的分布、刺激细胞介导的免疫、促进粘膜免疫、或在免疫学上未成熟个体或衰老个体中增强免疫应答。佐剂可以影响自然、体液或细胞介导的免疫应答,或它们的组合。
发明内容
本发明的发明人发现,一种特殊类别的合成糖脂,当与疫苗联合使用时,能够在向受试者给药时激活体液免疫应答和细胞免疫应答。因此,本发明提供了含有式I化合物的组合物,其中式I如下所示:
其中,R1和R2独立地选自-H或-OH;x为18-26的整数;n为10-15的整数。还提供了含有式I的化合物和抗原的组合物。
另一方面,本发明提供了一种方法,所述方法通过给药含有式I的化合物和抗原的组合物,增强了受试者对抗原的免疫应答。增强了的免疫应答可以是体液免疫应答、CD4+T细胞应答、CD8+T细胞应答或者抗原呈递细胞(APCs)的激活。受试者的免疫应答相对于合适的对照是被增强的。
另一方面,本发明的组合物是肌内注射的。
附图说明
图1为显示了静脉注射(IV)加入或不加卵白蛋白(Ova)的PBS-96、PBS-14或PBS-11的小鼠血液中,卵白蛋白特异(Ova-specific)的靶细胞的特异性裂解百分比的图表。
图2为显示了静脉注射(IV)加入或不加卵白蛋白(Ova)的αGalCer、PBS-57、PBS-96或PBS-14的小鼠血液中,卵白蛋白特异(Ova-specific)的靶细胞的特异性裂解百分比的图表。
图3为显示了肌内注射(IM)加入或不加卵白蛋白(Ova)的αGalCer、PBS-57、PBS-96或PBS-14的小鼠血液中,卵白蛋白特异(Ova-specific)的靶细胞的特异性裂解的图表。
图4A为显示了接种不同浓度PBS-57后24小时内小鼠血清中,IFNγ的积累的图表;图4B为显示了接种不同浓度PBS-14后24小时内小鼠血清中,IFNγ的积累的图表;图4C为显示了接种不同浓度PBS-96后24小时内小鼠血清中,IFNγ的积累的图表;图4D为显示了接种不同浓度αGalCer后24小时内小鼠血清中,IFNγ的积累的图表;
图5为比较了接种100ng的PBS-57、PBS-96、PBS-14或PBS-11后24小时内小鼠血清中IFNγ的积累的图表;
图6为显示了静脉注射(IV)加入或不加卵白蛋白(Ova)的PBS-11、PBS-57、PBS-96或PBS-14的小鼠血液中,卵白蛋白特异(Ova-specific)的靶细胞的特异性裂解的图表;
图7为显示了肌内注射(IM)100ng加入或不加卵白蛋白(Ova)的指示佐剂(indicated adjuvant)的小鼠中,卵白蛋白特异(Ova-specific)的靶细胞的特异性裂解的图表;
图8为显示了肌内注射(IM)10ng加入或不加卵白蛋白(Ova)的指示佐剂的小鼠中,卵白蛋白特异(Ova-specific)的靶细胞的特异性裂解的图表;
图9为显示了肌内注射(IM)1μg加入或不加卵白蛋白(Ova)的指示佐剂的小鼠中,应答于SIINFEKL五聚物的CD8+T细胞的百分比的图表;
图10为显示了肌内注射(IM)100ng加入或不加卵白蛋白(Ova)的指示佐剂的小鼠中,应答于SIINFEKL五聚物的CD8+T细胞的百分比的图表;
图11为显示了肌内注射(IM)100ng加入或不加卵白蛋白(Ova)的指示佐剂的小鼠血液中,IgG1的效价(titer)的图表;
图12为显示了肌内注射(IM)100ng加入或不加卵白蛋白(Ova)的所指示佐剂的小鼠血液中,IgG2a的效价(titer)的图表;
图13描述了PBS-14、PBS-96、PBS-11、PBS-57和αGalCer的结构式。
具体实施方式
在疫苗制备中,佐剂通过多种方式增强抗原的免疫原性。有效的佐剂也能用于与多种抗原联合,来增强通过给药抗原引起的免疫应答。例如,对于毒素,需要良好的体液免疫应答。对于细胞内细菌,主要由细胞毒性的T细胞和Th1细胞介导的细胞介导应答,是重要的。对于病毒性感染,体液免疫和细胞免疫都是控制感染的基础。佐剂不仅具有能增强体液免疫应答的能力也具有能增强细胞介导的免疫应答的能力,增加了发展为长效免疫的可能性。
已经研究了脂类的佐剂特性。一些天然或合成的脂类分子由抗原呈递细胞所加工,并被CD1分子呈递至NKT细胞。用于体外和体内研究NKT细胞激活的原型化合物是KRN7000,一种源自海绵(Agelas mauritianus)的α-半乳糖苷神经酰胺(“αGalCer”)。如PCT申请PCT/US07/66250所述,在此通过参考将其公开的内容引入,新近鉴定了一些其它的化合物,其中包括属于内源糖脂的异球三己糖苷神经酰胺(isoglobotrihexosylceramide,“iGB3”)和修饰的6“氨基6”脱氧半乳糖苷神经酰胺。这些化合物在体外激活NKT细胞,并上调细胞因子应答。但是,在体内接种疫苗的背景下,关于这些化合物的脂质佐剂有效性尚不清楚。
本发明的发明人发现,含有氨基基团和饱和脂肪酸链的式I的鞘糖脂,出乎意料地,在体内具有刺激细胞介导免疫应答和体液免疫应答的能力。此外,式I的化合物可以刺激抗较弱的标称抗原(weak nominal antigen)的免疫应答来产生抗体,并同时提供对表达特异表面抗原的细胞的细胞介导的裂解。已表明,命名为PBS-96和PBS-14的两种式I的化合物,在体内刺激细胞介导的免疫应答和体液免疫应答。这些化合物也可以刺激抗较弱的标称抗原(weak nominal antigen)的免疫应答来产生抗体,并同时引起细胞介导的应答。此外,已发现,这些化合物与其它鞘糖脂(如PBS-57和αGalCer)相比,在肌内注射时,能够刺激更强的应答或需要更低的剂量。
