CN100404070C - 包装的病毒样颗粒 - Google Patents
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- CN100404070C CN100404070C CNB2004800159525A CN200480015952A CN100404070C CN 100404070 C CN100404070 C CN 100404070C CN B2004800159525 A CNB2004800159525 A CN B2004800159525A CN 200480015952 A CN200480015952 A CN 200480015952A CN 100404070 C CN100404070 C CN 100404070C
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Abstract
本发明涉及疫苗学、免疫学和医学领域。本发明提供了增强抗原免疫应答的组合物和方法,所述抗原与由免疫刺激核酸包装的病毒样颗粒(VLP)偶合或融合,所述免疫刺激核酸优选含有至少一种非甲基化CpG序列和toll样受体(TLR)配体的低聚核苷酸。本发明可用于诱导产生强烈的抗体和T细胞应答,特别是用于治疗变态反应、肿瘤、慢性病毒性疾病和其它慢性病。
Description
背景技术
发明领域
本发明涉及疫苗学、免疫学和医学领域。本发明提供了增强抗原免疫应答的组合物和方法,所述抗原与由免疫刺激核酸包装的病毒样颗粒(VLP)偶合或融合,所述免疫刺激核酸优选含有至少一种非甲基化CpG序列和toll样受体(TLR)配体的低聚核苷酸。本发明可用于诱导产生强烈的抗体和T细胞应答,特别是用于治疗变态反应、肿瘤、慢性病毒性疾病和其它慢性病。
相关领域
通常诱导产生与自体抗原有关的抗体反应很难。一种改善接种效率的方法是提高使用抗原的重复程度。不同于分离蛋白,病毒在没有佐剂存在条件下不管有或没有T细胞帮助,都可以迅速有效地诱导产生免疫应答反应(Bachmann and Zinkernagel,Ann.Rev.Immunol:15:235-270(1991))。尽管病毒通常只由很少的蛋白构成,但它们比起其独立的各组分更能触发强烈的免疫应答反应。对于B细胞反应,已知一种影响病毒致免疫性的重要因素是表面表位的重复性和排列顺序。许多病毒表现为类晶体样表面,显示了与B细胞上表位特定免疫球蛋白有效交联的表位
a的有规律的排列。(Bachmann andZinkernagel,Immunol.Today17:553-558(1996))。B细胞上表面免疫球蛋白的交联是一个强烈的活化信号,直接诱导细胞周期进程和产生IgM抗体。进而,被触发的B细胞激活辅助T细胞,辅助T细胞反过来诱导B细胞从IgM到IgG抗体产生的转换和长期B细胞记忆的生成-接种疫苗的目的(Bachmannand Zinkernagel,Ann.Rev.Immunol.15:235-270(1997))。病毒结构甚至与自身免疫病中抗抗体的产生有关,并且是病原体天然应答一部分(参见Fehr,T.et al.JExp.1792(1997))。因而,高度组织化病毒表面递呈的抗原能诱导针对抗原的强烈抗体应答。
然而,正如所指出的那样,免疫系统通常不能产生针对自身结构的抗体。对于低浓度的可溶性抗原,这归因于辅助T细胞水平的耐受性。在这些条件下,将自身抗原偶合到能递送辅助T细胞的载体上能打破耐受性。对于高浓度的可溶性蛋白或低浓度的膜蛋白,B和辅助T细胞是有耐受力的。然而,B细胞耐受性是可逆的(无变应性),而且在给予与外来载体以高度有组织形式偶合的抗原时可以被打破(Bachmann and Zinkernagel,Ann.Rev.Immunol.15:235-270(1997))。
最新证据表明含有包装CpG的病毒样颗粒(VLP)能触发T细胞产生针VLP共轭抗原的应答(WO03/024481)。此外,包装CpG增强了VLP的稳定性,基本上除去了上述副作用如导致小鼠骨髓外血生成并伴有脾大和淋巴结病。
与CpG使TLR9接合到APCs上不同,其它TLR-配体单独不能增强VLP诱导的T细胞应答(Schwarz et al.(2003)Eur.J.Immunol.33,1465-1470)。特别地,TLR2的配体肽聚糖,TLR3的配体poly(I:C),TLR4的配体LPS,TLR5的配体鞭毛蛋白和TLR7的配体imiquimode,都不能以类似CpG的方式增强VLP诱导的CTL应答.
近来,在接种疫苗策略上已经有了显著进步,然而现有策略仍有需要改善的地方。特别地,该领域仍需要发展新的和改良的疫苗,其允许诱导强烈的T和B细胞应答而不产生严重的副作用,且特别地,允许如天然病原体一样能有效促进强烈CTL免疫应答和抗病原保护。
发明概述
本发明基于以下惊人发现:免疫刺激核酸,典型且优选能刺激Toll样受体(TLR9)的含CpG基序的DNA低聚核苷酸,经包装进VLP,能增强B和T细胞对与VLP偶合或对一起使用,如与包装的VLP混合使用,的抗原的应答然而其它TLRs配体,包括TLR2的配体肽聚糖,TLR3的配体poly(I:C),TLR4的配体LPS,TLR5的配体鞭毛蛋白和TLR7的配体imiquimode,都不能以类似CpG的方式增强VLP诱导的CTL应答(Schwarz et al.(2003)Eur.J.Immunol.33,1465-1470)。然而令人吃惊地,尽管TLR9的配体与其它TLRs不同,例如TLR4,不能增强T细胞对VLP偶合或融合抗原的应答,但在免疫刺激核酸存在条件下,特别在含非甲基化CpG低聚核苷酸存在条件下,他们能有效增强T细胞应答,因而,在TLRs配体和免疫刺激核酸之间存在协同增效作用。
在第一个优先实施方式中,本发明提供一种增强动物体内免疫应答的组合物,其中包括:(a)病毒样颗粒(VLP),(b)免疫刺激核酸,优选含非甲基化CpG的低聚核苷酸,其中核酸或低聚核苷酸经偶合、融合、或其它方式连接或装入病毒样颗粒,如与病毒样颗粒结合,优选用病毒样颗粒包装,(c)至少一种VLP偶合或融合的抗原,或与VLP混合的抗原,和(d)至少一种TLR配体。优选将本发明的TLR配体(d)与VLP(a)混合。
在一个同样优选的实施方式中,本发明提供一种增强动物体内免疫应答的组合物,其中包括:(a)VLP,(b)免疫刺激核酸,优选含非甲基化CpG的低聚核苷酸,其中核酸或低聚核苷酸与病毒样颗粒混合,(c)至少一种VLP偶合或融合的抗原或与病毒样颗粒混合的抗原,且(d)至少一种TLR配体。
在一个更优选的实施方式中,免疫刺激核酸不含CpG基序,但仍表现免疫刺激活性,例如WO 01/22972所描述的核酸。其中所描述的序列在这里引用作为参考。
在一个本发明的优选实施方式中,含非甲基化CpG的低聚核苷酸经磷酸二酯主链的硫代磷酸修饰后并未变得稳定。
在一个优选实施方式中,含非甲基化CpG的低聚核苷酸诱导人体细胞内的IFN-alpha。在另一个优选的实施方式中,IFN-alpha诱导低聚核苷酸侧翼有富含鸟嘌呤核苷重复侧翼连接序列,且含有回文序列。
在一个优选实施方式中,病毒样颗粒是重组病毒样颗粒。还优选,病毒样颗粒不含脂蛋白膜。优选地,重组病毒样颗粒包括,或可选择地由下述病毒的重组蛋白组成:乙肝病毒,麻疹病毒,辛德比斯病毒,轮状病毒,口蹄疫病毒,逆转录酶病毒,诺沃克病毒或人乳头瘤瘤病毒,RNA噬菌体,Q β-噬菌体,GA-噬菌体,fr-噬菌体,AP205-噬菌体和Ty。在一个特定实施方式中,病毒样颗粒包括,或可选择地由一种或多种乙肝病毒核心(衣壳)蛋白(HBcAg)组成.
在一个更优选的实施方式中,病毒样颗粒包括RNA噬菌体的重组蛋白或其片断片断,优选的RNA噬菌体是Q β-噬菌体,AP 205-噬菌体,GA-噬菌体,fr-噬菌体。
在另一个实施方式中,抗原或抗原混合物是重组抗原。在另一个实施方式中,抗原、多个抗原或抗原混合物提取自天然来源,其中包括但不限于花粉、粉尘、真菌、昆虫、食物、哺乳动物表皮、毛发、唾液、血清、蜜蜂、肿瘤、病原体和羽毛。
在另一个实施方式中,抗原与病毒性颗粒偶合或以遗传方式融合。
在另一个实施方式中,抗原选自:(1)适合诱导针对癌细胞的免疫应答的多肽;(2)适合诱导针对传染病的免疫应答的多肽;(3)适合诱导针对变态反应原的免疫应答的多肽;(4)适合诱导针对自身抗原的提高的免疫应答的多肽;和(5)适合诱导养殖动物或宠物免疫应答的多肽。
在另一个实施方式中,抗原、多个抗原或抗原混合物选自:(1)适合诱导针对癌细胞的免疫应答的有机分子;(2)适合诱导针对传染病的免疫应答的有机分子;(3)适合诱导针对变态反应原的免疫应答的有机分子;(4)适合诱导针对自身抗原的提高的免疫应答的有机分子;和(5)适合诱导养殖动物或宠物免疫应答的有机分子;和(6)适合诱导针对药物、荷尔蒙和有毒化合物的免疫应答的有机分子。
在一个特定的实施方案中,抗原包括,或可选择地由细胞毒性T细胞或Th细胞表位组成。在一个相关实施方式,抗原包括,或可选择地由B细胞表位组成。在一个相关实施方式中,病毒样颗粒包括乙肝病毒壳蛋白。
在一个优选的实施方式中,另外加入到载有CpG病毒样颗粒的TLRs配体被TLR4识别。例如,配体是LPS,优选去毒版的LPS,如MPL(Nat Biotechnol 17:1075)或合成的TLR4配体。
本发明另一方面,提供了一种增强人或其它动物种类体内免疫应答的方法,包括往动物体内导入一种组合物,包括(a)VLP,(b)免疫刺激核酸,优选含非甲基化CpG的低聚核苷酸,其中核酸或低聚核苷酸经混合、偶合、融合,或以其它方式连接或装入病毒样颗粒,如与病毒样颗粒结合,优选用病毒样颗粒包装,(c)至少一种VLP偶合或融合的抗原,或与病毒样颗粒混合的抗原,和(d)至少一种TLR配体。
也是在本发明的另一个实施方式中,组合物通过皮下、肌肉内、鼻内、皮内、静脉内,动物体内直接导入或直接引入淋巴结。在一个同样优选的实施方式中,针对需要预防接种的人,该增强免疫组合物在局部使用,靠近肿瘤或局部病毒储库(local vical reservoir)。
本发明一个优选的方面是,免疫应答是T细胞应答,且T细胞对抗原的应答增强了。在一个特定的实施方式中,T细胞应答是细胞毒性T细胞应答,且细胞毒性T细胞对抗原的应答增强了。在本发明的另一个实施方式中,免疫应答是B细胞应答,且B细胞对抗原的应答增强了。
本发明还涉及一种疫苗,其中包括免疫学有效量的本发明所述增强免疫组合物和药学上可接受的稀释剂、载体或赋形剂。本发明也提供了一种免疫和/或治疗动物的方法,其中包括给予动物免疫学有效量的所公开之疫苗。
在本发明的一个优选实施方式中,针对与修饰后VLP偶合或混合的抗原,将含免疫刺激核酸的VLP,和优选含非甲基化CpG的低聚核苷酸VLP用作动物或人的接种疫苗。修饰后的VLP能用于接种针对例如肿瘤、病毒病、或自身分子,疫苗能用作预防或治疗目的,或二者兼顾。修饰后的VLP能用于接种预防变态反应,或与变态反应相关的疾病如哮喘,以诱导针对变态反应原的免疫偏离和/或抗体应答。如接种疫苗和治疗分别能使得,如使以前患过敏症的动物和病人脱敏。
在多数情况下,预期免疫应答直接针对与含免疫刺激核酸偶合或混合的抗原,优选含非甲基化CpG的低聚核苷酸VLP。抗原是多肽、蛋白或功能域及其混合物。
优选的注射途径是皮下注射或肌内注射,但也可将含CpG的VLP通过皮内、鼻内、静脉内或直接用于淋巴结。在一个同样优选的实施方式中,对于进行接种预防的人,与抗原混合或偶合的含CpG的VLP在局部使用,靠近肿瘤或局部病毒灶。
显而易见前面的概述和下面的详细描述仅仅是示范性的和解释性的,目的是对本发明范围进行进一步的解释。
附图说明
图1显示VLP在对照孵育后或在用核糖核酸酶A消化后的非变性琼脂凝胶电泳(1%琼脂),上面用溴乙非啶(A)或考马斯蓝(B)染色以检测RNA或蛋白质的存在。
将重组获得的VLP用最终浓度为0.5μg/μl的蛋白质PBS缓冲液稀释,并且在核糖核酸酶A(100μg/ml)缺失(泳道1)或存在(泳道2)、温度37℃条件下孵育两小时(Sigma,Division of Fluka AG,瑞士瑞士)。样品随后补入6倍浓度的DNA载样缓冲液(MBS FermentasGmbH,Heidelberg,德囯),在100v电压下在1%非变性琼脂凝胶中跑30分钟。用μl Gene Rμler标记(MBS Fermentas GmbH,Heidelberg,德囯))作为VLP迁移速率的参照(泳道M)。各泳带表明装入VLP(A)内的RNA的存在或VLP自身(B)的存在。在3个独立实验中也获得相同结果。
图2显示在仅有缓冲液或含CpG的DNA低聚核苷酸时,VLP在对照孵育后或在用核糖核酸酶A消化后的非变性琼脂凝胶电泳(1%琼脂),上面用溴乙非啶(A)或考马斯蓝(B)染色以检测RNA/DNA或蛋白质的出现。将重组获得的VLP用最PBS缓冲液稀释,终浓度为0.5μg/μl蛋白质,并且在核糖核酸酶A(100μg/ml)缺失(泳道1)或存在(泳道2)、温度37℃条件下孵育两小时(Sigma,Division of Fluka AG,瑞士)。在核糖核酸酶A消化前,将5nmol CpG-低聚核苷酸(含磷酸主链的硫代磷酸修饰物)加入样品3。用Gene Ruler标记(MBSFermentas GmbH,Heidelberg,德囯))作为p33-VLP迁移速率的参照(泳道M)。各泳带表明装入p33-VLP(A)内的RNA/CpG-DNA的存在或p33-VLP自身(B)的存在。将正常磷键的CpG低聚核苷酸用于VLP与核糖核酸A的共孵育时得到的是可比的结果。
图3显示存在含CpG的DNA低聚核苷酸时,p33-VLP在用核糖核酸酶A消化之前或之后随后进行透析(除去未结合VLP的CpG低聚核苷酸)的非变性琼脂凝胶电泳(1%琼脂),用溴乙非啶溴化物(A)或考马斯蓝(B)染色以检测DNA或蛋白质的出现。将重组VLP用μgμlPBS缓冲液稀释至最终浓度为0.5μg/μl蛋白质,并且在核糖核酸酶A(100μg/ml)缺失(泳道1)或存在(泳道2至5)、温度37℃条件下孵育两小时(Sigma,Division of Fluka AG,瑞士)。在核糖核酸酶A消化前,将50nmol CpG-低聚核苷酸(含硫代磷酸键的硫代磷酸修饰物:泳道2和3,含正常磷酸主链的磷修饰物:泳道4和5)加入VLP。
用PBS(4500倍稀释)将样品彻底透析24小时,采用300kDaMWCO透析膜(Spectrum Medical Industries Inc.Houston,USA)除去过量的DNA(泳道3 and 5)。用(Gene Ruler标记(MBS FermentasGmbH,Heidelberg,德囯))作为p33-VLP迁移速率的参照(泳道M)。各泳带表明装入VLP(A)内的RNA/CpG-DNA的存在或VLP自身(B)的存在。
图4显示VLP在对照孵育后或在用核糖核酸酶A消化后的非变性琼脂凝胶电泳(1%琼脂),其中含CpG的DNA低聚核苷酸在RNA消化完成后才加入,上面用溴乙非啶溴化物(A)或考马斯蓝(B)染色以检测DNA/RNA或蛋白质的出现。将重组VLP用PBS缓冲液稀释至最终浓度为0.5μg/μl的蛋白质,并且在核糖核酸酶A(100μg/ml)缺失(泳道1)或存在(泳道2和3)、温度37℃条件下孵育两小时(Sigma,Division of Fluka AG,瑞士)。
在核糖核酸酶A消化后,5nmolCpG-低聚核苷酸(含磷酸主链的硫代磷酸修饰物)才加入样品3。用Gene Ruler(MBS Fermentas GmbH,Heidelberg,德囯))作为p33-VLP迁移速率的参照(泳道M)。各泳道表明装入VLP(A)内的RNA/CpG-DNA的存在或VLP自身(B)的存在。当正常磷键的CpG低聚核苷酸用于VLP的重新组装时得到类似的结果。
图5显示各种不同的TLRs配体,其中TLR9配体CpG例外,不能增强T细胞对乙肝病毒核抗原融合肽p33(p33-VLP)的应答。在PBS或TLRs的指示刺激物存在条件下用p33-VLP使小鼠免疫。使用100μg的HBc33和100μg的佐剂。8天后通过四聚物染色法检测p33-特定T细胞的频率。每根棒代表一个小鼠个体。(LTA=脂磷壁酸,PGN=肽聚糖,LPS来自E.coli K-235,Sigma).
图6显示原型佐剂矾和IFA不能增强VLP-诱导的免疫性。在PBS,CpG,矾or IFA存在条件下,用p33-VLP给小鼠接种,8天后以活LCMV(200pfu)攻击。五天后测定脾内病毒效价。
图7显示TLR4配体增强了针对与装载有CpG的VLP偶合的p33的CTL应答。在PBS、LPS、或MPL(1∶1混合)存在条件下,用与装载有NK-PO CpG的Qb偶合的p33给小鼠接种,8天后,用四聚物染色法(A)检测p33-特定T细胞的频率,在同一天,用重组疫苗病毒表达的LCMV-GP攻击小鼠并在五天后测定卵巢内病毒效价(B).
发明详述
除非另有定义,这里用的所有科技术语都与本领域普通技术人员按常规所能理解的含义相同。尽管任何与此处描述类似或相同的方法和原料都可以用于实施或验证本发明,后面只对优选的方法和原料进行描述。
1.定义
氨基酸连接体:这里所用的″氨基酸连接体″,或在说明书里以术语″连接体″称之,连接抗原或抗原决定簇至第二附着位点,或更优选,其中已经包括或含有第二附着位点,典型的但不是必需的如一个氨基酸残基,优选半胱氨酸残基。然而这里所用的术语″氨基酸连接体″,并非用于暗示这样一个氨基酸连接体仅仅由氨基酸残基组成,即使含有氨基酸残基的氨基酸连接体是本发明的优选实施方式。氨基酸连接体的氨基酸残基,优选地,由天然发生的氨基酸组成或本领域公知的非天然氨基酸组成,所有-L或所有-D或其混合物。然而,一个包括带巯基的分子或半胱氨酸残基的氨基酸连接体也包括在本发明的范围内。这类优选包括C1-C6烷基-,环烷基(C5,C6),芳基-或杂芳基部分的分子。但是,在氨基酸连接体之外,优选包括C1-C6烷基-,环烷基-(C5,C6),芳基-或杂芳基部分的连接体和不含任何氨基酸的连接体也包括在本发明的范围内。抗原或抗原决定簇或任意第二附着位点与氨基酸连接体之间的连接优选通过至少一种共价键,更优选通过至少一种肽键。
动物:这里所用术语″动物″的意思包括,例如人,绵羊,马,牛,猪,狗,猫,大鼠,小鼠,鸟,爬行类,鱼,昆虫和蜘蛛。
抗体:这里所用术语“抗体”指包括能结合到表位或抗原决定簇上的分子。术语的意思包括所有的抗体和其抗原结合片断片断,包括单链抗体。最为优选的抗体是人抗原结合抗体片断片断,包括但不限于Fab,Fab′和F(ab′)2,Fd,单链Fvs(scFv),单链抗体,二硫键连接的Fvs(sdFv)和包括VL或VH域的片断片断。抗体可以来自任何动物来源包括乌和哺乳动物。优选抗体是人、鼠、兔子、山羊、几内亚猪、骆驼、马或鸡。这里所使用的“人”抗体包括具有人免疫球蛋白的氨基酸序列的抗体和包括分离自人免疫球蛋白库的抗体或分离自一种或多种人免疫球蛋白的转基因动物的且不表达免疫球蛋白的抗体,例如在Kucherlapati等人的美囯专利No.5,939,598中所描述的。
在本发明优选的实施方式中,本发明的组合物用于设计治疗变态反应的疫苗。IgE同型抗体是变应性反应的重要成分。肥大细胞在其表面结合IgE抗体,释放组胺和其它变应性反应介质,使特定的抗原与结合在肥大细胞表面的IgE分子结合。因而,IgE抗体抑制产物是免除变态反应的很有希望的一个目标。这是可能通过达到获得预期的辅助T细胞应答实现的。辅助T细胞应答可以分为1型(TH1)和2型(TH2)辅助T细胞应答(Romagnani,Immunol.Today 18:263-266(1997))。TH1细胞分泌γ干扰素和其它引发B细胞产生IgG抗体的细胞因子。与之不同,TH2细胞产生的关键性的细胞因子是IL-4,促使B细胞产生IgE。在许多试验体系中,TH1和TH2应答的发展是互相排他的,因为TH1细胞压制了TH2细胞诱导,反之亦然。因而,引发强烈TH1应答的抗原同时抑制了TH2应答的发展,因此抑制了IgE抗体的产生。高浓度IgG抗体的出现可以阻止抗原与结合IgE的肥大细胞的结合,从而抑制了组胺的释放。因而,IgG抗体的出现可以保护远离IgE引起的变态反应。导致变态反应的典型物质包括,但不限于:花粉(如草,豕草,桦或西洋杉);室内粉尘和尘螨;哺乳动物表皮变态反应原和动物头皮屑;霉菌和真菌;昆虫尸体和昆虫毒液;羽毛;食物;和药物(例如,青霉素)。参见Shoμgh,H.等人的REMINGTON′S PHARMACEUTICAL SCIENCES,19th edition,(Chap.82),Mack Publishing Company,Mack Publishing Group,Easton,Pennsylvania(1995),这里全文引用作为参考。因而,凡是用与含包装富含非甲基化CG基序的DNA的病毒样颗粒混合的变应原免疫接种的个体,无论在变态反应开始前还是开始后都会获益。
抗原:这里所用的术语″抗原″指能被抗体或T细胞受体结合的分子,如由MHC分子递呈的话。这里所用的术语″抗原″也包括T细胞表位。抗原还要能被免疫系统识别和/或能诱导人产生能导致B或T淋巴细胞活化的体液和/或细胞免疫应答。然而这要求,至少在某些情况下要求,抗原含有Th细胞表位或与Th细胞连接并通过佐剂给予。一个抗原可以有一个或多个表位(B-和T-表位)。参照上述内容特异性应答的意思是指示该抗原优选,典型地是以高度选择性的方式,与其对应的抗体或TCR反应,而不与多数可由其它抗原唤起的其它抗体或TCRs反应。这里所用的抗原可以是几种单一抗原的混合物。
这里所用的″微生物抗原″是一种微生物的抗原,包括但不限于传染性病毒、传染性细菌、寄生虫和传染性真菌。此类抗原包括完整的微生物和天然分离物和其片断或衍生物,也包括诱导针对特定微生物的免疫应答,与天然微生物抗原相同或相似的合成或重组化合物,一个化合物与天然微生物抗原相似,如果其诱导针对天然微生物抗原的免疫应答(体液和/或细胞)。这些抗原在本领域按常规方法使用,且为本领域普通技术人员所公知。
这里所用的作为微生物抗原的传染性病毒、细菌和传染性真菌的例子,在WO03/024481中有述(第23页最后一段至第25页第3段),其中所公开的内容这里引用作为参考。
本发明的组合物和方法也用于通过刺激针对癌症抗原的抗原特异性免疫应答来治疗癌症。这里所用的“肿瘤抗原″是化合物,如与肿瘤或癌症相关,能刺激免疫应答的肽。特别地,化合物在MHC分子形式递呈时能激起免疫应答.肿瘤抗原从癌细胞中制备,比如从癌细胞的粗提物制备,如Cohen等人在Cancer Research,54:1055(1994)所描述的,或通过部分纯化抗原,通过重组技术或通过已有抗原的重头合成。肿瘤抗原包括整个肿瘤或癌多肽或其抗原部分。这类抗原能通过分离、重组或其本领域公知方法制备。癌症或肿瘤包括但不限于胆管癌、脑癌、乳房癌、宫颈癌、绒膜癌、结肠癌、子宫内膜癌、食管癌、胃癌、上皮内瘤、淋巴瘤、肝癌、肺癌(例如小细胞和非小细胞肺癌)、黑素瘤、成神经细胞瘤、口癌、卵巢癌、胰腺癌、前列腺癌、直肠癌、肉瘤、皮肤癌、睾丸癌、甲状腺癌、肾癌,以及其它癌症和肉瘤。
变态反应原在脊椎动物体内也作为抗原。这里所用的术语″变态反应原″也包括″变态反应原提取物″和″变态反应原表位″。变态反应原的例子包括,但不限于:花粉(例如草、豕草、桦和西洋杉);室内粉尘和尘螨;哺乳动物表皮变态反应原和动物皮屑、霉菌和真菌、昆虫尸体和昆虫毒液、羽毛、食物和药物(如青霉素)。
抗原决定簇:这里所用的术语″抗原决定簇″的意思指抗原的一部分,能被B或T淋巴细胞特异性地识别。对于相应的抗原决定簇,B淋巴细胞产生抗体,而T淋巴细胞通过为介导细胞和/或体液免疫所必需的增殖和效应子功能的确立来应答抗原决定簇。
抗原呈递细胞:这里所用的术语″抗原呈递细胞″的意思指一群异源的白细胞人群或骨髓来源的细胞,具有免疫刺激功能。例如,这类细胞能生成与MHC分子结合的肽,其中MHC分子能被T细胞识别。该术语与″佐细胞″含义相同,包括如胰岛细胞,交错突细胞,树突细胞,B细胞和巨噬细胞。在某些条件下,上皮细胞,内皮细胞和其它,非骨髓来源细胞也可作为抗原呈递细胞。
缔合:这里所用的术语“缔合”当其用于第一和第二附着位点时指的是第一和第二附着位点的结合,优选通过至少一种非肽键结合。天然的缔合可以是共价键、离子键、疏水键、极性键或其组合,优选的天然缔合是共价键,更优选的缔合通过至少一种,优选一种非肽键。这里所用的术语“缔合”当其用于第一和第二附着位点时,不仅包括第一位点和第二位点的直接结合或缔合形成本发明的组合物,也包括,选择地或优选地,第一位点和第二位点间接地结合或缔合获得本发明的组合物,这里典型地和优选地通过使用异双功能交联剂结合。
第一附着位点:这里所用的短语″第一附着位点″指非天然或天然来源的元件,典型和优选地,包括于病毒样颗粒,而第二位点,典型和优选地包括于抗原或抗原决定簇,与之缔合。第一附着位点可以是蛋白质、多肽、氨基酸、肽、糖、多核苷酸、天然或合成聚合物、次级代谢产物或化合物(生物素、荧光素、维生素A醇、地高辛配基、金属离子、苯甲基磺酰氟化物),或其组合,或其化学活性基团。典型和优选地,第一附着位点位于病毒样颗粒的表面。多数第一附着位点出现于病毒样颗粒的表面,典型为重复构型。优选地,第一附着位点是氨基酸或其化学反应基团。
第二附着位点:这里所用的短语″第二附着位点″指与抗原或抗原决定簇相缔合的元件,典型和优选地,包括于抗原或抗原决定簇,位于病毒样颗粒表面的第一附着位点与之缔合。抗原或抗原决定簇的第二附着位点可以是蛋白质、多肽、肽、糖、多核苷酸、天然或合成的聚合物、次级代谢产物或化合物(生物素、荧光素、维生素A醇、地高辛配基、金属离子、苯甲基磺酰氟化物),或其组合,或其化学活性基团。至少一个第二附着位点出现在抗原或抗原决定簇上。因此,术语“具有至少一个第二附着位点的抗原或抗原决定簇”指至少含有抗原或抗原决定簇和第二附着位点的抗原或抗原构造。然而,特别地,对于非天然来源的第二附着位点,也就是非抗原或抗原决定簇内非天然发生的那些,这些抗原或抗原构造含有“氨基酸连接体”。
结合:这里所用的术语“结合”指共价结合,例如本发明免疫刺激核酸与病毒样颗粒的化学偶合,或非共价结合,例如离子相互作用,疏水相互作用,氢键等。共价键的例子如酯键、醚键、磷酸酯键、酰胺键、肽键、亚胺键、碳-硫键、碳-磷键和类似键。该术语也包括物质封装或部分封装。术语″结合″范围更大,包括术语如″偶合″、″融合″、″封装″和″附着″。此外,关于与病毒样颗粒结合免疫刺激物质,术语“结合”也包括免疫刺激物质的封装或部分封装。因此,关于与病毒样颗粒结合的免疫刺激核酸,术语“结合”范围更大,包括“术语”如″偶合″、″融合″、″封装″、″包装″和″附着″。例如,免疫刺激核酸如含非甲基化CpG的低聚核苷酸可以封装于VLP却没有实质上的结合,既不是以共价键方式也不是以非共价键方式,这类低聚核苷酸被固定仅仅是通过“包装”。
偶合:这里所用的术语“偶合”通过共价键附着或通过强的非共价相互作用附着,典型和优选地通过共价键附着。此外,关于抗原与病毒样颗粒的偶合,术语“偶合”优选指分别至少通过一个非肽键的缔合和连接。任何本领域普通技术人员用于偶合生物活性材料的常规方法都可以用于本发明。
融合:这里所用的术语″融合″指不同来源的氨基酸序列通过其编码核苷酸序列的符合读框的联合形成的以一条多肽链形式的组合。术语″融合″很清楚地包括内部融合,也就是在与其一个末端的融合之外,不同来源序列的插入多肽链之中。
CpG:这里所用的术语″CpG″指低聚核苷酸,其中包括至少一个非甲基化胞嘧啶,鸟嘌呤二核苷酸序列(如″CpG-低聚核苷酸″或含胞嘧啶的DNA,胞嘧啶后面是鸟嘌呤,两者通过磷酸酯键相连),且刺激/激活,如有致有丝分裂效应,或诱导或通过脊椎动物骨髓来源的细胞提升细胞因子表达。例如,CpG用于激活B细胞,NK细胞和抗原呈递细胞,如树突细胞,单核细胞和巨噬细胞。CpG也包括核苷酸类似物,如含硫代磷酸酯键且能可以是双链或单链的核苷酸类似物。一般而言,双链分子在体内更稳定,而单链分子有更高的免疫活性。
外壳蛋白:这里所用的术语″外壳蛋白″指噬菌体或RNA-噬菌体蛋白质(s),能合并入噬菌体或RNA-噬菌体装配衣壳中。然而,当所指为RNA-噬菌体外壳蛋白基因的特异性基因产物时,使用术语″CP″。例如,RNA-噬菌体Q β外壳蛋白基因的特异性基因产物被指称为″Q βCP″,鉴于此,噬菌体Qb″外壳蛋白″包括″Q βCP″以及A1蛋白。噬菌体Q β衣壳主要由Q βCP组成,还有少量的A1蛋白。同样地,VLPQ外壳蛋白主要含有Q βCP,和少量的A1蛋白。
表位:这里所用的术语″表位″指多肽的连续或非连续部分,在动物体内,优选在哺乳动物体内,更优选在人体内有抗原或免疫活性。表位在MHC分子环境下通过其T细胞受体被抗体或T细胞识别。这里所用的″致免疫表位″被定义为多肽一部分,能引起在动物体内抗体应答或T细胞应答,可由本领域任何已知方法测得。(参见,如,Geysenetal.Proc.Natl.Acad.Sci.USA 81:3998-4002(1983)).这里所用的术语″抗原表位″,被定义为蛋白的一部分,在此部分抗体能免疫特异性地结合其抗原,这一点由本领域任何公知的方法测得。免疫特异结合将非特异结合排出在外,但不必排除与其它抗原的交叉反应。抗原表位并非必需是致免疫的。抗原表位也可是T细胞表位,这种情况下他们能在MHC分子环境之下通过T细胞受体免疫特异地结合。
表位在其空间构型中可包括3个氨基酸对于其表位是独特的。一般来说,表位由至少约5个这样的氨基酸组成,更常见地,由约8-10个这样的氨基酸组成。如果表位为有机分子,它可以与硝基苯一样小。
免疫应答:这里所用的术语″免疫应答″指体液免疫应答和/或细胞免疫应答,导致B-和/或T-淋巴细胞和/或抗原呈递细胞的活化或增殖,然而,免疫应答的强度可能较低,只有在使用至少一种本发明的物质后才能检测到。″致免疫的″指药物刺激活生物体的免疫系统,使免疫系统的一种或多种功能获得提升,且直接指向致免疫原。“致免疫多肽″是引发细胞和/或体液免疫应答的多肽,无论单独还是与其它载体连接,有还是没有佐剂。优选地,抗原呈递细胞可被激活。
免疫:这里所用的术语″使免疫″或″免疫″或相关术语指的是授予能针对靶抗原或表位的逐步积累巨大的免疫应答的能力(包括抗体和/或细胞免疫性,如效应器CTL)。这些术语不要求获得完全的免疫性,但所产生的免疫应答显著大于基线。例如,哺乳动物将被认为对靶抗原免疫,如果应用本发明方法后发生了对靶抗原的细胞和/或体液免疫应答。
免疫刺激核酸:这里所用的术语免疫刺激核酸指能诱导和/或增强免疫应答的核酸。这里所用的免疫刺激核酸包括核糖核酸,特别是脱氧核糖核酸。优选地,免疫刺激核酸含有至少一个CpG基序,例如CG二核苷酸,其中C非甲基化。CG二核苷酸可以是回文回文序列的一部分或能被非回文序列围绕在内。上述不含CpG基序的免疫刺激核酸包括,例如缺乏CpG二核苷酸的核酸,以及含有带甲基化CG二核苷酸的CG基序的核酸。这里所用的术语″免疫刺激核酸″应该也指含改性碱基的核酸,如4-溴-胞嘧啶。
免疫刺激物:这里所用的术语“免疫刺激物”指一种能诱导和/或增强免疫应答的物质。这里所用的免疫刺激物,包括但不限于,toll样受体激活物和诱导细胞因子分泌物。Toll样受体激活物包括但不限于免疫刺激核酸、肽聚糖、脂多糖、脂磷壁酸、咪唑喹啉化合物、鞭毛蛋白、脂蛋白和免疫刺激有机物如紫杉醇。
混合的:这里所用的术语“混合的”指两种或两种以上物质、成分或元件加在一起的联合,彼此之间不是化学结合,是能分离开的。