在一种实施方式中,本发明提供了含有式I的化合物的组合物,其中式I为:
其中,R1和R2独立地选自-H或-OH;x为18-26的整数;n为10-15的整数。适宜地,式I的化合物在半乳糖或葡萄糖分子的C6位置上具有氨基基团,并且在该化合物的神经酰胺部分具有饱和的酰基链。该组合物可以进一步含有生理上可接受的载体。“生理上可接受”的载体为适合于体内给药
(如经口服、经皮给药或注射给药)或体外使用(如细胞培养)的任何载体。适用于体内给药的生理上可接受的载体包括:水、缓冲液和葡萄糖溶液,以及其他载体。除了所述的生理上可接受的载体以外,该组合物的其他成分可以包括:赋形剂(如稳定剂)、防腐剂、稀释剂、乳化剂或润滑剂。合适的赋形剂包括,但不限于:吐温20、二甲基亚砜(DMSO)、蔗糖、L-组氨酸(histadine)、聚山梨醇酯20和血清。适宜地,式I的化合物配置在脂质体中。适宜地,该脂质体为一种小型单层泡(SUV),含有比例为8微摩尔/2微摩尔/5微摩尔/1毫克的磷脂酰胆碱(PC)/磷脂酰甘油(PG)/胆固醇。本领域的技术人员能够知道,式I的化合物可以制成多种剂型,以用于受试者。
在另一种实施方式中,本发明提供了通过给药含有抗原和式I的化合物的组合物以在受试者中增强对抗原的免疫应答的方法。此处所指的受试者为哺乳动物,如小鼠,或更适合为人。“增强免疫应答”指的是:相对于合适的对照,该化合物增强受试者对抗原的体液免疫应答和/或细胞调节的免疫应答的能力。增加的抗原呈递细胞的激活也包括在对受试者增强的免疫应答中。为确定免疫应答相对于对照是否增强,可以将接种抗原和该化合物的受试者的样本的信号和只接种抗原的受试者的样本的信号,进行定量比较。对抗原的免疫应答可以用多种方法检测,所述检测方法对本领域技术人员是显而易见的。举例说,免疫应答可用细胞毒特异的细胞裂解分析、五聚体结合分析、或酶联免疫应答(ELISA)分析的检测方法来检测,所述检测方法是本领域技术人员所公知的。
在具体实施例中,相对于合适的对照,免疫应答增强至少25%、至少30%、至少50%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少100%、至少150%、至少200%、至少400%、至少500%、至少750%、或至少1000%。合适的对照为给药抗原但不使用本发明所述组合物的受试者。可以按以下公式计算百分率的增强:
[(用含有式I化合物的组合物处理后受试者的免疫应答值)-(对照的免疫应答值)/(用含有式I化合物的组合物处理后受试者的免疫应答值)]×100。
此处所指的“给药”、“共给药”和“共给予”指佐剂和抗原联用,也就是,在时间上同时,或循序(也就是,在给药佐剂后给药抗原,或在给药抗原后给药佐剂)。在给药佐剂或抗原后,另一组分可大致上在其后立即给药,或者在其后一段有效时期后给药;所述有效时期为实现组分给药的最大收益而给定的时间量。作为另一种选择,佐剂和抗原可以共制剂。
所述的抗原可以是:多肽、多核苷酸、或碳水化合物部分、或它们的组合,如糖蛋白。所述抗原适宜地来自传染原(如病原微生物)、肿瘤或内源分子(如“自身”分子),或者,以研究为目的的,标称抗原(nominal antigen),如卵白蛋白(此处所指的“OVA”)。适宜地,所述抗原包含在疫苗中。疫苗组合物适宜地制成包含式I的化合物的形式。“疫苗”指一种组合物,在给予受试者时,诱导细胞免疫应答或体液免疫应答。本发明的药物组合物适宜地含有式I的化合物和疫苗。在一些具体实施方式中,本发明的药物组合物含有PBS-96和抗原,或PBS-14和抗原。PBS-96和PBS-14的结构如图13所示。PBS-96和PBS-14在体内和体外激活NKT细胞。PBS-96和PBS-14都在半乳糖的C6位置上具有氨基基团,且在该化合物的神经酰胺部分具有饱和的酰基链。在体内,PBS-96和PBS-14增强CD8+T细胞对抗原的应答,并且PBS-96和PBS-14介导IFN-γ的释放。此外,在低浓度使用时,以及肌内注射时,PBS-96和PBS-14意想不到地优于其他鞘糖酯。
含有式I化合物的组合物可用多种本领域技术人员公知的制备方法和非活性成分来配置(Remington的药学科学,Mack出版公司,2000,在此合并为参考文献)。本发明的组合物也可以含有合适的抗原递送系统,以将抗原靶向至免疫细胞。抗原递送系统为本领域公知,包括但不限于:修饰的安卡拉病毒(MVA)、腺病毒、慢病毒(lentivirus)、百日咳或志贺毒素的易位亚单位、或封有抗原的脂质体。在疫苗组合物中,式I的化合物的有效剂量可以由本领域技术人员决定,虽然有效剂量可以典型地为每千克体重约1000微克或略少,但典型的范围可以是每千克体重约1纳克到约10000微克。在一些具体实施方式中,有效剂量的范围是每千克体重约10纳克到约1000微克。在另一实施方式中,有效剂量的范围是每千克体重约100纳克到约500微克。在另一实施方式中,有效剂量的范围是每千克体重约1微克到约250微克。为了研究目的,根据给药的途径,对小鼠的剂量是每100微升剂量1纳克到1微克式I的组合物。例如,约100纳克的剂量适合于小鼠静脉注射,小至10纳克的剂量也表明在肌内注射下有效。含有式I的化合物的组合物可以单次剂量来给药,或者分为数周或数月的多次剂量。