低聚核苷酸:这里所用的术语″低聚核苷酸″或″低聚物″指包括2个或更多核苷酸的核酸序列,一般至少约6个至约100,000核苷酸,优选约6个至约2000个核苷酸,更优选约6个到约300个核苷酸,甚至更优选约20至约300个核苷酸,甚至更优选约20至约100个核苷酸。术语″低聚核苷酸″或″低聚物″也指包括超过100指约2000个核苷酸的核酸序列,优选超过100至约1000个核苷酸,更优选约超过100至约500个核苷酸。″低聚核苷酸″一般也指任何多聚核糖核苷酸或多聚脱氧核糖核苷酸,其可以是未改性RNA或DNA或改性RNA或DNA。修饰可包括主链或核酸类似物。″低聚核苷酸″包括,而不限于,单链和双链DNA,单链和双链区混合的DNA,单链和双链RNA,单链和双链区混合的RNA,以及包括单链或更典型地双链或单链和双链区混合的DNA和RNA的杂交分子。此外″低聚核苷酸″指包括RNA或DNA或RNA与DNA兼有的三链区。低聚核苷酸还可是合成的、基因组的或重组的,例如λ-DNA,粘粒DNA,人造细菌染色体,酵母人造染色体和丝状噬菌体如M13。
术语″低聚核苷酸″也包括为了稳定或其它原因含一个或多个修饰碱基的DNAs或RNAs,及主链修饰的DNAs或RNAs。例如,适当的核酸修饰物/类似物包括肽核酸、肌苷(inosin)、三苯甲游基化碱基,硫代磷酸基,烷基硫代磷酸基,5-硝基吲哚脱氧呋喃核糖基,5-甲基脱氧胞嘧啶和5,6-二氢-5,6-二羟基脱氧脱氧胸苷。可以对DNA和RNA进行各种不同的修饰,因而,″低聚核苷酸″包括典型常见于自然界的多核苷酸的化学的、酶的或代谢修饰形态,以及病毒和细胞DNA和RNA特性的化学形态。其它核苷酸类似物/修饰物对本领域普通技术人员是显而易见的。
包装:这里所用的术语″包装″指免疫刺激物质的状态,特别是与VLP有关的免疫刺激核酸的状态。这里所用的术语“包装”包括共价键,例如化学偶合或非共价键,例如离子相互作用、疏水键相互作用或氢键等。例如,共价键可以是如,酯键、醚键、磷酸酯键、酰胺键、肽键、亚胺键、碳-硫键、碳-磷键和类似键。术语″包装″包括术语如″偶合″和″连接″,且特别地,优选术语“包装″也包括物质封装或部分封装。例如,免疫刺激物质如含非甲基化CpG的低聚核苷酸可以被封装入VLP而不用任何实际上的结合,既不用共价键也不用非共价键。因此,优选的含义,这里所用的术语“包装”,如果所述免疫刺激物质是免疫核酸,则特别表明包装状态的核酸不受DNAse或RNAse的水解作用的影响。在优选的实施方案中,免疫刺激核酸包装在VLP衣壳内,更优选以非共价键的方式。
PCR产物:这里所用的术语″PCR产物″指靶DNA序列的扩增拷贝,其中靶DNA序列起到PCR起始材料的作用。靶序列包括,例如双链DNA。用于PCR的DNA来源可以是互补DNA,也称作″cDNA″,可以是mRNA使用逆转录酶获得的转化产物。用于PCR的DNA来源可以是提取自细胞中的总基因组DNA。可以从中提取DNA用于PCR的细胞的来源包括,但不限于血样;人、动物、或植物组织;真菌;和细菌。用于PCR的DNA反应起始物可以是未纯化的、部分纯化的,或高度纯化的。用于PCR的DNA来源来自于载体中的克隆插入物,其中包括但不限于,质体载体和噬菌体载体。术语″PCR产物″与术语″聚合酶链反应产物″可互换。
本发明组合物可任意与药学上可接受的载体联合。这里所用的术语“药学上可接受的载体”指一种或多种适于对人体或其它动物进行给药的适宜的固体或液体填充剂,稀释剂或装胶囊物质。术语“载体”指示有机或无机成分,天然或合成,活性成分与之结合以获得更好地应用。
多肽:这里所用的术语“多肽″指通过酰胺键(已知如肽键)线性连接的单体(氨基酸)组成的分子。它指示一个氨基酸分子链,而不是特定长度的产物。因而,肽、低聚肽和蛋白质都包括在多肽的定义中。该术语也用来指多肽的表达前修饰物,例如糖基化、乙酰化、磷酸化和类似修饰物。重组或衍生的多肽不必转化自指定的核酸序列。它可以以任何方式生成,包括化学合成。
″增强″免疫应答的物质指相对于不加入该物质时所测量的同一免疫应答,能观察当该物质加入时,免疫反应以任意方式增大或增强或偏离。例如,在有和没有该物质的情况下,测量细胞毒性T细胞的溶胞活性,例如用51Cr释放射线测试。当活性相对于没有该物质的CTL溶胞活性增强时该物质的用量被称为增强动物对抗原免疫应答的足够量。在优选的实施方式中,免疫应答增强至少约2倍、更优选约3倍或更多。分泌的细胞因子的量或类型可以改变。可选择地,诱导的抗体量和其分型可以改变。
有效量:这里所用的术语“有效量”指必需的剂量或足够的剂量以实现预期的生物效应。组合物的有效量应当获得选定的结果,这样一个剂量是本领域普通技术人员按常规可以决定的。例如,用于治疗免疫系统缺乏的有效量应是激活免疫系统所需的剂量,遇到抗原时发生抗原特异性免疫应答。该术语与″足够量″同义。
任意特定用途的有效量根据诸多因素如所治疗的疾病或不适,特定组合物的给药方式,受试者的尺寸,和/或疾病或不适的严重程度。本领域普通技术人员根据经验完全可以决定本发明特定组合物的有效量而不必进行过度的试验。
Toll样受体(TLR)配体:这里所用的术语″Toll样受体配体″或″TLR配体″指任何能激活至少一个TLRs的配体(参见如Beutler,B.2002,Curr.Opin.Hematol.9,2-10,Schwarz et al.2003,Eur.J.Immunol.33,1465-1470)。本发明的TLR配体激活而不限制至少一种toll样受体1(TLR1),TLR2,TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9,TLR10,或TLR11。例如,肽聚糖(PGN)或脂磷壁酸(LTA)典型和优选地激活TLR2(Aliprantis et al.Science(1999),285:736-9;Underhill,等人,Nature,(1999),401:811-5);双链RNA,例如poly(I:C),典型和优选地激活TLR3(Alexopoμlou等人,Nature(2001),413:732-8);脂多糖(LPS)典型和优选激活TLR4(Poltorak,el at.Science(1998),282:2085-8);鞭毛蛋白典型和优选地激活TLR5(Hayashi等人Nature(2001),410:1099-103);单链RNA,如细菌RNA,和某些合成物质如咪唑喹啉,典型和优选地激活TLR7和TLR8(Diebold S.等人Science 303:1529;Heil,FH.et al.Science 303:1526);细菌DNA,特别是含CpG基序的DNA典型和优选地激活TLR9(Schnare等人Curr.Biol.(2000),10:1139-42;Hemmi H et al.Nature(2000),408:740-5)。这些被引用的论文这里引入作为参考。TLR配体的概述见Abreu′s综述论文表,这里也引用作为参考(Abreu M.T.and Arditi M.J.Pediatrics(2004),421-9),对TLR11及其配体的描述见Zhang等人,Science,(2004),303:1522-6。通过参考这些引用的论文,再结合本领域的公知常识,在常规操作范围内就可以检测一个分子是否是本发明所说的TLR配体,以及是否TLR配体激活至少一个TLR。典型和优选的这类检测是按下述步骤:3×106HEK293细胞在200伏和960uF条件下用1μg的TLR表达质粒和20ng NF-KB的荧光素酶受体质粒电穿孔。过量的质粒DNA通过加入适当空表达的载体,维持恒定在每次电穿孔15μg。以每孔105个细胞接种细胞,隔夜培养后用受试配体再刺激7到10个小时。已知TLR配体浓缩范围的典型例子是与DOTAP复合的25μg/ml RNA40-42(促进RNA在细胞内的内化),1μMCpG-ODN 2006,10μMR-848,50μg/ml poly(I:C)或1μg/mlPam3Cys(Heil,FH.等人Science 303:1526)。受刺激的细胞使用受体细胞溶解缓冲液溶解(Promega,Mannheim,德囯)且根据厂商说明,使用发光计分析溶胞产物的荧光素酶活性,典型和优选Berthold发光计(Wildbad,德囯)。这是本领域普通技术人员应知道对前述试验作相应调整,以检测任意配体。
根据本发明当诱导产生的荧光素酶活性在统计学上显著高于从阴性对照组测得的阈值(同样的试验、同样的试验条件,只是不加入受试配体)时,认为配体激活TLR。这里所指的阈值是阴性对照组的荧光素酶活性,阴性对照组以六个独立试验的结果加六个独立试验荧光素酶活性的三次标准差计算。典型和优选地,当配体荧光素酶活性高于如上述所测的阈值时,认为配体″统计学上显著地″激活TLR。优选地,当配体荧光素酶活性高于如上述指示所测的阈值至少两倍,优选高于三倍,更优选高于五倍时,认为配体″统计学上显著地″激活TLR。
典型和优选地,在本发明免疫刺激核酸激活TLR配体的情况下,本发明TLR配体(d)激活的TLR不同于免疫刺激核酸所激活的配体。例如,免疫刺激核酸是TLR9配体CpG,而本发明组合物的TLR配体(d),则其次级TLR配体激活的次级TLR可以是任何TLR而不是TLR9,激活如TLR1,2,3,4,5,6,7,8,10,或11。另一方面,如果免疫刺激核酸的例子是poly(I:C),TLR3配体,本发明组合物的TLR配体(d),和其次级TLR配体激活的次级TLR可以是任何TLR而不是TLR3,激活如TLR1,2,4,5,6,7,8,9,10,或11。
Toll样受体4(TLR4)配体:TLR4配体以TLR4依赖方式,向细胞内发生信号。典型和优选的例子是LPS和其衍生物,gp96,热激蛋白和防卫素。优选TLR 4配体是LPS和其衍生物如缺少脂质A尾侧链的脱毒版的LPS(Persing等人,(2002),Trends Microbiol.10(10Suppl),32-37),如MPL,单磷酰脂A和其衍生物(Johnson等人,(1999),J MedChem.42(22),4640-4649)或LPS经化学改变的和合成的类似物(Fernandes et al,(1997),34(8-9)569-576;Przetak等,(2003),21,961-970)。所有引用的参考文件这里全文引用。本发明优选的LPS衍生物,如脱毒版LPS,LPS经化学改变的和合成的类似物按本领域人员公知的方法在兔体内进行热源性测试。典型和优选地,优选的LPS衍生物在兔体内没有或没有显著的热源性测试。
自体抗原:这里所用的术语″自体抗原″指宿主基因组或DNA编码的蛋白质和按宿主基因组或DNA编码的蛋白质或RNA的产物,定义为自体。优选地,这里所用的术语″自体抗原″指按人基因组或DNA编码的蛋白质或人基因组或DNA编码的蛋白质或RNA的产物,被定义为自体。本发明组合物,药物组合物,和含自体抗原的疫苗,当用于宿主时,特别地能够打破对自体抗原的耐受性。在本文中,″打破对自体抗原的耐受性″指,特别是在将本发明的含自体抗原组合物、药物组合物、和的疫苗用于宿主时,针对自体抗原的免疫应答优选B或T细胞应答增强。此外,两个或多个自身分子组合物产生的蛋白质,或递呈自身分子的一部分蛋白质,与如上所述两个自身分子具有高度同源性的蛋白质(>95%,优选>97%,更优选>99%)也被认为自体。在本发明一个更优选的实施方式中,抗原为自体抗原。本发明可用的自体抗原更优选的实施方式在WO 02/056905有详细描述,其中所公开的内容这里全文引用作为参考。
治疗:这里所用的术语″治疗″指预防和/或治疗。当用于传染病时,例如,该术语指预防性治疗,能提高受试者对病原体传染的抵抗力,换句话,降低了受试者被病原体感染或表现出传染病病症的可能性,以及在受试者感染疾病后与感染斗争进行治疗,如减少或除去感染或阻止病情恶化。
疫苗:这里所用的术语“疫苗”指包含本发明组合物的制剂,具有可以对动物进行给药的形式。典型地,疫苗包括常规的盐水或缓冲水溶液介质,本发明的组合物混悬或溶解于其中。以这种形式,本发明的组合物能方便地用于预防、改善、或治疗疾病。在导入宿主后,疫苗能够引起免疫应答,其中包括但不限于抗体和/或细胞因子的产生和/或细胞毒性T细胞、抗原呈递细胞、辅助T细胞、树突细胞的激活和/或其它细胞应答。
任选地,本发明的疫苗还包含佐剂,相对于本发明的化合物,它可能占一小部分或大部分。这里所用的术语“佐剂”指免疫应答的非特异性刺激物,或可以在宿主中产生贮存的物质,当本发明的疫苗与该物质组合能够产生更强的免疫应答。有多种佐剂可以使用,例子包括弗式不完全佐剂、氢氧化铝、和修饰的胞壁酰二肽。
病毒样颗粒:这里所用的术语“病毒样颗粒″(VLP)指装配有病毒的结构,但并未证明有致病性。
典型地,本发明的病毒样颗粒不携带编码病毒样颗粒蛋白的遗传信息。一般而言,病毒样颗粒缺少病毒基因组,因此是非感染性的。病毒样颗粒通常也能通过异源表达大量生产,且易于纯化。某些病毒样颗粒可能含有不同于其基因组的核酸。典型地,本发明的病毒样颗粒是非复制性和非传染性的,因为它缺乏全部或部分基因组,特别是病毒基因组的复制性和感染性部分。本发明的病毒样颗粒可能含有不同于其基因组的核酸。本发明病毒样颗粒的一个典型的优选实施方案是病毒衣壳,如相应病毒、噬菌体或RNA噬菌体的病毒衣壳。术语″病毒衣壳″或″衣壳″,在此可以互换使用,指由病毒蛋白质亚单位组成的大分子装配体。典型而且优选地,病毒蛋白质亚单位分别装配为病毒衣壳和衣壳,具有固有的重复组织的结构,其中这种结构一般是球形或管状。例如,RNA噬菌体或HbcAg的衣壳是二十面体对称的球形。这里所用的术语“衣壳样结构”指由病毒蛋白质亚单位组成的大分子装配体,它类似于上述衣壳形态,但是与典型的对称装配体不同,而保持足够程度的顺序和重复性。
RNA噬菌体外壳蛋白的VLP:衣壳结构由RNA噬菌体外壳蛋白的180个亚单位自装配而成。任选地含有宿主RNA的衣壳结构,被称为“RNA噬菌体外壳蛋白的VLP″。一个具体例子是Q β外壳蛋白VLP。在此具体情况下,Q β外壳蛋白的VLP可能仅仅由Q βCP亚单位(SEQ ID NO:1)装配而成,该亚单位通过表达含有如TAA终止密码子的Q βCP基因产生,所述中止密码子通过抑制来阻止更长A1蛋白的任何表达,参见Kozlovska,T.M.et al.Intervirology 39:9-15(1996)),或者在衣壳装配体中还含有A1蛋白亚单位(SEQ ID NO:2)。通读过程的效率低,在VLP中只有极少量的A1蛋白。已经对包装的ISS与偶合的抗原的不同组合已有大量的实施例。当使用仅由QβCP亚单位装配的Q β外壳蛋白的VLP或在衣壳中还含有A1蛋白亚单位的Q β外壳蛋白VLP时,偶合效率和包装未见差异。此外,没有观察到这些QβVLP样本的免疫应答之间有差别。因此,为了更清楚,说明书实施例所用的术语″Q βVLP″不仅代表只从Q βCP亚基装配而来的Q β外壳蛋白的VLP,还代表在衣壳中含另外A1蛋白亚单位的Q β外壳蛋白的VLP。
这里所用的术语″病毒颗粒″指病毒的形态学的形状。在一些病毒类型中病毒包括被蛋白衣壳包裹的染色体;其它的则具有另外的结构(例如,膜,尾等)。
无膜病毒颗粒由包围和保护病毒染色体的蛋白质衣壳组成。有膜病毒也具有包裹病毒染色体的衣壳结构,但此外还有脂质双分子层包裹在衣壳上。
在本发明优选的实施方式中,VLP没有脂蛋白膜或含脂蛋白的膜。在更优选的实施方式中,VLP完全没有膜。
一个:当术语″一个″在公开的内容中使用时,表示″至少一个″或″一个或更多,″除非有其它指示。
本领域普通技术人员应该清楚,本发明某些实施方式涉及重组核酸技术的应用,如克隆、聚合酶链反应、DNA和RNA纯化、重组蛋白在原核细胞和真核细胞中的表达等。这类方法学的东西是本领域人员公知的,在出版的方法手册中很容易找到(例如,Sambrook,J.等人,eds.MOLECMLAR CLONING,A LABORATORY MANUAL,2nd.edition,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.(1989);Ausubel,F.等人,eds.CURRENT PROTOCOLS INMOLECMLAR BIOLOGY,John H.Wiley & Sons,Inc.(1997)).组织培养细胞系工作所需的实验室基本技术(Celis,J.ed.CELL BIOLOGY,Academic Press,2″d edition,(1998))和抗体基础知识(Harlow,E.andLane,D.″Antibodies:A Laboratory Manual,″Cold Spring HarborLaboratory,Cold Spring Harbor,N.Y.(1988);Deutscher,M.P.″Guideto Protein Purification,″Meth.Enzymol.128,Academic Press San Diego(1990);Scopes,R.K.″Protein Purification Principles and Practice,″3rded.SpringerVerlag,New York(1994))在这些著作中也得到了足够的描述,此处全部引用作为参考。
2.增强免疫应答的组合物和方法
本发明公开提供增强动物针对一种或多种抗原的免疫应答的组合物和方法。本发明的组合物包括,或可选择地由下述组成:(a)病毒样颗粒,(b)免疫刺激核酸,优选含非甲基化CpG的低聚核苷酸,其中核酸或低聚核苷酸与病毒样颗粒偶合、融合或以其它方式连接或附着如结合、优选包装,(c)至少一种与VLP偶合或结合的抗原或与VLP混合的抗原,和(d)至少一种TLR配体。优选地,TLR配体(d)与本发明的VLP(a)混合。此外,本发明很容易使执业医师构建这样一个组合物,以达到各种不同的治疗/预防目的,其中包括预防和/或治疗传染病,和慢性传染病,预防和/或治疗癌症,和预防和/或治疗变态反应或与变态反应相关的疾病,例如哮喘。
在本申请中所出现的病毒样颗粒指VLP,在WO 03/024481第39页至第59页有详细描述,其中公开的内容此处引用作为参考。VLP的例子包括但不限于,乙肝病毒,RNA噬菌体,Ty,fr-噬菌体,GA-噬菌体,AP 205-噬菌体和,特别是,Q β-噬菌体的壳蛋白。在更具体的实施方式中,VLP包括或可选择地由重组多肽或其片断片断组成或基本由其组成。在优选的实施方案中,病毒样颗粒包括,基本上由,或可选择地由RNA-噬菌体的重组蛋白或其片断组成。优选地,RNA-噬菌体选自:a)噬菌体Q β;b)噬菌体R17;c)噬菌体fr;d)噬菌体GA;e)噬菌体SP;f)噬菌体MS2;g)噬菌体M11;h)噬菌体MX1;i)噬菌体NL95;k)噬菌体f2;1)噬菌体PP7;和m)噬菌体AP205。在本发明更优选的实施方实中,重组蛋白包括,基本上由,或可选择地由RNA噬菌体外壳蛋白组成。
用于制备本发明组合物的特别优选的噬菌体外壳蛋白的例子在WO 03/024481(第41页最后第49页第二段)有详细描述,其中公开的内容此处引用作为参考,其中包括RNA噬菌体外壳蛋白,例如噬菌体Q β(PIR Database,Accession No.VCBPQ指Q βCP and AccessionNo.AAA16663指Q βAl protein),噬菌体R17(PIR Accession No.VCBPR7),噬菌体fr(PIR Accession No.VCBPFR),噬菌体GA(GenBank Accession No.NP-040754),噬菌体SP(GenBank AccessionNo.CAA30374指SP CP and Accession No.NP 695026指SP Alprotein),噬菌体MS2(PIR Accession No.VCBPM2),噬菌体M11(GenBank Accession No.AAC06250),噬菌体MX1(GenBankAccession No.AAC 14699),噬菌体NL95(GenBank Accession No.AAC 14704),噬菌体f2(GenBank Accession No.P03611),噬菌体PP7(SEQ ID NO:3),噬菌体AP205(SEQ ID NO:32or 33).
有四个赖氨酸残基暴露于Qβ外壳蛋白衣壳表面。本发明也可用精氨酸替换暴露赖氨酸残基的Q β突变体。本发明在实施中可用下列Q β外壳蛋白突变体和突变的Q βVLP:″Q β-240″(Lys13-Arg;SEQID NO:4),″Q β-243″(Asn 10-Lys;SEQ ID NO:5),″Q β-250″(Lys 2-Arg,Lys13-Arg;SEQ ID NO:6),″Q β-251″(SEQ ID NO:7)and″Q β-259″(Lys 2-Arg,Lys16-Arg;SEQ ID NO:8)。因此,在本发明进一步优选的实施方案中,病毒样颗粒包含、基本上由或可选择地由突变QB外壳蛋白重组蛋白组成。其包含具有下列氨基酸序列的蛋白质:a)氨基酸序列SEQ ID NO:4;b)氨基酸序列SEQ ID NO:5;c)氨基酸序列SEQ ID NO:6;d)氨基酸序列SEQ ID NO:7;和e)氨基酸序列SEQ ID NO:8。上述Q β外壳蛋白、突变Q β外壳蛋白VLP和衣壳的构造、表达和纯化分别在WO 02/056905中描述。
本发明还包括包含蛋白的组合物,蛋白包括,或可选择地基本由与上述序列有至少80%,85%,90%,95%,97%,或99%相同的氨基酸序列组成。VLP片断仍保留诱导免疫应答的能力,其中包括,或可选择由多肽组成,所述多肽长度约15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,110,120,130,140,150,160,170,180,190,200,250,300,350,400,450或500个氨基酸,但显然这取决于含有VLP的亚单位序列的长度。这类片断的例子包括这里所讨论的蛋白质片断,适合于制备免疫应答增强组合物。
如前所述,本发明包括病毒样颗粒或其重组形式。本领域普通技术人员知道如何制备这类颗粒和混合抗原。以提供其它实施例的方式,本发明在这里提供乙肝病毒样颗粒的制备作为制备病毒样颗粒的范例(实施例1)。
在一个实施方式中,本发明组合物所使用的颗粒由乙肝病毒衣壳(核)蛋白(HBcAg)或HbcAg片断构成,或经修饰除去或减少了游离半胱氨酸残基数量的HbcAg构成。特别优选的HbcAg蛋白的例子有,例如HBcAg SEQ ID NO:9或其变体能用于制备本发明的组合物,这在WO 03/024481(第52页第4段到第58页最后一段)中有详细描述,其中所公开的内容这里引用作为参考。本发明使用的乙肝病毒样颗粒的制备方法在WO 00/32227中已经公开,特别在实施例17至19和21至24中,在WO 01/85208也公开过,特别在实施例17至19,21至24,31至41中,而且在WO 02/056905也有公开。在后一申请中,特别是实施例23,24,31和51。这三篇文献这里都详细地引用作为参考。
大量的适合在本发明实施中使用的天然发生的HBcAg变体已经确认大量的适合在本发明实施中使用的天然发生的HBcAg变体(例如Yuan等人,(RVirol.73:10122-10128(1999))。还有的适合在本发明实施中使用的HBcAg变体在WO 03/024481(第54页第三段至第55页第一段)公开了,其中公开的内容这里引用作为参考。
本发明适用的HbcAgs衍生自任何生物体,只要它们能封装或偶合或以其它方式附着到含非甲基化CpG的低聚核苷酸,并能诱导免疫应答。
在本发明的某些实施方式中,将赖氨酸残基导入HbcAg多肽,介导抗原或抗原决定簇与HbcAg结合。在优选实施方案中,本发明组合物优选使用的HbcAg包括,或可选择地由SEQ ID NO:10的氨基酸1-144,或1-149,或1-185组成,进行修饰使对应于79位和80位的氨基酸被氨基酸序列为Gly-Gly-Lys-Gly-Gly(SEQ ID NO:34)的肽置换,使得HbcAg变异体氨基酸序列为SEQ ID NO:96.在更优选的实施方式中,SEQ ID NO:10在48位和107位的半胱氨酸残基突变为丝氨酸(SEQ ID NO:36)。本发明还包括包括对应的多肽组合物,其中多肽具有WO 03/024481(第54页第三段至第55页第一段)所示的氨基酸序列,也有上述的氨基酸更替。还包括在本发明范围内的是另外的与形成衣壳或VLP有关的氨基酸,具有上述氨基酸更替。因而,本发明还包括含HbcAg多肽的组合物,多肽中包括或可选择地由氨基酸序列组成,氨基酸序列与任何野生型氨基酸序列至少有80%,85%,90%,95%,97%或99%的同一性,如果适当,蛋白质的形态经过加工,可以除去N-末端前导序列并通过上述改造进行修饰。
本发明的一个方面,病毒样颗粒,结合了含非甲基化CpG的低聚核苷酸,与期望增强免疫应答的抗原/免疫原偶合或混合。在一些例子中,单一抗原与这类修饰后的病毒样颗粒偶合或混合。在其它例子中,这类修饰后VLP与几种抗原或甚至与复合抗原混合物偶合或混合。抗原可由重组制备或从天然来源中提取,天然来源包括但不限于花粉、粉尘、真菌、昆虫、食物、哺乳动物表皮、羽毛、蜜蜂、肿瘤、病原体和羽毛。
在本发明的一个实施方式中,加入组合物的物质包括含至少一个免疫刺激核酸,优选至少一个含非甲基化CpG的低聚核苷酸的VLP,以及与VLP偶合/融合或混合的抗原,以及至少一个TLR配体,它能够引发激活TLR,典型和优选地,本发明的免疫刺激核酸不能激活的第二个TLR。
在一个实施方式中,本发明提供了一种增强动物体内免疫应答的组合物,包括(a)病毒样颗粒(VLP),(b)免疫刺激核酸,优选含非甲基化CpG的低聚核苷酸,其中核苷酸或低聚核苷酸与病毒样颗粒偶合、融合,或者附着或封装入病毒样颗粒,优选以病毒样颗粒包装,(c)至少一种VLP偶合或融合的抗原或与VLP混合的抗原,和(d)至少一种TLR配体。优选地,TLR配体(d)与本发明的VLP(a)混合。优选地,免疫刺激核酸(b)激活的TLR与配体(d)激活的TLR不同。
TLRs被描述为模式识别分子,是免疫系统进行自身/非自身辨识的关键。目前已知十个人toll样受体。它们由各种配体激活。TLR2被肽聚糖、脂蛋白、脂多糖、脂磷壁酸,和酵母多糖激活,且被巨噬菌体激活脂肽MALP-2激活;TLR3被双链RNA如poly(I:C)激活;TLR4被脂多糖、脂磷壁酸和紫杉醇和热激蛋白如热激蛋白HSP-60,Gp96和防卫素激活;TLR5被细菌鞭毛,尤其是鞭毛蛋白激活;TLR6被肽聚糖激活;TLR7被imiquimoid和咪唑喹啉化合物激活,如R-848,loxoribine和bropirimine,TLR9被细菌DNA,特别是CpG-低聚核苷酸激活。TLR1,TLR8,TLR10,和TLR 11的配体目前还不清楚。然而,进来的研究表明相同的受体可以与不同的配体反应,且更多的受体是已有受体。上述配体列表并非穷举,且更多的配体是本领域普通技术人员所公知的。一般而言,是通过触发TLRs激活抗原呈递细胞(APC)。因而,触发TLRs可激活APCs从而增强T细胞应答。在本发明中,令人吃惊的发现不同TLRs刺激可以产生协同反应。具体地,TLR9经包装在VLP中的CpG刺激能与TLR4经LPS或其它TLR4配体刺激起协同增效作用。因而,在优选的实施方式中,对于CpG刺激的TLR9,额外TLR刺激可以是TLR4。已知各种不同的TLR4配体。包括LPS,天然的TLR4配体。此外,脱毒版的LPS,缺少如脂质A尾侧链的,也是TLR4潜在的激活剂。单磷酰脂A和其衍生物是本领域公知的。优选的衍生物是3去-氧-酰单磷酰脂A,,在British Patent No.2220211中公开。不管其刺激TLR4的能力如何,这些非天然配体相对无毒,因此优选用作疫苗中刺激TLR4的物质(CurrDrμg Targets Infect Disord.2001 Nov;1(3):273-86.)。近来,TLR配体家族已经扩大到包括热激蛋白(J Biol Chem.2002 Apr 26;277(17):15107-12.)和防卫素(Science.2002 Nov 1;298(5595):1025-9.)。因此,防卫素和热激蛋白也在本发明的范围内。
在一个实施方式中,本发明组合物所用的免疫刺激核酸选自:(a)核糖核酸;(b)脱氧核糖核酸,(c)嵌合核酸;和(d)(a),(b)和/或(c)中至少一种的任意混合物。在一个优选的实施方案中,本发明的免疫刺激核酸是poly-(I:C)。在另一个实施方式中,免疫刺激核酸选自(a)含非甲基化CpG的低聚核苷酸;和(b)不含非甲基化CpG基序的低聚核苷酸,本发明的免疫刺激核酸优选含非甲基化CpG的低聚核苷酸。
两类核酸,换句话说,1)含免疫刺激序列特别是含于特定侧翼碱基之内(指CpG基序)的非甲基化CpG二核苷酸的细菌DNA,和2)由各种类型的病毒合成的双链RNA,代表了增强免疫应答的微生物组分的重要成员。合成的双链(ds)RNA如聚肌苷-聚胞苷酸(poly I:C)能诱导树突细胞产生趋炎症细胞因子(proinflammatory)并表达高水平的联合刺激分子。
Tokunaga和Yamamoto等人所进行的一系列的研究显示细菌DNA或合成低聚脱氧核苷酸诱导人PBMC和小鼠脾细胞产生I型干扰素(IFN)(综述在Yamamoto等人,Springer Semin Immunopathol.22:11-19)。poly(I:C)最初合成作为潜在的I型IFN诱导剂,但也诱导其它细胞因子如IL-12。
优选的核糖核酸包括聚肌苷-聚胞苷酸双链RNA(poly I:C)。核糖核酸和其修饰物以及它们的制备方法已经被Levy,H.B(MethodsEnzymol.1981,78:242-251),DeClercq,E(Methods Enzymol.1981,78:227-236)和Torrence,P.F.(Methods Enzymol1981;78:326-331)和其中的参考文献公开。更优选的核糖核酸包括肌苷酸和胞苷酸,如其中两条链形式的双链RNApoly(IC),的多核苷酸。核糖核酸分离自生物体。核糖核酸也包括合成的核糖核酸,特别是合成的poly(I:C)低聚核苷酸,通过磷酸二酯主链的修饰,特别是硫代磷酸修饰,引起了核酸酶抵抗性。在更优选的实施方式中,poly(I:C)的核糖主链被脱氧核糖取代。本领域普通技术人员知道如何合成人造低聚核苷酸的方法。
一般来说,含非甲基化CpG的低聚核苷酸包括序列:
5′X1X2CGX3X43′
其中X1,X2,X3和X4是任意核苷酸。此外,低聚核苷酸包括约6个至约100,000个核苷酸,优选约6个至约2000个核苷酸,更优选约20至约2000个核苷酸,而且甚至更优选地包括约20至约300个核苷酸。此外,低聚核苷酸包括超过100至约2000个核苷酸,优选超过100至约1000个核苷酸,而且更优选超过100至约500个核苷酸。
在优选的实施方式中,含CpG的低聚核苷酸含有一个或多个磷酸主链的硫代磷酸修饰物。例如有一个或多个磷酸主链修饰或所有的磷酸主链经修饰的含CpG的低聚核苷酸,和其中一个、一些或全部核酸磷酸主链修饰是硫代磷酸修饰,都在本发明的范围内。