在组合物中可以含有一种或多种抗原,或者单独地制备。此处所指的“抗原”指当给药于受试者时刺激免疫应答的分子。容易得到,抗原的剂量依赖于具体的抗原、受试者的年龄和免疫状态、以及其它可以由本领域技术人员决定的相关因素。
整体微生物或微生物的部分(如膜血影(menbrane ghosts)、天然的膜制品(crude membrane preparation)、裂解液或其它微生物制品)可以用做抗原。适宜地,抗原来自弱化的或灭活的感染原。抗原可来自的感染原包括但不限于:病原体或微生物,如细菌、寄生虫和病毒。在一些环境中,合适的抗原取自或来自与人类疾病有关的病毒性病原体包括但不限于:HIV//AIDS(逆转录病毒科Retroviridae,如,gp120分子之于HIV-1和HIV-2种群、HTLV-I,HTLV-II)、流感病毒(正粘病毒科Orthomyxoviridae,如A型、B型和C型)、疱疹(如,单纯性疱疹病毒,HSV-1和HSV-2糖蛋白gB、gD和gH)、轮状病毒感染(呼肠病毒科Reoviridae)、呼吸感染(副流感病毒和呼吸道合胞病毒)、脊髓灰质炎(小核糖核酸病毒科Picornaviridae,如脊髓灰质炎病毒、鼻病毒)、麻疹和流行性腮腺炎(副黏液病毒科Paramyxoviridae)、风疹(披膜病毒科Togaviridae,如风疹病毒),肝炎(如肝炎病毒A、B、C、D、E和/或G)、巨细胞病毒(如gB和gH)、肠胃炎(杯状病毒科Caliciviridae)、黄热和西尼罗热(黄病毒科Flaviviridae)、狂犬病(弹状病毒科Rhabdoviridae)、朝鲜出血热(布尼雅病毒科Bunyaviridae)、委内瑞拉出血热(沙粒病毒科Arenaviridae)、疣(乳头瘤病毒)、猿猴免疫缺损病毒、脑炎病毒、水痘带状疱状病毒、爱泼斯坦-巴尔二氐(Epstein-Barr)病毒、和其它病毒科,包括冠状病毒科(Coronaviridae)、双核糖核酸病毒科(Birnaviridae)和线状病毒(Filoviridae)。
合适的细菌抗原和寄生虫抗原也能取自或来自已知的致病体,并可以用在抗疾病疫苗组合物中,所述疾病包括但不限于:白喉、百日咳、破伤风、结核病、细菌性或真菌性肺炎、中耳炎、淋病、霍乱、伤寒、脑膜炎、单核细胞增多症、瘟疫、志贺氏菌病(shigellosis)或沙门氏菌病、军团菌病(Legionnaires’disease)、莱姆病(Lyme disease)、麻风病、疟疾、十二指肠病、盘尾丝虫病、血吸虫病、锥体虫病、利什曼病(leishmaniasis)、贾第虫病(giardiases)、阿米巴病(amoebiasis)、丝虫病(filariasis)、包柔氏螺旋体(Borrelia)和旋毛虫病。抗原还能取自或来自其它非常规的病原体,比如:库鲁病(kuru)、克劳伊登病(CJD)、痒病(scrapie)、貂传染性脑病(transmissible mink encephalopathy)和慢性消耗病(chronic wasting diseases)的病原体;或取自或来自传染性蛋白颗粒,如与疯牛病相关的朊病毒。
更加详细地,可用于抗原的特殊病原体包括:结核分枝杆菌(M.tuberculosis)、衣原体(Chlamydia)、淋病奈瑟菌(N.gonorrhoeae),志贺氏杆菌(Shigella)、沙门氏菌(Salmonella)、霍乱弧菌(Vibrio cholera),苍白密螺旋体(Treponema pallidum)、假单胞菌(Pseudomonas)、百日咳杆菌(Bordetellapertussis)、布鲁氏菌(Brucella)、土拉弗朗西斯菌(Francisellatularensis)、幽门螺旋杆菌(Helicobacter pylori)、钩端螺旋体(Leptospirainterrogans)、嗜肺军团菌(Legionellapneumophila)、鼠疫菌(Yersinia pestis)、链球菌(Streptococcus(A型和B型))、肺炎双球菌、脑膜炎球菌、流感嗜血杆菌(Haemophilus influenza,b型)、弓形虫(Toxoplasma gondii)、卡他莫拉菌(Moraxella catarrhalis)、杜诺凡病、以及放线菌;真菌病原体,包括念珠菌和曲霉病;寄生病原体,包括绦虫(Taenia)、吸虫(flukes)、蛔虫、阿米巴病(amebiasis)、贾第虫病(giardiasis)、隐孢子虫(Cryptosporidium)、血吸虫(Schistosoma)、肺卡氏肺囊虫(Pneumocystis carinii)、滴虫病(trichomoniasis)和旋毛虫病(trichinosis)。本发明还可以用来对多种动物疾病提供合适的免疫应答,所述疾病如口蹄疫,冠状病毒,多杀性巴氏杆菌(Pasteurella multocida)、螺杆菌(Helicobacter)、普通圆形线虫(Strongylusvulgaris)、放线杆菌胸膜肺炎(Actinobacillus pleuropneumonia)、牛病毒性腹泻病毒(BVDV),克雷伯肺炎链球菌(Klebsiellapneumoniae)、大肠杆菌(E.coli)、百日咳杆菌(Bordetellapertussis)、副百日咳(parapertussis)和支气管脓毒博德氏菌(brochiseptica)。