含CpG的低聚核苷酸可以是重组的、基因组的、合成的、cDNA的、质粒衍生的、单链的或双链的。为了在本发明中立即使用,核酸可以重新使用本领域公知的任意步骤的工艺来合成。例如b-氰乙基磷酰胺化方法(Beaucage,S.L.和Caruthers,M.H.Tet.Let.22:1859(1981);核苷H-磷酸盐方法(Garegg等人,Tet.Let.27:4051-4054(1986);Froehler等人,Nucl.Acid.Res.14:5399-5407(1986);Garegg等人,Tet.Let.27:4055-4058(1986),Gaffney等人,Tet.Let.29:2619-2622(1988)).这些化学方法可通过各种不同的市售自动低聚核苷酸合成器来完成。可选择地,CpG可以质粒中大量生产,(参见Sambrook,T.等人,″Molecμlar Cloning:A Laboratory Manual,″ColdSpring Harbor laboratory Press,New York,1989)给予受试者降解为低聚核苷酸。低聚核苷酸通过使用公知技术从现有核酸序列中制得(例如,基因组的或cDNA),如使用限制酶,外切核酸酶和内切核酸酶。
免疫刺激核酸以及含非甲基化CpG的低聚核苷酸可以通过任何本领域公知的方法与VLP结合,提供给予受试者后增强动物体内免疫应答的组合物。例如低聚核苷酸共价键或非共价键结合。此外,VLP可以封装全部地或部分地,免疫刺激核酸以及含非甲基化CpG的低聚核苷酸。优选地,免疫刺激核酸以及含非甲基化CpG的低聚核苷酸与一个VLP结合的位点如低聚核苷酸结合点(天然或是非天然发生的),DNA结合点或RNA结合点结合。在另一个实施方式中,VLP位点包括富含精氨酸重复序列或富含赖氨酸重复序列。将本发明的免疫刺激核酸包装入本发明VLP的方法,例如装入HBcAg,RNA-噬菌体Q β或AP205,是本领域人员公知的,在WO 03/024481已公开(特别是在实施例11到17),其中所公开的内容这里引用作为参考。
本发明组合物一个特殊的用途是激活树突细胞,以增强针对抗原的特异性免疫应答。树突细胞使用来自体内或体内技术增强。来自体内工艺可使用自体同源的或异种细胞,但是优选使用自体同源的细胞。在更优选的实施方式中,树突细胞分离自外周血或骨髓,但也能分离自任何树突细胞来源。为了癌症免疫疗法进行的树突细胞来自体内操作已经在多篇本领域的文献中公开,包括Engleman,E.G.Cytotechnology25:1(1997);Van Schooten,W.等人,MolecμlarMedicine Today,June,255(1997);Steinman,R.M.ExperimentalHematology24:849(1996);和Gluckman,J.C.Cytokines,Cellμlar和Molecμlar Therapy 3:187(1997)。树突细胞可通过体内方法与本发明的组合物接触。为了实现这一目标,CpG与和抗原偶合或混合的VLP联合给药,另外的TLR配体直接加入给予需要免疫疗法的受试者。在一些实施方式中,优选VLP/CpG被施用于肿瘤局部域,可以用本领域已知的任何方法完成,例如直接注射入肿瘤内。
在本发明一个更为优选的实施方式中,含非甲基化CpG的聚核苷酸包括,或可选择地基本上由,或可选择地由,序列GGGGGGGGGGGACGATCGTCGGGGGGGGGG(SEQ ID NO:54)组成。后者之前被发现在体外能刺激血细胞(Kuramoto E.等人,JapaneseJournal Cancer Research 83,1128-1131(1992).
在另一个本发明优选的实施方式中,免疫刺激核酸是含非甲基化CpG的低聚核苷酸,其中所述非甲基化CpG低聚核苷酸的CpG基序是回文序列的一部分。优选的所述回文序列是GACGATCGTC(SEQID NO:39)。在另一个更优选的实施方式中,回文序列在其3′末端和5′末端侧翼连接至少10个鸟嘌呤核苷体,其中所述回文序列优选GACGATCGTC(SEQ ID NO:39)。在一个更优选的实施方式中,回文序列在其N末端侧翼连接至少3个和至多9个鸟嘌呤核苷体,且其中所述回文序列在其C末端侧翼连接至少6个和至多9个鸟嘌呤核苷体。出人意料地发现这些本发明的免疫刺激核酸能高效地装入VLP。相对于相应的其序列GACGATCGTC(SEQ ID NO:39)在5′和3′末端侧翼连接10个乌嘌呤核苷体的免疫刺激核酸,其包装能力得到了增强。
在本发明优选的实施方式中,回文序列包括,或可选择地基本上由,或可选择地由或就是GACGATCGTC(SEQ ID NO:39),其中所述回文序列在其5′末端侧翼连接有至少3个和至多9个鸟嘌呤核苷体,其中所述回文序列在其3′末端侧翼连接有至少6个和至多9个鸟嘌呤核苷体。
在本发明更优选的实施方式中,免疫刺激核酸是含非甲基化CpG的低聚核苷酸,其中所述非甲基化CpG的低聚核苷酸的CpG基序是回文序列的一部分,其中所述非甲基化CpG的低聚核苷酸的核酸序列选自:(a)GGGGACGATCGTCGGGGGG((SEQ ID NO:40);和典型地简化为G3-6),(b)GGGGGACGATCGTCGGGGGG((SEQ ID NO:41);典型地简化为G4-6),(c)GGGGGGACGATCGTCGGGGGG((SEQID NO:42);典型地简化为G5-6),(d)GGGGGGGACGATCGTCGGGGGG((SEQ ID NO:43);典型地简化为G6-6),(e)GGGGGGGGACGATCGTCGGGGGGG((SEQ ID NO:44);典型地简化为G7-7),(f)GGGGGGGGGACGATCGTCGGGGGGGG((SEQ ID NO:45);典型地简化为G8-8),(g)GGGGGGGGGGACGATCGTCGGGGGGGGG((SEQ ID NO:46);典型地简化为G9-9),和(h)GGGGGGCGACGACGATCGTCGTCGGGGGGG((SEQ ID NO:47);典型地简化为G6).
在本发明更为优选的实施方案中,免疫刺激核酸含非甲基化CpG的低聚核苷酸,其中所属含非甲基化CpG的低聚核苷酸的CpG基序是回文序列的一部分,其中所述回文序列为GACGATCGTC(SEQ IDNO:39),且所述回文序列在其5′末端侧翼连接至少4个,最多9个鸟嘌呤核苷体,其中述回文序列在其3′-末端侧翼连接至少6个,最多9个鸟嘌呤核苷体。
在本发明更优选的实施方式中,免疫刺激核酸是含非甲基化CpG的低聚核苷酸,其中所述含非甲基化CpG的低聚核苷酸的CpG基序是回文序列的一部分,其中所述回文序列为GACGATCGTC(SEQ IDNO:39),且所述回文序列在其5′末端侧翼连接至少5个,最多8个鸟嘌呤核苷体,且所述回文序列在其3′末端侧翼连接至少6个,最多8个鸟嘌呤核苷体。
试验数据表明优选的本发明免疫刺激核酸易于包装,也就是说,侧翼连接回文序列鸟嘌呤核苷,回文的和含非甲基化CpG的低聚核苷酸,其中回文序列为GACGATCGTC(SEQ ID NO:39),且其中回文序列在其3′和5′末端侧翼连接少于少10个鸟嘌呤核苷体,如果回文序列侧翼连接较少的鸟嘌呤核苷体,则更容易进入VLP侧翼连接于回文序列的鸟嘌呤核苷体数目降低导致在体外对血细胞的刺激下降。因而,包装能力的代价是降低本发明所指免疫刺激核酸的活性。优选的实施方式表现为包装能力和生物活性的折中。
在本发明更优选的实施方式中,免疫刺激核酸为含非甲基化CpG的低聚核苷酸,其中所述含非甲基化CpG的低聚核苷酸CpG基序是回文序列的一部分,其中所属非甲基化具有核酸序列SEQ ID NO:45,也就是说免疫刺激核酸是G8-8。
在本发明特定的一个优选实施方式中,组合物包括(a)VLP,(b)至少一种免疫刺激核酸,(c)至少一种抗原,和(d)至少一种TLR配体,其中所述免疫刺激核酸(b)是含非甲基化CpG的低聚核苷酸,且其中所述配体(d)是TLR 1,2,3,4,5,6,7,8,10或11的配体,其中所述TLR配体激活至少一种选自TLR 1,2,3,4,5,6,7,8,10和11。
在本发明更优选的一个特定实施方式中,组合物包括(a)VLP,(b)至少一种免疫刺激核酸,(c)至少一种抗原,和(d)至少一种TLR配体,其中所述免疫刺激核酸(b)是poly(I:C),且其中所述配体(d)是TLR1,2,4,5,6,7,8,10或11的配体,其中所述TLR配体激活至少一种选自TLR 1,2,4,5,6,7,8,10和11。
本发明组合物还包括与修饰的病毒样颗粒混合或偶合的抗原或抗原决定簇。本发明提供的组合物根据考虑预期治疗效应而选择的抗原和抗原决定簇来变化。本发明适用的抗原或抗原决定簇在WO00/32227、WO01/85208和在WO 02/056905中已经公开,所公开的内容这里全文引用以作参考。
抗原可以是任何已知和未知来源的抗原。可以分离自细菌;病毒或其它病原体;肿瘤;或树、草、野草、植物、真菌、食物、或动物,在敏感患者中可引起变态反应。可选择地,抗原也可以是重组抗原,得自适当核酸编码的表达。在优选的实施方式中,抗原是重组抗原。当然,抗原的选择依赖于预期的免疫应答和宿主。
本发明可适用于多种抗原。在优选的实施方式中,抗原为蛋白质、多肽或肽。
本发明的抗原选自:(a)适合诱导针对癌细胞的免疫应答的多肽;(b)适合诱导针对传染病的免疫应答的多肽;(c)适合诱导针对变态反应原的免疫应答的多肽;(d)适合在饲养动物或昆虫体内诱导免疫应答的多肽;(e)多肽上天然出现的碳水化合物,和(f)(a)-(e)中任意多肽的片断(例如,域)。
优选的抗原包括来自病原体(例如病毒、细菌、寄生虫、真菌),肿瘤(尤其是与肿瘤相关的抗原或“肿瘤标记”)和变态反应原。
其它优选的抗原分别是自身抗原和自体抗原。
在一些例子中,使用含肽p33的VLP。应该注意的是含肽p33的VLP仅仅是为了方便而使用,野生型VLP也同样可用于本发明。肽p33衍生自淋巴脉络丛脑炎病毒(LCMV)。p33肽代表一种深入研究的CTL表位。p33-特异性T细胞已经显示诱导转基因小鼠产生致死糖尿病(Speiser等人,J.Exp.Med.186:645(1997))。因此,这种特异性表位,特别适合于研究自身免疫、肿瘤免疫和病毒性疾病。
在本发明一个具体实施方式中,抗原或抗原决定簇可用于传染病的预防。这类治疗对多种对宿主影响广泛的传染病很有效,宿主例如人、奶牛、绵羊、猪、狗、猫、其他哺乳动物种类和非哺乳动物种类。本领域已知的传染病的例子中包括病毒病源性的传染病,例如HIV,流感,疱疹,病毒性肝炎,EB病毒,脊髓灰质炎,病毒性脑炎,麻疹,鸡瘟,乳头状瘤病毒等;细菌病原性传染病如肺炎,肺结核,梅毒等;或寄生虫病源性传染病,如疟疾、锥虫病、利什曼病、滴虫病、阿米巴病等。因而本发明组合物所选的抗原或抗原决定簇是医学领域所公知的,抗原或抗原决定簇的例子包括下述:HIV抗原gpl40和gpl60;流行性感冒抗原血细胞凝集素,M2蛋白和神经氨酸酶,乙肝病毒表面或核心抗原或疟疾环子孢子蛋白或其片断。
如上所述,抗原包括天然来源或合成的传染性微生物如病毒、细菌和真菌和其片断。
传染性微生物如病毒的例子有RNA病毒,或例如在脊椎动物体内作为抗原的DNA病毒,用于本发明组合物的病毒在WO 03/024481(特别是第86到89页)有详细描述,其中公开的内容这里引用作为参考。
在本发明的具体实施方式中,抗原包括一种或多种细胞毒性T细胞表位,Th细胞表位,或细胞毒性T细胞和Th细胞表位的组合。
增强人体内抗原特异性免疫应答之外,优选实施方式的方法特别适用于治疗其它哺乳动物或动物,例如鸟类如母鸡、小鸡、火鸡、鸭子、鹅、鹌鹑和野鸡。鸟类是各种传染病的易感目标。其它用于本发明组合物的抗原的例子在WO 03/024481(第90至93页)中公开。
本发明另一方面提供了疫苗组合物,适用于预防和/或减轻因“自身”基因产物引起或加剧的疾病或病情的方法。(例如肿瘤坏死因子)。因而,本发明的疫苗组合物包括产生抗体的组合物,预防和/或减轻因“自身”基因产物引起或加剧的疾病或病情。这类疾病或病情的例子包括移植物抗宿主疾病,IgE-介导的变态反应,过敏反应,成人呼吸窘迫综合症,Crohn′s病,过敏性哮喘,急性淋巴细胞白血病(ALL),非何杰金氏淋巴瘤(NHL),葛雷夫斯氏病,系统性红斑狼疮(SLE),自体免疫炎症,重症肌无力,免疫增生性淋巴结病(IPL),血管免疫增生性淋巴结病(AIL),免疫母细胞淋巴结病(IBL),风湿性关节炎,糖尿病,多发性硬化症,阿尔茨海默氏症和骨质疏松症。
在相关的特定实施例中,本发明的组合物是一种免疫治疗剂,能用于变应性、癌症或毒瘾的治疗和/或预防。
医学领域治疗这类疾病的人应该知道如何选择组合物制备和在治疗变态反应的方法中所用到的抗原或抗原决定簇。这类抗原或抗原决定簇的例子分别为下述:蜂毒磷脂酶A2;Amba1(豕草花粉变态反应原),BetvI(桦树花粉变态反应原);5Dol mV(白面大黄蜂毒变态反应原);Derp1,Derf2和Der2(室内尘螨变态反应原);Lep d2(尘螨变态反应原);Alt a1,Aspf1,和Aspf 16(真菌变态反应原);Ara h1,Arah2,和Ara h3(花生变态反应原)及其各自的片断,能引起免疫应答。此外,本发明在使用分离自生物体或部分生物体的变态反应原混合物,如花粉提取物或蜂毒时特别有效。
在优选的实施方式中,花粉提取物包括或可选择地由树、草、杂草和公园植物组成。花粉提取物的例子包括但不限于下述:金合欢、桤木(灰色)、杏仁、苹果树、杏树、侧柏、岑树、白杨、月桂、山毛榉、桦树(春),桦树(白),红千层,羽叶槭,角豆树、雪松,包括但不限于日本柳杉、樱桃、栗树、三叶杨、柏树、接骨木、榆树(美洲)、桉树、冷杉、朴树、榛子树、铁杉、山核桃树、霍布叶铁木、铁木、刺柏、洋槐、槭树、白千层、牡豆树、山梅花、桑树、橡树(白橡)、橄榄树、桔树、桑橙树、假紫荆、桃树、梨树、美洲山核桃树、胡椒树、松树、李树、杨树、女贞、红杉、沙枣、云杉、香枫、小无花果树、美洲落叶松、臭椿、胡桃和柳树。菁草花粉提取物的例子包括但不限于:百喜草、大麦、山毛榉、剪股颖、狗牙草、早熟禾(草地早熟禾)、雀麦草、从生草、草芦、雀麦草(chess)、玉米、羊茅(牛尾草)、格兰马草、蒋森草、六月草、koeler’s、燕麦、鸭茅、偃麦草、小槺草、黑麦草(多年生草本)、盐草、高粱、苏丹草、甜欧洲香草、梯牧草、绒毛剪股颖、小麦和冰草。野草和园林植物的例子包括但不限于:紫花苜蓿、苋属植物、紫菀、凤仙花根、雾冰藜、beach bur、金雀花、burrow bush、careless weed、蓖麻子、chamise、三叶草、苍耳、金鸡菊、大波斯菊、水仙花、雏菊、蒲公英、酸模、臭甘菊、柳兰、唐菖蒲、一枝黄花、肉叶刺茎藜、大麻、忍冬、蛇麻草、iodonebush、总状花藜、地肤、藜、百合、金盏花、marshelder、土荆芥、艾属植物、芥菜、荨麻、pickleweed、苋、车前草(英囯)、罂粟、povertyweed、大滨藜、豕草(三裂叶豕草)、豕草(短豕草)、豕草(西方豕草)、玫瑰、俄罗斯蓟、三齿蒿、滨藜、鳞苞、苏格兰金雀花、seablight、酸模、金鱼草、甜菜、向日葵、western waterhemp、winterfat、美洲土荆芥。
在优选的实施方式中,花粉提取物包括,或可选择地由黑麦组成。