在其他实施方式中,包含在可以用于本发明的组合物中的抗原为肿瘤来源的抗原或自体或异体的肿瘤全细胞。适宜地,肿瘤抗原是肿瘤特异性抗原(TSA)或肿瘤相关性抗原(TAA)。若干种肿瘤抗原及其表达模式为本领域公知,并能基于肿瘤治疗类型进行选择。非限制性的肿瘤抗原的实例包括:cdk4(黑色素瘤)、β-连环蛋白(黑色素瘤)、半胱天冬酶-8(鳞状细胞癌)、MAGE-1和MAGE-3(黑色素瘤、乳腺癌、胶质瘤)、酪氨酸酶(黑色素瘤)、独特型表面免疫球蛋白(如BCR)(淋巴癌)、Her-2/neu(乳腺癌、卵巢癌)、MUC-1(乳腺癌、胰腺癌)和HPVE6和E7(子宫颈癌)。其他合适的肿瘤抗原包括前列腺特异性抗原(PSA)、唾液酸Tn(STn)、热激蛋白和相关的肿瘤肽(如gp96)、神经节苷脂分子(如GM2、GD2和GD3)、癌胚抗原(CEA)和MART-1。
如本领域技术人员所了解的,药物组合物适宜地制备成适用于给予途径的形式。合适的给予途径的实例包括:注射,包括静脉注射、皮内注射、皮下注射、肌内注射;口服(比如吸入);肠内给予;皮肤(局部)给予;经粘膜给予和经直肠给予。如实施例中所示,化合物I在肌内注射后显示,提供了意料之外免疫应答的稳定增强。
本发明的另一种实施方式是刺激对抗原的体液免疫应答的方法。如上所述,该方法包括向受试者共给予式I的化合物和抗原。此处所指的“体液免疫应答”指通过B细胞产生抗体,以及相伴的其他附属过程,包括但不限于:如Th2的激活和细胞因子的产生、生发中心(germinal center)的形成和同型转换、亲和成熟的产生(affinity maturation production)和记忆细胞的产生。为了确定体液免疫应答是否激活,可以将接种抗原和该化合物的受试者的样本的信号和只接种抗原的受试者的样本的信号,进行定量比较。体液免疫应答可以通过检测抗体效果功能来衡量,所述功能包括:病原体或毒素的中和作用、经典的互补激活作用、以及吞噬作用和病原体消除的亲菌素(opsonin)促进。由共给予式I化合物和抗原诱发产生的抗体可以是任何类型,比如IgM、IgA、或IgG(如IgG1或IgG2)。体液免疫应答可以通过本领域公知的任何定量方法进行化验,比如ELISA、单放射性免疫扩散分析(SRID)、酶免疫分析(EIA)或血凝抑制试验(HAI)。
本发明的另一种实施方式是激活受试者体内CD4+T细胞的方法。如本领域所公知,CD4+T细胞,或“T辅助细胞”,是识别由抗原呈递细胞表面上的II型主要组织相容性标记(MHC)呈递的抗原的细胞,该细胞分泌淋巴因子以刺激细胞介导的和抗体介导的支路免疫系统。CD4+T细胞的激活促进了淋巴因子的分泌、免疫球蛋白的同型转换、抗体应答的亲和成熟、巨噬细胞的激活和天然杀伤(NK)细胞和细胞毒性T(CTL)细胞的增强活性。淋巴因子是由淋巴细胞分泌的蛋白,可以影响他们自己的活性和/或其它细胞的活性。淋巴因子包括但不限于:白细胞介素和细胞因子,如IL-2、IL-4、IL-5、IL-6、IL-I0、IL-12或IFNγ。为了确定CD4+T细胞是否激活,可以将接种抗原和该化合物的受试者的样本的信号和只接种抗原的受试者的样本的信号,进行定量比较。CD4+T细胞激活的分析方法是本领域公知的。
本发明的另一种实施方式是激活受试者体内CD8+T细胞的方法。CD8+T细胞能够识别由MHC I型分子呈递的抗原(呈递在所有有核细胞表面上)。MHC I型多肽复合体的形成,导致裂解颗粒向靶细胞的传递,引起靶细胞的裂解。CD8+T细胞激活的所用的分析方法为本领域公知,包括但不限于:酶联免疫斑点试验(ELISPOT)、ELISA、分析四聚体/五聚体结合的流式细胞术(FACS)、以及细胞毒性试验。可供替代选择地,小鼠模型可以通过使用荧光试验来检测细胞介导的细胞毒性,以用于监测CD8+T细胞的激活,如Hermans等的描述,2004,免疫学方法杂志,285:25-40,在此整体引入作为参考)所述。在该分析中,小鼠在第0天分别用加入测试化合物和未加测试化合物的疫苗进行免疫。同源靶细胞通过从第二组小鼠中分离脾细胞得到,并用两种独立的细胞标记荧光染料或高低的浓度单一荧光染料,标记所述细胞,比如CFSE或CMTMR。一组靶细胞加载抗体特异肽段,同时第二组靶细胞加载无关肽段。将两种靶细胞群等量混合后,注射到免疫过的小鼠中。24小时后,处死小鼠,取得脾细胞和血液样品。每组靶细胞的水平用流式细胞仪分析。CD8+T细胞的激活是通过对接种抗原和测试化合物的样本中的靶细胞数目和只接种抗原的样本中的靶细胞数目,进行定量比较而确定的。
参考以下非限制性的实施例和附图,对本发明的其他方面进行详细的说明。
实施例
实施例1:在小鼠模型中检测静脉注射PBS-96、PBS-14和PBS-11对CD8+T细胞应答的增强作用
用小鼠模型来检测通过测试佐剂化合物和抗体经静脉注射引起的体内特异性细胞毒性T细胞应答(CD8+)。8组(每组3只)小鼠在第0天用加和不加佐剂的抗原(卵白蛋白,Ova,级别VII,西格玛,圣路易斯,MO)、单独佐剂、或单独载体(对照),在100微升总体积的PBS中,经静脉(尾侧静脉)免疫。测试佐剂化合物为加或不加50微克的卵白蛋白(OVA)抗原的1微克PBS-96、1微克PBS-14、1微克PBS-11。
同系基因型的靶细胞通过以下方式制备:从第二组C57/B1/6J CD45.2雌性小鼠中分离脾细胞,并用低浓度(0.6微摩尔,8分钟,37℃)或高浓度(6微摩尔,8分钟,37℃)的CFSE(荧光染料)标记分离的脾细胞。用高浓度CFSE标记的组,用5微摩尔SIINFEKL肽段(卵白蛋白特异肽段,NeoMPS,有限公司,圣地亚哥,CA)预加载(60分钟,37℃)。用低浓度CFSE标记的组,用5微升LCMV gp33-41肽段(卵白蛋白非特异肽段,NeoMPS,有限公司,圣地亚哥,CA)预加载(60分钟,37℃)。靶细胞以低浓度CFSE加载细胞与高浓度CFSE加载细胞之间的比例为47/53的终比例混合(每100微升共2×107个细胞),在第10天时静脉注射到每只免疫过的小鼠体中。第11天时处死小鼠,收集脾细胞和眼静脉窦血液样本。通过流式细胞仪分析,计算相对于对照组的肽段脉冲的靶细胞的平均存活率(高浓度CFSE标记)。细胞毒性活性用特异裂解百分率表示(100减去肽段脉冲靶细胞的平均存活百分率)。图1描述了免疫小鼠血液中靶细胞的特异裂解百分比。只有给药Ova和PBS-96或PBS-14导致了Ova特异靶细胞的细胞毒性裂解。相反,给药PBS-11没有导致细胞的特异裂解。
实施例2:在小鼠模型中比较静脉注射和肌内注射PBS-96、PBS-14、PBS-11、PBS-57和αGalCer对CD8+T细胞应答的增强作用
为了确定测试佐剂化合物与抗原结合给药时,介导特异性体内细胞毒T细胞应答(CD8+)的能力,测试佐剂化合物用实施例1中所述的方法进一步分析。在第0天分别静脉免疫(第1-9组,每组3只)或肌内免疫(第10-18组,每组3只)的18组小鼠为:
组1:400微克Ova溶于100微升PBS中,静脉注射
组2:1微克αGalCer溶于100微升PBS中,静脉注射
组3:1微克PBS-57溶于100微升PBS中,静脉注射
组4:1微克PBS-14溶于100微升PBS中静脉注射
组5:1微克PBS-96溶于100微升PBS中静脉注射
组6:400微克Ova+1微克αGalCer溶于100微升PBS中,静脉注射
组7:400微克Ova+1微克PBS-57溶于100微升PBS中,静脉注射
组8:400微克Ova+1微克PBS-14溶于100微升PBS中,静脉注射
组9:400微克Ova+1微克PBS-96溶于100微升PBS中,静脉注射
组10:400微克Ova溶于50微升PBS中,肌内注射
组11:1微克αGalCer溶于50微升PBS中,肌内注射
组12:1微克PBS-57溶于50微升PBS中,肌内注射
组13:1微克PBS-14溶于50微升PBS中,肌内注射
组14:1微克PBS-96溶于50微升PBS中,肌内注射
组15:400微克Ova+1微克αGalCer溶于50微升PBS中,肌内注射
组16:400微克Ova+1微克PBS-57溶于50微升PBS中,肌内注射
组17:400微克Ova+1微克PBS-14溶于50微升PBS中,肌内注射
组18:400微克Ova+1微克PBS-96溶于50微升PBS中,肌内注射
靶细胞以低浓度CFSE加载的细胞与高浓度CFSE加载的细胞之间的比例为50/50的终比例混合(各浓度1×107个细胞,每100微升共2×107个细胞),在第10天时静脉注射到每只免疫过的小鼠体中。第11天时处死小鼠,收集脾细胞和眼静脉窦血液样本。OVA特异性靶细胞的细胞裂解,用外周血细胞的流式细胞术来检测。特异性细胞裂解按如上所述的方法确定。
图2展示了静脉注射小鼠的结果。单独用Ova处理的小鼠的平均的Ova特异的细胞毒性应答为11.8±14.4%,Ova和αGalCer为79.9±.8%,在用Ova和PBS-57处理的小鼠中为88.1±6.2%,在用Ova和PBS-14处理的小鼠中为83.3±6.1%,在用Ova和PBS-96处理的小鼠中为89.2±10.3%。结果表明PBS-14和PBS-96与PBS-57在介导体内OVA特异的细胞毒性应答中效果一致。
图3展示了肌内注射小鼠的结果。单独用Ova处理的小鼠的平均的Ova特异的细胞毒性应答为1.60±14.33%,在用Ova和αGalCer处理的小鼠中为-5.85±11.01%,在用Ova和PBS-57处理的小鼠中为56.11±13.34%,在用Ova和PBS-14处理的小鼠中为52.07±29.56%,在用Ova和PBS-96处理的小鼠中为50.29±42.6%。结果证明PBS-14和PBS-96都与PBS-57在静脉注射和肌内注射中引起免疫应答中效果一致,并且PBS-14、PBS-96和PBS-57在肌内注射后比αGalCer有效得多。
实施例3:通过佐剂检测化合物在体内刺激IFNγ
为了测试佐剂检测化合物(adjuvant test conpounds)在体内刺激细胞因子释放的能力,C57BL/6小鼠通过静脉给予不同浓度的化合物,24小时后用ELISA检测血清中IFNγ的生产量。每组3只小鼠,按如下所述在第0天静脉(尾静脉)接种:
组1:单独的100微升PBS
组2:1微克αGalCer溶于100微升PBS中
组3:100纳克αGalCer溶于100微升PBS中
组4:1纳克αGalCer溶于100微升PBS中
组5:0.1纳克αGalCer溶于100微升PBS中
组6:100纳克αGalCer+400微克Ova溶于100微升PBS中
组7:1微克PBS-57溶于100微升PBS中
组8:100纳克PBS-57溶于100微升PBS中
组9:1纳克PBS-57溶于100微升PBS中
组10:0.1纳克PBS-57溶于100微升PBS中
组11:100内克PBS-57+400微克Ova溶于100微升PBS中
组12:1微克PBS-14溶于100微升PBS中
组13:100纳克PBS-14溶于100微升PBS中