豕草花粉的季节性出现在(9-10月),在许多个体中诱导哮喘(Marshall,J.et al.J.Allergy Clin.Immunol.108:191-197(2001))。哮喘的特征在于肺部炎症、可逆性气流堵塞和呼吸道高反应性。对空气变应原的复杂免疫应答级联导致呼吸道中白细胞的募集。具体而言,淋巴细胞、巨噬细胞、嗜酸性粒细胞、嗜中性粒细胞、浆细胞和肥大细胞浸润支气管粘膜(Redman,T.等人,Exp.Lung Res.27:433-451(2001))。嗜酸性粒细胞的募集与TH2细胞因子IL-4和IL-5的产生增加有关,这两种细胞因子是引起慢性炎症过程的哮喘发病机制的关键因子(Justice,J.等人,Am.J.Physiol.Lung Cell Mol.Physiol.282:L302-L309(2002),其中全部内容引入作为参考)。短豕草(Ambrosiaartemisiifolia)中的免疫显性变应原是Amba1(Santeliz,J.etal.JAllergy Clin.Immunol.109:455-462(2002))。在本发明的一个具体实施方式中,组合物含有与病毒样颗粒混合的Amba1。
在另一个优选的实施方式中,粉尘提取物包括或可选择地由室内粉尘和尘螨组成。室内粉尘的例子包括但不限于:室内粉尘、褥垫粉尘和装修粉尘、尘螨的例子包括但不限于美洲尘螨(D.farniae),欧洲尘螨(D.ptreronysiinus),尘螨混合物和害嗜鳞螨(L.destructor)。粉尘提取物包括但不限于雪松和红松粉尘、轧棉机粉尘、栎木屑、谷物(谷仓)屑、紫檀木屑和木屑
尘螨是气候湿润的发达囯家中室内长期变应原的一个重要来源(Arlian,L.Current Allergy and Asthma ReportsL581-586(2001)).所有变应性支气管哮喘病患者中约有60-85%对室内尘螨欧洲尘螨过敏(Arlian,L.Current Allergy and Asthma Reports 1:581-586(2001))。免疫显性欧洲尘螨变应原包括Der p1,Der f2,和Der2(Kircher,M.etal.J.Allergy Clin.Immunol.109:517-523(2002)and Clarke,A.et al.Int.Arch.Allergy Immunol.120:126-134(1999),其中全部内容这里引用作为参考)。在本发明具体的实施方案中,组合物包括Der p1,Der f2,Der2,或其片断,或其与病毒样颗粒偶合或混合的抗原混合物。特别是在农村,粉尘变态反应的一个重要成因是害嗜鳞螨(Ericksson,T.等人,Clinical and Exp.Allergy 31:1181-1890(2001))。一种免疫显性害嗜鳞螨变态反应原是Lep d2(Ericksson,T.等人,Clinical and Exp.Allergy 31:1181-1890(2001))。在本发明的一个具体实施方式中,组合物含有与病毒样颗粒偶合或混合的Lep d2。
在优选的实施方式中,真菌提取物包括或由下列成分组成:链格孢属、曲霉属、葡萄孢属、假丝酵母属、头孢属、复端孢属、毛壳属、支孢属、隐球酵母属、弯孢属、附球菌属、表皮癣菌属、镰孢属、麻孢壳属、地霉属、粘帚属、长蠕孢属、单孢枝霉属、小孢霉属、毛霉属、疣孢霉属、黑孢属、拟青霉属、青霉属、茎点霉属、芽霉属、根霉属、红酵母属、锈菌、酵母属、黑粉菌、椎枝孢属、匍柄霉属、木霉属、发癣菌属和轮枝孢属。
在美国,链格孢(Alternaria alternata)被认为是引起变应性疾病的最重要的真菌之一,在美国和澳大利亚的沙漠地区,链格孢属是主要的哮喘相关变应原,在美国中西部地区已经报道可引起严重呼吸停止和死亡(Vailes,L.等人,J.Allergy Clin.Immunol.107:641(2001)和Shampain,M.等人,Am.Rev.Respir.Dis.126:493-498(1982),其中全部内容引用作为参考)。免疫显性链格孢抗原是Alt a1(Vailes,L.等人,J.Allergy Clin.Immunol.107:641(2001))。超过80%的链格孢致敏的个体都含有抗Alta的IgE抗体(2001))。在本发明一个具体的实施方式中,该组合物含有与病毒样颗粒混合或偶合的Alta1。
另一种机会性致病真菌是烟曲霉(Aspergillus fumigatus),它与多种肺病有关,包括过敏性哮喘。免疫显性烟曲霉抗原包括Aspf1和Aspf 16(Vailes,L.等,J.Allergy Clin.Immunol.107:641(2001))。在本发明的一个具体实施方式中,组合物包括Aspf1或Aspf16或者是其与病毒样颗粒偶联或混合的抗原性混合物。
在另一个优选的实施方式中,昆虫提取物包括,或可选择地由整个虫体都能诱导变态反应的有刺昆虫组成,有刺昆虫的毒液蛋白诱导变态反应,昆虫诱导吸入的变态反应。整个虫体诱导变态反应的有刺昆虫包括,但不限于:蚂蚁(黑)、蚂蚁(红)、杂交蚂蚁(黑/红)、蚂蚁(火)。毒液蛋白诱导变态反应的有刺昆虫的例子包括,但不限于:蜜蜂、大黄蜂、黄蜂、小黄蜂、白面黄蜂和杂交黄蜂。诱导吸气变态反应的昆虫的例子包括,但不限于蚜虫、黑蝇、蝴蝶、石蛾、蝉/蝗虫、蟋蟀、蟑螂、水蚤、鹿虻、果蝇、蜜蜂(全身)、马虱、家蝇、叶蝉、蜉蝣、墨西哥豆象鼻虫、螨(尘)、蚊子、蛾、蘑菇蝇、幼蝇、母猪虫、蜘蛛和水蚤。
在另一个优选的实施方式中,食品提取物包括,或由其组成,但不限于动物产品和植物产品。动物产品的例子包括但不限于:鹿、牛、鸡、鸭子、蛋(鸡)、鱼、山羊、鹅、小羊、奶(奶牛)、奶(山羊)猪肉、兔、贝类和火鸡。植物产品的例子包括,但不限于:苹果、杏、竹芋、朝鲜蓟、芦笋、avodaco、香蕉、豆、甜菜、浆果、卷心菜类、胡萝卜、旱芹、樱桃、巧克力、柑橘类、椰子、咖啡、黄瓜、枣椰子、茄子、谷物、葡萄、绿色植物、树胶、啤酒花、莴苣、麦芽、芒果、甜瓜、蘑菇、坚果、黄秋葵、橄榄、洋葱、番木瓜、欧洲防风草、豌豆、花生、梨子、西班牙甘椒、凤梨、李子、土豆、梅干、南瓜、萝卜、大黄、香料/调味品、菠菜、果汁、木薯粉、茶、西红柿、西瓜和酵母。
两种主要的变应原性花生蛋白,其被95%的患者通过花生变态反应识别,是Ara h1和Ara h2(Bannon,G.等人,Int.Arch.AllergyImmunol.124:70-72(2001)和Li,X.等人,J.AllergyClin.Immunol.106:150-158(2000)),其全部内容此处引用作为参考)。Ara h3被约45%的花生变态反应患者识别。在一个具体的实施方案中,组合物包括与病毒样颗粒偶合或混合的抗原Ara h1、Ara h2或Ara h3或其抗原混合物。
在另一个优选的实施方式中,哺乳动物表皮变应原包括但不限于:骆驼、猫的毛发、猫的毛皮、灰鼠毛皮、牛、鹿、狗、沙鼠、山羊、豚鼠、仓鼠、猪、马、马海毛、猴、小鼠、兔、羊毛(绵羊)、在另外一个优选的实施方式中,羽毛包括但不限于:金丝雀、鸡、鸭、鹅、鹦鹉、鸽子、火鸡,在另一个优选的实施方式中,其它吸入物包括但不限于:阿拉伯胶、藻类、蓖麻子、棉绒、棉籽、鱼藤根、蕨类孢子、谷粒尘、大麻纤维、指甲花、亚麻籽、胍尔胶、黄麻、刺梧桐树胶、木棉、皮革、石松、鸢尾根、除虫菊、丝(生丝)、剑麻、烟叶、黄耆胶和木屑。
在另一个优选的实施方式中,典型地包括从天然来源纯化的或重组表达的限定的哺乳动物反应原。包括但不限于来自猫的Fel d1,Feld3(半胱氨酸蛋白酶抑制剂)和来自猫、骆驼、灰鼠毛皮、牛、鹿、狗、沙鼠、山羊、豚鼠、仓鼠、猪、马、马海毛、猴、小鼠、羊毛的白蛋白。
医学领域的技术人员在治疗这类疾病时应知道如何为治疗癌症的组合物和方法选择抗原或抗原决定簇(参见Renkvist等人,Cancer.Immunol.Immunother.50:3-15(2001)这里引用作为参考),这些抗原或抗原决定簇包括于本发明的范围内,这类抗原或抗原决定簇的代表性例子包括:Her2(乳腺癌);GD2(神经母细胞瘤);EGF-R(恶性胶质母细胞瘤);CEA(甲状腺髓样癌);CD52(白血病);人黑素瘤蛋白gplOO;人黑素瘤蛋白gplOO表位,如氨基酸154-162(序列:KTWGQYWQV,SEQ ID NO:14)、209-217(ITDQVPFSV,SEQ ID NO:15)、280-288(YLEPGPVTA,SEQ ID NO:16),457-466(LLDGTATLRL,SEQ ID NO:17)和476-485(VLYRYGSFSV,SEQ IDNO:18);人黑素瘤蛋白melan-A/MART-1;人黑素瘤蛋白melan-A/MART-1表位,如氨基酸26-35(EAAGIGILTV)(SEQ ID NO:37),26-35AL(ELAGIGICTV,SEQ ID NO:38),27-35(AAGIGILTV,SEQID NO:19)和32-40(ILTVILGVL,SEQ ID NO:20);酪氨酸酶和酪氨酸酶相关蛋白(例如,TRP-1和TRP-2);酪氨酸酶表位,如氨基酸1-9(MLLAVLYCL,SEQ ID NO:21)和368-376(YMDGTMSQV,SEQ IDNO:22);NA17-A nt蛋白;NA17-A nt蛋白表位如氨基酸38-64(VLPDVFIRC,SEQ ID NO:23);MAGE-3蛋白;MAGE-3蛋白表位如氨基酸271-279(FLWGPRALV,SEQ ID NO:24);其它人肿瘤抗原,例如CEA表位如氨基酸571-579(YLSGANLNL,SEQ ID NO:25);p53蛋白;p53蛋白表位如氨基酸65-73(RMPEAAPPV,SEQ ID NO:26),149-157(STPPPGTRV,SEQ ID NO:27)和264-272(LLGRNSFEV,SEQ ID NO:28);Her2/neu表位如氨基酸369-377(KIFGSLAFL,SEQID NO:29)和654-662(IISAVVGIL,SEQ ID NO:30);HPV16E7蛋白;HPV16E7蛋白表位如氨基酸86-93(TLGIVCPI,SEQ ID NO:31);以及能够用来引发免疫应答的各自的片断或突变体。
医学领域的技术人员在治疗这类疾病时应当知道如何为治疗其它自身抗原相关疾病的组合物和方法选择抗原或抗原决定簇。这类抗原或抗原决定簇的代表性例子包括,例如:淋巴毒素(例如淋巴毒素α(LTα),淋巴毒素β(LT(β)),和淋巴毒素受体,核因子kappaB受体激活剂(RANKL),破骨细胞相关受体(OSCAR),血管内皮生长因子(VEGF)和血管内皮生长因子受体(VEGF-R),白介素17和淀粉样β肽A β1-42,TNFα,MIF,MCP-1,SDF-1,Rank-L,M-CSF,血管紧张肽原,血管紧张素I,血管紧张素II,Endoglin,嗜酸细胞活化趋化因子(Eotaxin),Grehlin,BLC,CCL21,IL-13,IL-17,IL-5,IL-8,IL-15,缓激肽,抵抗素,LHRH,GHRH,GIH,CRH,TRH和胃泌素,以及能用于引发免疫应答的各自的片断。
在本发明的一个特定实施方案中,抗原和抗原决定簇选自:(a)HIV的重组多肽;(b)流行性感冒病毒的重组多肽(例如,流行性感冒病毒M2多肽或其片断);(c)丙肝病毒的重组多肽;(d)乙肝病毒的重组多肽;(e)弓形体重组多肽;(f)恶性疟原虫(Plasmodium falciparum)重组多肽;(g)间日疟原虫(Plasmodium vivax)重组多肽;(h)Plasmodiumovale重组多肽;(i)Plasmodium malariae重组多肽;(j)乳腺癌细胞重组多肽;(k)肾癌细胞重组多肽;(1)前列腺癌细胞重组多肽;(m)皮肤癌细胞重组多肽;(n)脑癌细胞重组多肽;(o)白血病细胞重组多肽;(p)arecombinant profiling;(q)蜂针变态反应重组多肽;(r)坚果变态反应重组多肽;(s)花粉重组多肽;(t)室内粉尘重组多肽;(u)猫或猫毛发变态反应重组多肽;(v)食物变态反应重组蛋白;(w)哮喘重组蛋白;(x)衣原体重组蛋白;(y)提取自(a-x)中任意蛋白来源的抗原;和(z)(a)-(x)中任意蛋白的片断。
在本发明的另一个实施方式中,与包装了免疫刺激性核酸或含非甲基化CpG的低聚核苷酸的本发明病毒样颗粒偶合或混合的抗原是T细胞表位,它是细胞毒性表位或Th细胞表位。在本发明的另一个实施方案中,与包装了免疫刺激性核酸或含非甲基化CpG的低聚核苷酸的本发明病毒样颗粒偶合或混合的抗原是B细胞表位,在更为优选的实施方式中,抗原至少是两种、优选地不同表位的组合物,其中至少两种表位直接链接或通过连接序列连接。这些表位优选地选自细胞毒性表位和Th细胞表位。
本发明的抗原,特别是所述表位可以被合成或重组表达,并且与病毒样颗粒偶合,或利用重组DNA技术与病毒颗粒融合。抗原与病毒样颗粒的示范性连接方法在WO 00/32227,WO01/85208和WO02/056905中公开,其中公开的内容在此引用作为参考。,
本发明也提供一种用于预防和/或减轻病情的疫苗组合物。本发明的疫苗组合物包括,或可选择地由免疫有销量的本发明免疫增强组合物和药学上可接受的稀释剂、载体或赋形剂组成。
本发明还提供一种用于预防和/或减轻动物病情的接种疫苗的方法。在本发明的一个实施方式中,本发明提供防止多种动物传染病的方法,特别是哺乳动物如人、猴、奶牛、狗、猫、马、猪等。疫苗可设计用于治疗各种病毒所致的传染病,如HIV,流感,疱疹,病毒性肝炎,EB病毒,脊髓灰质炎,病毒性脑炎,麻疹,鸡瘟等;细菌病原性传染病如肺炎,肺结核,梅毒等;或寄生虫病源性传染病,如疟疾、锥虫病、利什曼病、滴虫病、阿米巴病等。
在另一个实施方式中,本发明提供了预防各种癌症的疫苗,特别是预防哺乳动物如人、猴子、奶牛、狗、猫、马、猪等。疫苗可设计用于治疗各种类型的癌症,包括但不限于淋巴瘤、癌症、肉瘤、黑色素瘤。
本领域普通技术人员应当理解,当对动物施用本发明的组合物时,该组合物可以含有盐、缓冲液、佐剂或希望用来提高组合物效力的其它物质,在大量资料中提出了适于制备药用组合物的材料的例子,包括REMINGTON′SPHARMACEUTICAL SCIENCES(Osol,A,编著,Mack Publishing Co.(1990))。
本发明组合物是接受者个体在给药时可以耐受的则称为″药学上可接受的″。此外,本发明组合物给药是以″治疗有效量″(也就是说,足以产生预期药效的剂量)。
本发明组合物可以通过本领域公知的各种方式给药。具体选定的模式取决于病程,对于特定的所选组合物,取决于所治疗病情的严重程度和有效治疗所需的剂量。一般来说,本发明的方法可以用医学上可以接受的任何给药方式即任何可以产生活性化合物的有效水平而不引起临床上不可接受的副反应,包括口服、直肠、非胃肠道、脑池内、阴道内、腹膜内、局部(通过粉末、软膏、滴丸或经皮贴剂),面颊或口或鼻喷雾。此处所用的术语″非胃肠道″指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液在内的给药方式。本发明的组合物也可以直接注射到淋巴结内。
用于给药的组合物组分包括无菌水溶液(例如生理盐水)或非水溶液和混悬液。非水性溶剂的例子包括丙二醇、聚乙二醇、植物油如橄榄油,和注射用有机酯如油酸乙酯。可以利用载体或封闭性包衣提高皮肤透过性并促进抗原吸收。
联合给药可以同时,例如以混合物的形式,分开但同时给药或共同给药,或相继给药。这包括组合物药剂作为治疗混合物一起施用的形式,以及各种组合药剂分开但同时施用的方法,例如通过不同的静脉输入同一个体内,“联合”给药还包括先给予一种化合物或抗原,接着再给与第二种。
剂量水平有赖于给药模式,受试者的特性,和载体/佐剂的剂型质量。VLP、抗原和佐剂的典型用量范围为每个受试者约O.001μg至约20mg。优选用量每个受试者至少约10μg至约500μμg。优选使受试者免疫的多种给药方式,方案是本领域的标准程序,适于正在处理的受试者。典型的抗原用量范围与没有加入VLP时的典型用量范围是可比的、相似的或相同的。
组合物很容易以单位剂量的形式出现,可以通过药学领域任意已知方法制备。方法中包括使本发明的组合物与含有一种或多种附属成分的载体联合的步骤。一般来说,制备组合物是通过将本发明组合物统一与液体载体、微粉化的固体载体、或二者一起,进行紧密的联合,以及之后如果需要的话再进行产品塑形。
适于口服的组合物可表现为不连续单位,如胶囊、片剂或锭剂,每一种含有预订量的本发明组合物。其它组合物还包括水性液体或非水性液体混悬液,如糖浆、酏剂或乳剂。
其它给药系统包括定时释放、延迟释放或缓释给药系统。这些系统可以避免重复施用上述本发明组合物,方便了医生和患者,有多种类型的释放给药系统可以应用,这是本领域技术人员公知的。
本发明的其它实施方式包括生产本发明组合物的方法,和利用该组合物治疗癌症和变态反应的方法。
因而,本发明尤其涉及一下发现:病毒样颗粒(VLP)分别载有和包装有免疫刺激核酸,优选富含非甲基化C和G(CpG)和TLR配体的DNA低聚核苷酸,这些抗原与VLP偶合或混合,就诱导产生增强的针对这些抗原的免疫应答。令人吃惊的是,如果在组合物中加入TLR配体,免疫原性显著增强。此外,针对这些抗原的T细胞应答特指Thl型。
下述实施例只是说明性的,并非对本发明由权利要求所限定的范围的限制。本领域普通技术人员应当理解,在不背离本发明精神和范围的情况下,可以对本发明的方法进行多种修改和变化。因此,本发明还覆盖本发明的各种修改和变化后形式,只要它们在权利要求和其等同物的范围内。
本文提及的所有专利、专利申请和公开文献在此均全文引用作为参考。
实施例1
VLP的制备
含有来自LCMV的肽p33的HBcAg DNA序列在SEQ ID NO:12中给出。所述p33-HBcAg VLP(p33-VLP)按如下方法制备:含有乙肝病毒完整病毒基因组的乙型肝炎克隆pEco63购自ATCC,表达质粒的制备之前已有描述(参见WO03/024481)。
为了良好地表达,选择克隆大肠杆菌K802,用上述质粒对其进行转染,培养细胞并重悬浮于5ml裂解缓冲液(10mMNa2HP04,30mMNaCI,10mM EDTA,0.25%Tween-20,pH 7.0)中,加入200μl溶菌酶溶液(20mg/ml)。超声处理后,加入4μl Benzonase和10mMMgCl2,悬浮液在室温下孵育30分钟,在4℃以15,000rpm离心15分钟,保留上清液。
然后,向上清液中添加20%(w/v)(0.2g/ml裂解液)硫酸铵。在冰上孵育30分钟后,在4℃以20,000rpm离心15分钟,弃去上清液,将沉淀重悬浮于2-3ml PBS,20ml PBS-溶液上样到Sephacryl S-400凝胶(Amersham Phanmacia Biotechnology AG)过滤柱上,将级分上样到SDS-Page凝胶上,合并含有纯化p33-HBcAg VLP衣壳的部分。将合并后的部分上样到羟基磷灰石柱上,收集流出液(含纯化p33-HBcAg VLP衣壳)。按照标准程序进行电子显微镜检查,Storni T.等人,(2002)J Immunol.168(6):2880-6图1显示一个范例。
应当指出只是为了方便才使用含有p33的VLP,本发明同样能够使用野生型VLP。在整个说明书中,术语p33-HBcAg VLP,HBcAg-p33VLP,p33-VLP和HBc33可以互换使用。
实施例2
将含CpG低聚核苷酸包装入HBcAg VLP。
如实施例1所示制得重组VLP,进行非变性琼脂糖(1%)凝胶电泳,并用溴化乙锭或考马斯蓝染色,以检测RNA/DNA或蛋白质(图.1)。细菌产生的VLP含有高水平的单链RNA,X射线结晶学显示,该单链RNA可能与靠近HBcAg蛋白C端在结构上位于VLP内部的精氨酸重复片断结合。通过VLP与Rnase孵育,污染的RNA很容易消化除去。高活性的RnaseA分子量约为14kDa,可以小到足以进入VLP,从而去除不希望的核糖核酸。
重组VLP在经RNase A消化前添加富含CpG的低聚核苷酸(参见SEQ ID NO:11)。如图2所示,CpG-低聚核苷酸的存在保持了衣壳结构,与未处理的p33-VLP类似的迁移证明了这一点。通过透析去除未结合的低聚核苷酸,纯化含CpG-低聚核苷酸VLP(PBS中稀释4500倍,24小时,使用300kDa MWCO透析膜(参见图3).
实施例3
通过RNAse除去RNA随后将低聚核苷酸包装入VLP,含CpG的低聚核苷酸能被装入VLP。
VLP(含有细菌单链RNA,如实施例1所述制备)首先与RnaseA孵育以除去RNA,第二步,向样品中添加免疫刺激性CpG-低聚核苷酸(具有正常的磷酸二酯结构,并且具有磷酸主链的硫代磷酸修饰)(图.4)。该试验清楚地表明,在RNA降解反应过程中不是绝对地同时需要CpG-低聚核苷酸,而是可以在稍后添加。
实施例4
通过核糖核酸酶消化,将CpG低聚核苷酸包装到RNA噬菌体Qb内。
本实验使用RNA噬菌体Qb的外壳蛋白构成的VLP。使用未经处理的或使用有磷酸主链硫代磷酸修饰的CpG-2006低聚核苷酸(SEQ-ID NO:114)包装的VLP。CpG-2006的包装过程为,加入0.2ml的100mM ZnSO4溶液,在60℃将8ml的Qb VLP溶液(2.2mg/ml)孵育过夜。这样处理导致Qb VLP含有的RNA水解。在20mMHepes,pH 7.5条件下透析,透析管(阀值MWCO 300000),将CpG-2006以130nmol/l ml VLP溶液加入,在37℃孵育3小时,以650rpm振摇。之后以50U/ml Benzonase(Merck),加入1mM MgCl2,在37℃处理3小时随后如上所述在20mM Hepes,pH 7.5下透析。除去未包装的CpG-2006。
CpG-2006的包装通过琼脂糖凝胶电泳检验,以溴化乙锭染色使核酸可见,随后以考马斯蓝染色使蛋白质可见。此外,包装后的的VLP经TBE-尿素凝胶分析,估计已包装好的CpG-低聚核苷酸的量。约6.7nmol的CpG-2006被包装入100μg Qb VLP。
实施例5
将免疫刺激核酸包装入VLP.
RNaseA和ZnSO4引起VLP核酸内容物的降解。
用RNaseA在低离子强度条件下(20mM Hepes pH 7.4或4mMHepes,30mM NaCl,pH 7.4)处理Q βVLP。可选择地,用ZnSO4在低离子强度条件下(20mM Hepes pH 7.4or 4mM Hepes,30mM NaCIpH 7.4)处理Q βVLP和AP205VLP,类似于实施例11所描述的情况。AP205VLP(1mg/ml)在20mM Hepes pH 7.4或20mM Hepes,1mM Tris,pH 7.4条件下,在Eppendorf Thermomixer内用2.5mMZnSO4在50℃处理48小时,以550rpm振摇.Q βand AP205VLP在14000rpm下离心,随后用10.000MWCOSpectra/Por透析管(Spectrum,Cat.nr.128118)先在2升20mM Hepes,pH 7.4条件下于4℃处理2小时,之后换缓冲液过夜。样品在透析后是澄清的,如实施例4所述,上清液的蛋白质浓度通过Bradford分析测定。
将ISS包装入RnaseA和ZnSO4处理的VLP.
RNA水解和透析后,Q β和AP205VLP(1-1.5mg/ml),用每毫升VLP 130μl的CpG低聚核苷酸混合(NKCpG-cf.表1;G3-6,G8-8-cf.表2;1mM低聚核苷酸存于10mM Tris pH 8)。样品在37℃在650rpm的热摇动器中培养3小时。随后,样品用125U Benzonase/mlVLP(MerckKGaA,Darmstadt,德国)处理,透析前在2mM MgCl2条件下在37℃孵育3小时。样品在300.000MWCOSpectra/Por透析管中(Spectrum,Cat.nr.131447)经20mM Hepes,pH 7.4在4℃透析2小时,然后用同样缓冲液更换该冲液并过夜透析后样品在14000rpm离心分离,上清液的蛋白浓度通过Bradford透析测定。
琼脂糖凝胶电泳,随后以溴化乙锭和考马斯蓝染色显示低聚核苷酸已包装入VLP内。
实施例6
将核糖核酸包装到VLP中。
VLP核酸内容物的ZnSO4依赖降解。
QβVLP用ZnSO4处理,在低离子强度条件(20mM Hepes pH7.4或4mM Hepes,30mM NaCl,pH 7.4)进行,如同实施例11.
AP205VLP(1mg/ml)在20mM Hepes pH 7.4或20mM Hepes,1mM Tris,pH 7.4于550rpm振摇48小时,2.5mM ZnSO4中于50℃,用Eppendorf Thermomixer,Q β和AP205VLP样品如同实施例8在14000rpm离心分离和在20mM Hepes,pH 7.4中透析。
将poly(I:C)包装入经ZnSO4处理的VLP:
免疫刺激核糖核酸poly(I:C),(Cat.nr.27-4732-01,poly(I)poly(C),Pharmacia Biotech)溶解于PBS(Invitrogen cat.nr.14040)或水中,浓度为4mg/ml(9μM)。poly(I:C)在60℃孵育10分钟,然后冷却至37摄氏度。将孵育后的poly(I:C)10倍摩尔数过量的量加入ZnSO4-处理的Q β或AP205VLP(1-1.5mg/ml),混合物在650rpm的thermomixer中于37℃培养3小时。随后,过量的游离poly(I:C)经酶水解,具体是与125U Benzonase/毫升VLP混合物在加入2mMMgCl2条件下于37℃在300rpm的thermomixer孵育30分钟。Benzonase水解样品在14000rpm离心分离,上清液在300.000MWCOSpectra/Por透析管(Spectrum,Cat.nr.131447)中透析,用2升20mM Hepes,pH 7.4于4℃透析2小时,用相同的缓冲液换缓冲液过夜。透析后,样品在14000rpm离心分离,上清液中蛋白质浓度通过Bradford分析测定。
在1%琼脂糖凝胶,在蛋白酶K降解后,在TBE/尿素凝胶确认包装成功。
实施例7
将核糖核酸包装入HBcAg VLP内
HBcAg VLP用ZnSO4处理,在低离子强度条件下(20mM HepespH 7.4or 4mM Hepes,30mMNaCI,pH 7.4),类似于实施例11,如实施例22经20mM Hepes pH 7.4下透析。加入摩尔数10倍过量于HBcAg VLP(1-1.5mg/ml)的poly(I:C),在650rpm的thermomixe中于37℃培养3小时。如同实施例24。随后过量的游离poly(I:C)进行酶水解,具体是与每毫升VLP 125U Benzonase的混合物在加入2mM MgCl2条件下在300rpm的thermomixer中于37C孵育3小时。样品在Benzonase水解后变得澄清,类似于实施例4的情况,如实施例9进行透析。透析后,样品在14000rpm下离心,上清液的蛋白质浓度由Bradford分析测定。
实施例8
只有CpG能增强针对与HBcAg融合的p33(p33-VLP)的CTL应答。
p33-VLP按下述方法制备:含有全部乙肝病毒的病毒基因组的乙肝病毒克隆pEco63购自ATCC。在tac启动子控制下,编码HBcAg的基因导入表达载体pKK223.3(Amersham Pharmacia Biotech Inc.NJ)的EcoRI/HindIII限制位点。衍生自LCMV的p33肽(KAVYNFATM)(SEQ ID NO:60)按照标准PCR方法通过三个亮氨酸连接体与HBcAg(aa1-183)的C-末端融合。E.coli K802d用该质粒转染,以2升的培养物生长直到光学密度为1(600nm波长下)。通过加入IPTG诱导细胞4小时(Sigma,Division of Fluka AG,瑞士)至最终浓度为1mM。
离心分离收集细菌,使重悬浮于5ml溶解缓冲液(10mMNa2HPO4,30mMNaCl,10mM EDTA,0.25%Tween-20,pH 7.0)。加入μl200μl的溶菌酶溶液(20mg/ml)。超声降解后,将4μl benzonase(Merck,Darmstadt,德囯)和10mM MgCl2补充入细胞溶解产物。混悬液在RT下孵育30分钟,在27000x g下离心15。保留的混悬液补充20%(w/v)硫酸铵盐。在冰上孵育30分钟后,在48000x g下离心分离15分钟,弃去混悬液,颗粒状物重悬浮于2-3ml磷酸缓冲液。将制得物上样到Sephacryl S-400凝胶过滤柱(Amersham Pharmacia BiotechInc.NJ)进行纯化。在SDS PAGE凝胶中分析流分的蛋白质含量,合并含纯HBc衣壳的流分。按照标准程序进行电子显微镜检查。.在各种TLR配体(每一种100μg)存在条件下用p33VLP(100μg)致小鼠免疫μg(参见图.5)。
LPS(E.coli K-235)购自Sigma(Buchs,瑞士),poly(I:C)来自Amersham Biosciences(Dubendorf,瑞士),肽聚糖(金黄色葡萄球菌(S.aureus)来自Fluka(Buchs,))瑞士),Imiquimodum(asAldara cream)来自3M(Ruschlikon,瑞士)。脂磷壁酸(金黄色葡萄球菌和链球菌(Streptococcus))由LUNAMeD AG(Zurich,Schwitzerland)提供。硫代磷酸修饰的CpG-ODN由Microsynth合成(Balgach,瑞士)。十二天后,用四聚物染色法测定血液中p33-特异T细胞的频率。收集血样加入FACS缓冲液(PBS,2%FBS,5mM EDTA),通过密度梯度法离心分离淋巴细胞,条件是在淋巴细胞-M溶液中在1200g、22℃条件下分离20分钟(Cedarlane Laboratories Ltd.Hornby,Canada)。冲洗后淋巴细胞重悬浮于FACS缓冲液在4℃用PE-标记的p33-H-2b四聚复合物染色10分钟,之后用抗鼠CD8a-FITC抗体在37℃染色30分钟,(Pharmingen,clone 53-6.7)细胞在FACSCalibur上使用CellQuest软件分析(BD Biosciences,Mountain View,CA)。
图5显示不同的TLRs配体,TLR9配件CpG例外,不能增强针对肽p33融合的乙肝病毒核心抗原(p33-VLP)的T细胞应答。在PBS或指示的TLRs刺激存在条件下用p33-VLP致小鼠免疫。用100μgμgHBc33和100μμg佐剂。八天后,用四聚物染色法测定p33-特异T细胞的频率。每个柱代表一个小鼠个体(LTA=脂磷壁酸,PGN=肽聚糖,LPS来自E.coliK-235,Sigma).