组14:1纳克PBS-14溶于100微升PBS中
组15:0.1纳克PBS-14溶于100微升PBS中
组16:100内克PBS-14和400微克Ova溶于100微升PBS中
组17:1微克PBS-96溶于100微升PBS中
组18:100内克PBS-96溶于100微升PBS中
组19:1纳克PBS-96溶于100微升PBS中
组20:0.1纳克PBS-96溶于100微升PBS中
组21:100纳克PBS-96和400微克Ova溶于100微升PBS中。
接种24小时后,收集小鼠血液样品,IFNγ水平用ELISA试剂盒来检测。使用了两个ELISA试剂盒,Quantikine小鼠IFNγ(RD系统)用于检测所有的组,而ELISAmIFNγ(Diaclone)用于检测组1、2、3、6、7、8、11、12、13、16、17、18和21。所有的血清在用于ELISA前按如下所述进行稀释:
组1:1/1 组2:1/50 组3:1/50
组4:1/20 组5:1/10 组6:1/50
组7:1/50 组8:1/50 组9:1/20
组10:1/10 组11:1/50 组12:1/50
组13:1/50 组14:1/20 组15:1/10
组16:1/50 组17:1/50 组18:1/50
组19:1/20 组20:1/10 组21:1/50
结果以血清中IFNγ浓度(皮克/毫升)表示,并考虑到稀释比例。图4描述了用RD系统的Quantikine小鼠IFNγ试剂盒得到的结果。图4A描述了接种PBS-57小鼠血清中,IFNγ水平的结果;图4B描述了接种PBS-14小鼠血清中,IFNγ水平的结果;图4C描述了接种PBS-96小鼠血清中,IFNγ水平的结果;图4D描述了接种αGalCer小鼠血清中,IFNγ水平的结果。在0.1纳克处,所有的佐剂候选物都诱导细胞因子的释放,但是接种αGalCer的小鼠产生的IFNγ是接种PBS-57、PBS-14或PBS-96的三分之一到四分之一(分别为1540.57±397.53皮克/毫升,4398.05±880.86皮克/毫升,6669.31±1231.82皮克/毫升,5823.33±720.69皮克/毫升)。在使用1纳克测试佐剂化合物时,PBS-57、PBS-14或PBS-96(平均值分别是11425.98±833.04皮克/毫升,7481.15±3454.03皮克/毫升,6271.95±3737.53皮克/毫升)表现出比αGalCer更强的应答(平均值3802.99±586.02皮克/毫升)。在使用100纳克测试佐剂化合物时,PBS-57、PBS-14和PBS-96产生了比αGalCer高的IFNγ水平(平均值分别是PBS-57的21432.76±4312.76皮克/毫升,PBS-96的19679.89±1443.48皮克/毫升,PBS-14的19582.18±3421.20皮克/毫升,αGalCer的7714.37±3529.07皮克/毫升)。在1使用微克测试化合物时,与100纳克的剂量(21432.76±4312.76皮克/毫升)相比,PBS-57表现出较低的应答(3353.45±867.57皮克/毫升),同时,与100纳克剂量相比(应答分别是19582.18±3421.20皮克/毫升和19679.89±1443.48皮克/毫升),PBS-14或PBS-96仍然表现出较低但是稳定的应答(分别是16392.53±5957.70皮克/毫升和17720.11±2869.97皮克/毫升)。
另外一组小鼠用于通过上述方法比较佐剂化合物在体内刺激细胞因子释放的能力。5组C57BL/6小鼠静脉给予在100微升PBS中的100纳克的PBS-57、PBS-14、PBS-96、或PBS-11,或者单独给予100微升PBS。24小时后用ELISA测定小鼠血清中IFNγ的产生量。图5描述了接种100ng的PBS-11、PBS-96、PBS-14和PBS-57的小鼠的结果。
总之,使用PBS-14和PBS-96具有与使用PBS-57相似的IFNγ应答,并且与使用PBS-11相比,具有意想不到的较强的应答。
实施例4:PBS-96、PBS-14、PBS-11和PBS-57对CD8+T细胞应答增强的比较
为了确定测试佐剂化合物结合抗原诱导体内特异细胞毒性T细胞应答(CD8+)的能力,该测试化合物按实施例1中的方法进行测试。9组小鼠按如下所述在第0天经静脉(IV)免疫:
组1:400微克Ova溶于100微升PBS中;
组2:1微克PBS-11溶于100微升PBS中;
组3:1微克新式PBS-57溶于100微升PBS中;
组4:1微克PBS-14溶于100微升PBS中;
组5:1微克PBS-96溶于100微升PBS中;
组6:400微克Ova+1微克PBS-11溶于100微升PBS中;
组7:400微克Ova+1微克新式PBS-57溶于100微升PBS中;
组8:400微克Ova+1微克PBS-14溶于100微升PBS中;
组9:400微克Ova+1微克PBS-96溶于100微升PBS中。
靶细胞,以低浓度CFSE加载的细胞/高浓度CFSE加载的细胞为50/50的终比例混合(各浓度1×107细胞,每100微升共2×107细胞),在第10天时静脉注射到每只免疫过的小鼠体中。第11天时处死小鼠,收集脾细胞和眼静脉窦血液样本。OVA特异靶细胞的细胞裂解,通过外周血细胞的流式细胞术来检测。特异细胞裂解按如上所述的方法确定。结果见图6。单独用Ova处理的小鼠的平均Ova特异细胞裂解为11.8±14.4%,用Ova和PBS-11处理的小鼠为32.3±2.5%,用Ova和PBS-57处理的小鼠为88.1±6.2%,用Ova和PBS-14处理的小鼠为83.3±6.1%,用Ova和PBS-96处理的小鼠为89.2±10.3%。这些结果证明在与抗原结合经静脉给予后,PBS-14和PBS-96介导的体内细胞毒性应答与PBS-57一样有效。
实施例5:通过减少肌内注射佐剂数量比较CD8+T细胞应答的增强
为了确定测试佐剂化合物增强免疫应答的相对能力,进行了与实施例2相似的实验。在本实验中,小鼠用减少量的佐剂(分别是10纳克和100纳克)与50微克OVA抗原,在第0天,按如下安排进行静脉注射。
实验A:
组1:50微克Ova溶于100微升PBS中
组2:100纳克αGalCer;
组3:100纳克PBS-11;
组4:100纳克PBS-14;
组5:100纳克PBS-57;
组6:100纳克PBS-96;
组7:50微克Ova+100纳克αGalCer;
组8:50微克Ova+100纳克PBS-11;
组9:50微克Ova+100纳克PBS-14;
组10:50微克Ova+100纳克PBS-57;
组11:50微克Ova+100纳克PBS-96;
实验B:
组1:50微克Ova溶于100微升PBS中
组2:10纳克αGalCer;
组3:10纳克PBS-11;
组4:10纳克PBS-14;
组5:10纳克PBS-57;
组6:10纳克PBS-96;
组7:50微克Ova+10纳克αGalCer;
组8:50微克Ova+10纳克PBS-11;
组9:50微克Ova+10纳克PBS-14;
组10:50微克Ova+10纳克PBS-57;
组11:50微克Ova+10纳克PBS-96;
靶细胞在实验的第10天给药,第11天收集血液。图7表示用100微克每种佐剂实验A的结果。图8表示实验B的结果。图7和图8证明,以低剂量以肌内给药时,与其它佐剂相比,PBS-14和PBS-96在增强对抗原的CD8+T细胞应答上具有意料不到的好效果。事实上,在肌内给药OVA和只给药10纳克的PBS-14或PBS-96后,通过CD8+T细胞的靶细胞的特异裂解百分率仍然高于60%,同时,给药OVA和相同数量的PBS-57、PBS-11或αGalCer后,靶细胞的特异裂解百分率与对照无差别。
实施例6:肌内注射后通过减少佐剂的量比较CD8+T细胞应答的增强
为了验证用如上实施例中描述的体内细胞毒性试验得到的结果,进行了相似的实验,通过用五聚体试验,检测OVA特异的CD8+T细胞的百分比来确定CD8+T细胞的活化。简要说,小鼠用所述OVA和测试佐剂化合物,分别以1微克或100纳克,在第0天进行肌内注射。
实验A:
组1:100微升PBS
组2:50微克Ova溶于100微升PBS中
组3:50微克Ova+1微克αGalCer
组4:50微克Ova+1微克PBS-11
组5:50微克Ova+1微克PBS-14
组6:50微克Ova+1微克PBS-57
组7:50微克Ova+1微克PBS-96
实验B:
组1:100微升PBS
组2:50微克Ova溶于100微升PBS中
组3:50微克Ova+100纳克αGalCer
组4:50微克Ova+100纳克PBS-11
组5:50微克Ova+100纳克PBS-14
组6:50微克Ova+100纳克PBS-57
组7:50微克Ova+100纳克PBS-96
第二次注射在第14天对小鼠实施,血液在第21天收集。收集淋巴细胞并在FACS上用H-2Kb SIINFEKL五聚体和CD8抗体分析,以检测对OVA发生应答的CD8+T细胞。图9表示实验A的结果,图10表示实验B的结果。图9证明了在接种后,给药1微克PBS-14、PBS-96和PBS-57增强了OVA特异的CD8+T细胞的百分率,而PBS-11和αGalCer并不同样有效。图10证明了在100纳克的低浓度下,PBS14和PBS-96在增强CD8+T细胞对抗原应答上意想不到地好于PBS-57、PBS-11和αGalCer。
实施例7:肌内注射佐剂和抗原后体液应答增强的比较。
为了衡量体液免疫应答和CD4+T辅助细胞免疫应答,通过给药测试佐剂和抗原是否也增强,在用加入有OVA和未加入有OVA的测试佐剂接种的小鼠中,检测了IgG1和IgG2a抗体应答。按如下设计,单独使用50微克OVA或与100纳克的所述佐剂的结合(弗氏佐剂用做阳性对照)肌内注射小鼠(每组6只):
组1:500微克Ova+CFA/IFA(阳性对照)
组2:50微克Ova
组3:50微克Ova十100纳克αGalCer
组4:50微克Ova+100纳克PBS-11
组5:50微克Ova+100纳克PBS-14
组6:50微克Ova+100纳克PBS-57
组7:50微克Ova+100纳克PBS-96
注射后14天,收集血液样本,用OVA同型IgG1或IgG2a特异的鼠单克隆抗体,进行IgG1和IgG2a的ELISA。以外周血中抗体(纳克/毫升)的效价表示结果。图11描述了IgG1的结果,图12描述了IgG2a的结果。如图11所示,与单独接种OVA或OVA与PBS-11或αGalCer结合相比,PBS-14,PBS-96和PBS-57都能引起IgG1的稳定效价,并增强了OVA特异的IgG1效价。出乎意料地,PBS-14和PBS-96增强了OVA特异的IgG2效价的效果,大致与弗氏佐剂相同,但好于PBS-57。
虽然在示例性的实施方式中描述了本发明的组合物和方法,但对本领域技术人员而言,在不背离本发明内容、精神和范围的情况下,显而易见的是,在本组合物和方法、以及在所述方法的步骤或者步骤的顺序,可以进行多种改变。更详细地说,显而易见的是,在化学上和生理上相关的特定的药剂可以替代此处所述的药剂,从而达到相同或相近的结果。所有这种对本领域技术人员显而易见的相似的替代物和修饰物,在本发明的精神、范围和内容以内。此外,此处列出和描述的所有专利和出版物都的全文引入作为参考。
如本说明书和附加的权利要求所描述的,除了在内容中特别说明以外,单数形式“一个”和“这个”包括复数指示对象。因此,例如,参照一种含有“一种多核苷酸”的组合物,包括两种或两种以上的多核苷酸的组合物的混合物。还需指出的是,除了在内容中特别说明以外,术语“或”通常包括“和/或”的意思。本说明书中所有参考的出版物、专利和专利申请书是为说明本发明相关的本领域普通技术人员的水平。所有的出版物、专利和专利申请书在此明确地全文引入作为参考,就如同每个相同内容的单独出版物或专利申请被详细地和独立地以参考文献展示一样。如果本发明与引入的出版物、专利和专利申请书发生抵触,以本发明的公开为准。
需要详细了解的是,在此叙述的所有数值包括从低值到高值的所有数值,也就是所有在最低值和最高值之间的数值组合,都在本申请中的范围内。
Claims (27)
2.根据权利要求1所述的组合物,其中,x为23。
3.根据权利要求1所述的组合物,其中,x为21。
4.根据权利要求1-3中的任意一项所述的组合物,其中,n为13。
5.权利要求1所述的组合物在制备疫苗中的用途,其中式I所示的化合物增强受试者对抗原的免疫应答,其中,所述受试者对抗原的免疫应答与单独接种抗原的受试者对抗原的免疫应答相比增强。
6.根据权利要求5所述的用途,其中,所述受试者的免疫应答与单独接种抗原的受试者对抗原的免疫应答相比增强了至少50%。
7.根据权利要求5所述的用途,其中,所述受试者的免疫应答与单独接种抗原的受试者对抗原的免疫应答相比增强了至少100%。
8.根据权利要求5所述的用途,其中,所述受试者的免疫应答与单独接种抗原的受试者对抗原的免疫应答相比增强了至少1000%。
9.根据权利要求8所述的用途,其中,所述组合物的给药方式选自由以下方式组成的组中:经静脉、经肌肉、经皮下、经皮内、经腹膜内、经鼻内和经吸入。
10.根据权利要求9所述的用途,其中,所述组合物经肌肉给药。
11.权利要求1所述的组合物在制备疫苗中的用途,其中式I所示的化合物增强受试者对抗原的体液免疫应答,其中,所述受试者对抗原的体液免疫应答与单独接种抗原的受试者对抗原的免疫应答相比增强。
12.根据权利要求11所述的用途,其中,所述体液免疫应答包括IgG抗体的产生。
13.根据权利要求11所述的用途,其中,所述体液免疫应答包括IgA抗体的产生。
14.权利要求1所述的组合物在制备疫苗中的用途,其中式I所示的化合物增强受试者对抗原的CD4+T细胞应答,其中,所述的受试者对抗原的CD4+T细胞应答与单独接种抗原的受试者对抗原的CD4+T细胞应答相比增强。
15.根据权利要求14所述的用途,其中,增强的CD4+T细胞应答包括CD4+T淋巴细胞的激活。
16.根据权利要求15所述的用途,其中,CD4+T淋巴细胞的激活包括Th1免疫应答的增加。
17.根据权利要求15所述的用途,其中,CD4+T淋巴细胞的激活包括Th2免疫应答的增加。
18.根据权利要求15所述的用途,其中CD4+T淋巴细胞的激活包括Th1免疫应答和Th2免疫应答的增加。
19.权利要求1所述的组合物在制备疫苗中的用途,其中式I所示的化合物增强受试者对抗原的CD8+T细胞应答,其中,所述受试者对抗原的CD8+T细胞应答与单独接种抗原的受试者对抗原的CD8+T细胞应答相比增强。
20.根据权利要求19所述的用途,其中,增强的CD8+T细胞应答包括CD8+T淋巴细胞的激活。
21.根据权利要求20所述的用途,其中,CD8+T淋巴细胞的激活包括细胞毒性应答的增加。
22.权利要求1所述的组合物在制备疫苗中的用途,其中式I所示的化合物增强受试者的抗原呈递细胞对抗原的激活,其中,所述受试者对抗原的免疫应答与单独接种抗原的受试者的抗原呈递细胞对抗原的激活相比增强。
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AU2008350531A1 (en) | 2009-08-20 |
RU2010127339A (ru) | 2012-01-10 |
US20090162385A1 (en) | 2009-06-25 |
BRPI0820960A2 (pt) | 2017-05-09 |
ZA201003964B (en) | 2011-02-23 |
US20100322952A1 (en) | 2010-12-23 |
EP2231145B1 (en) | 2014-09-17 |
BRPI0820960B1 (pt) | 2020-04-07 |
WO2009101475A3 (en) | 2009-10-22 |
JP2011506306A (ja) | 2011-03-03 |
CN101917985A (zh) | 2010-12-15 |
US8211861B2 (en) | 2012-07-03 |
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