实施例9
标准佐剂如矾和IFA不能增强p33-特异CTL应答。按照标准程序在CyCpGpt(20nmol),矾或IFA,用100μgp33-融合的HBcAg(p33-VLP)致小鼠免疫,12天后,用活LCMV(200pfu)攻击小鼠以测定抗病毒保护力。五天后,测脾内病毒效价。在含2%胎牛血清的极限必需培养基(Gibco)中用匀化器研磨脾脏,并补充谷氨酸盐,earls′s盐和抗生素(青霉素/链霉素/两性霉素)。混悬液稀释十倍后迅速在MC57细胞上滴定。孵育一小时后用含5%胎牛血清、1%甲基纤维素和抗生素(青霉素/链霉素/两性霉素)的DMEM覆盖。接着在37下孵育两天,用细胞内染色法(感染病毒核蛋白)测定细胞感染LCMV的情况。细胞用4%甲醛固定30分钟,之后用1%Triton X-100进行20分钟的细胞溶解。用10%胎牛血清孵育1小时阻断非特异性结合,细胞用大鼠抗-LCMV-抗体(VL-4)染色1小时。以过氧化酶-缀合的山羊抗-鼠-IgG(Jackson ImmunoResearch Laboratories,Inc)作为第二抗体使用,然后与ODP底物发生颜色反应,按照标准程序进行(图6)。
图6显示原型佐剂矾和IFA不能增强VLP诱导的免疫性。小鼠在PBS,CpG,矾或IFA存在条件下接种p33-VLP,8天后用活LCMV(200pfu)激发免疫反应。五天后测脾内病毒效价。
实施例10
TLR4配体增强了由装载CpG的VLP诱导的T细胞应答
如同实施例7,肽p33与Qb偶合并装载CpG。本试验所用CpG为NK CpG(GGGGTCAACGTTGAGGGGG(SEQ ID NO:52)。
随后在PBS,MPL(Sigma,根据厂商指示,用a 1∶1的混合物)或LPS(20μgμg,E.coli K-235,Sigma)存在条件下,用p33-Qb/CpG(180μμg)致小鼠免疫。十天后,用四聚物染色法测定p33-特异T细胞的频率(Fig 7A)。将采集的血样放入FACS缓冲液(PBS,2%FBS,5mM EDTA)且在淋巴细胞通过密度梯度浓缩分离淋巴细胞,条件是在淋巴细胞-M溶液中在1200g、22℃条件下分离20分钟(CedarlaneLaboratories Ltd.Hornby,Canada)。冲洗重悬浮于FACS缓冲液中的淋巴细胞之后,在4℃下用PE标记的p33-H-2b四聚络合物染色10分钟,随后在37℃用抗鼠CD8a-FITC抗体染色30分钟(Pharmingen,clone 53-6.7)。在FACS Calibur上使用CellQuest软件(BD Biosciences,Mountain View,CA)分析细胞。
同日,用表达LCMV-GP(肽p33的来源)的重组疫苗病毒经腹膜内给药攻击小鼠,且在五天后测定卵巢内的病毒效价(图7B)。在含5%胎牛血清的极限必需培养基(Gibco)中用匀化器研磨卵巢,并补充谷氨酸盐,earls′s盐和抗生素(青霉素/链霉素/两性霉素)。混悬液稀释十倍后迅速在BSC40细胞上滴定。在37℃下孵育过夜,粘着细胞层用含50%乙醇、2%结晶紫和150mMNaCI的溶液染色,使病毒斑可见。
图7显示TLR4配体增强了CTL针对装载CpG的VLP偶合的p33而产生的免疫应答。在PBS,LPS或MPL(1∶1混合物)存在条件下,小鼠接种与装载NK-PO CpG的Qb偶合的p33。八天后,用四聚物染色法测定p33-特异T细胞的频率(A)。同日,用表达LCMV-GP的重组疫苗病毒攻击小鼠,且在五天后测定卵巢内的病毒效价(B)。
实施例11
常规的佐剂不能增强由装载CpG的VLP诱导的T细胞应答。
同实施例21,肽p33与Qb偶合并装载CpG。本试验所用CpG为NK CpG(GGGGTCAACGTTGAGGGGG(SEQ ID NO:52)或G10-PO(GGGGGGGGGGGACGATCGTCGGGGGGGGGG)(SEQ ID NO:54)。随后按照标准程序,在PBS,矾或IFA存在的条件下,用p33-Qb/CpG(180μg)使小鼠免疫。十天后,用四聚物染色法测定p33-特异T细胞的频率。将采集的血样放入FACS缓冲液(PBS,2%FBS,5mMEDTA)且在淋巴细胞通过密度梯度浓缩分离淋巴细胞,条件是在淋巴细胞-M溶液中在1200g、22℃条件下分离20分钟(CedarlaneLaboratories Ltd.Hornby,Canada)。冲洗重悬浮于FACS缓冲液中的淋巴细胞之后,在4℃下用PE标记的p33-H-2b四聚络合物染色10分钟,随后在37℃用抗鼠CD8α-FITC抗体染色30分钟(Pharmingen,clone 53-6.7)。在FACS Calibur上使用CellQuest软件(BD Biosciences,Mountain View,CA)分析细胞。
同日,用表达LCMV-GP(肽p33的来源)的重组疫苗病毒经腹膜内给药攻击小鼠,且在五天后测定卵巢内的病毒效价。在含5%胎牛血清的极限必需培养基(Gibco)中用匀化器研磨卵巢,并补充谷氨酸盐,earls′s盐和抗生素(青霉素/链霉素/两性霉素)。混悬液稀释十倍后迅速在BSC40细胞上滴定。在37℃下孵育过夜,粘着细胞层用含50%乙醇、2%结晶紫和150mM NaCI的溶液染色,使病毒斑可见。
表1:说明书中所用到的一些免疫刺激核酸的术语和序列.
小写字母表示通过硫代磷酸键连接的脱氧核糖核酸,大写字母表示通过磷酸二酯键连接的脱氧核糖核酸。
术语 | 序列 | SEQ ID NO |
CyCpGpt | tccatgacgttcctgaataat | 11 |
CpG-2006 | tcgtcgttttgtcgttttgtcgt | 48 |
CyCpG | TCCATGACGTTCCTGAATAAT | 49 |
B-CpGpt | tccatgacgttcctgacgtt | 50 |
B-CpG | TCCATGACGTTCCTGACGTT | 51 |
NKCpG | GGGGTCAACGTTGAGGGGG | 52 |
CyCpG-rev-pt | attattcaggaacgtcatgga | 53 |
g10gacga-PO(G10-PO) | GGGGGGGGGGGACGATCGTCGGGGGGGGGG | 54 |
g10gacga-PS(G10-PS) | gggggggggggacgatcgtcgggggggggg | 55 |
(CpG)20OpA | CGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGAAATGCATGTCAAAGACAGCAT | 56 |
Cy(CpG)20 | TCCATGACGTTCCTGAATAATCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCG | 57 |
Cy(CpG)20-OpA | TCCATGACGTTCCTGAATAATCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCGAAATGCATGTCAAAGACCAT | 58 |
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Bachmann,Martin F
Schwarz,Katrin
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Gln Val Lys Ile Gln Asn Pro Thr Ala Cys Thr Ala Asn Gly Ser Cys
65 70 75 80
Asp Pro Ser Val Thr Arg Gln Lys Tyr Ala Asp Val Thr Phe Ser Phe
85 90 95
Thr Gln Tyr Ser Thr Asp Glu Glu Arg Ala Phe Val Arg Thr Glu Leu
100 105 110
Ala Ala Leu Leu Ala Ser Pro Leu Leu Ile Asp Ala Ile Asp Gln Leu
115 120 125
Asn Pro Ala Tyr
130
<210>7
<211>132
<212>PRT
<213>人工序列
<220>
<223>噬菌体Q-beta 251突变体
<400>7
Ala Lys Leu Glu Thr Val Thr Leu Gly Asn Ile Gly Lys Asp Gly Arg
1 5 10 15
Gln Thr Leu Val Leu Asn Pro Arg Gly Val Asn Pro Thr Asn Gly Val
20 25 30
Ala Ser Leu Ser Gln Ala Gly Ala Val Pro Ala Leu Glu Lys Arg Val
35 40 45
Thr Val Ser Val Ser Gln Pro Ser Arg Asn Arg Lys Asn Tyr Lys Val
50 55 60
Gln Val Lys Ile Gln Asn Pro Thr Ala Cys Thr Ala Asn Gly Ser Cys
65 70 75 80
Asp Pro Ser Val Thr Arg Gln Lys Tyr Ala Asp Val Thr Phe Ser Phe
85 90 95
Thr Gln Tyr Ser Thr Asp Glu Glu Arg Ala Phe Val Arg Thr Glu Leu
100 105 110
Ala Ala Leu Leu Ala Ser Pro Leu Leu Ile Asp Ala Ile Asp Gln Leu
115 120 125
Asn Pro Ala Tyr
130
<210>8
<211>132
<212>PRT
<213>人工序列
<220>
<223>噬菌体Q-beta 259突变体
<400>8
Ala Arg Leu Glu Thr Val Thr Leu Gly Asn Ile Gly Lys Asp Gly Arg
1 5 10 15
Gln Thr Leu Val Leu Asn Pro Arg Gly Val Asn Pro Thr Asn Gly Val
20 25 30
Ala Ser Leu Ser Gln Ala Gly Ala Val Pro Ala Leu Glu Lys Arg Val
35 40 45
Thr Val Ser Val Ser Gln Pro Ser Arg Asn Arg Lys Asn Tyr Lys Val
50 55 60
Gln Val Lys Ile Gln Asn Pro Thr Ala Cys Thr Ala Asn Gly Ser Cys
65 70 75 80
Asp Pro Ser Val Thr Arg Gln Lys Tyr Ala Asp Val Thr Phe Ser Phe
85 90 95
Thr Gln Tyr Ser Thr Asp Glu Glu Arg Ala Phe Val Arg Thr Glu Leu
100 105 110
AlaAla Leu Leu Ala Ser Pro Leu Leu Ile Asp Ala Ile Asp Gln Leu
115 120 125
Asn Pro Ala Tyr
130
<210>9
<211>185
<212>PRT
<213>乙肝病毒
<400>9
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Glu Asp Pro Ala
65 70 75 80
Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95
Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110
Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125
Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140
Glu Thr Thr Val Val Arg Arg Arg Asp Arg Gly Arg Ser Pro Arg Arg
145 150 155 160
Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175
Arg Ser Gln Ser Arg Glu Ser Gln Cys
180 185
<210>10
<211>185
<212>PRT
<213>乙肝病毒
<400>10
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Glu Asp Pro Ala
65 70 75 80
Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95
Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110
Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125
Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140
Glu Thr Thr Val Val Arg ArgArg Asp Arg Gly Arg Ser Pro Arg Arg
145 150 155 160
Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175
Arg Ser Gln Ser Arg Glu Ser Gln Cys
180 185
<210>11
<211>21
<212>DNA
<213>人工序列
<220>
<223>CyCpG
<400>11
tccatgacgt tcctgaataa t 21
<210>12
<211>594
<212>DNA
<213>人工序列
<220>
<223>含有p33的乙肝病毒
<220>
<221>CDS
<222>(1)..(594)
<400>12
atg gac att gac cct tat aaa gaa ttt gga gct act gtg gag tta ctc 48
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
tcg ttt ttg cct tct gac ttc ttt cct tcc gtc aga gat ctc cta gac 96
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
acc gcc tca gct ctg tat cga gaa gcc tta gag tct cct gag cat tgc 144
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
tca cct cac cat act gca ctc agg caa gcc att ctc tgc tgg ggg gaa 192
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
ttg atg act cta gct acc tgg gtg ggt aat aat ttg gaa gat cca gca 240
Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Glu Asp Pro Ala
65 70 75 80
tcc agg gat cta gta gtc aat tat gtt aat act aac atg ggt tta aag 288
Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95
atc agg caa ctattg tgg ttt cat ata tct tgc ctt act ttt gga aga 336
Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110
gag act gta ctt gaa tat ttg gtc tct ttc gga gtg tgg att cgc act 384
Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125
cct cca gcc tat aga cca cca aat gcc cct atc tta tca aca ctt ccg 432
Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140
gaa act act gtt gtt aga cga cgg gac cga ggc agg tcc cct aga aga 480
GluThrThrValValArg Arg Arg Asp Arg Gly Arg Ser Pro Arg Arg
145 150 155 160
aga act ccc tcg cct cgc aga cgc aga tct caa tcg ccg cgtcgc aga 528
Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175
aga tct caa tct cgg gaa tct caa tgt ctt ctc ctt aaa gct gtt tac 576
Arg Ser Gln Ser Arg Glu Ser Gln Cys Leu Leu Leu Lys Ala Val Tyr
180 185 190
aac ttc gct acc atgtaa 594
Asn Phe Ala Thr Met
195
<210>13
<211>197
<212>PRT
<213>人工序列
<220>
<223>含有p33的乙肝病毒
<400>13
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Glu Asp Pro Ala
65 70 75 80
Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95
Ile Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110
Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125
Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140
Glu Thr Thr Val Val Arg Arg Arg Asp Arg Gly Arg Ser Pro Arg Arg
145 150 155 160
Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175
Arg Ser Gln Ser Arg Glu Ser Gln Cys Leu Leu Leu Lys Ala Val Tyr
180 185 190
Asn Phe Ala Thr Met
195
<210>14
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>14
Lys Thr Trp Gly Gln Tyr Trp Gln Val
1 5
<210>15
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>15
Ile Thr Asp Gln Val Pro Phe Ser Val
1 5
<210>16
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>16
Tyr Leu Glu Pro Gly Pro Val Thr Ala
1 5
<210>17
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>17
Leu Leu Asp Gly Thr Ala Thr Leu Arg Leu
1 5 10
<210>18
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>18
Val Leu Tyr Arg Tyr Gly Ser Phe Ser Val
1 5 10
<210>19
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>19
Ala Ala Gly Ile Gly Ile Leu Thr Val
1 5
<210>20
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>20
Ile Leu Thr Val Ile Leu Gly Val Leu
1 5
<210>21
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>21
Met Leu Leu Ala Val Leu Tyr Cys Leu
1 5
<210>22
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>22
Tyr Met Asp Gly Thr Met Ser Gln Val
1 5
<210>23
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>23
Val Leu Pro Asp Val Phe Ile Arg Cys
1 5
<210>24
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>24
Phe Leu Trp Gly Pro Arg Ala Leu Val
1 5
<210>25
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>25
Tyr Leu Ser Gly Ala Asn Leu Asn Leu
1 5
<210>26
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>26
Arg Met Pro Glu Ala Ala Pro Pro Val
1 5
<210>27
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>27
Ser Thr Pro Pro Pro Gly Thr Arg Val
1 5
<210>28
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>28
Leu Leu Gly Arg Asn Ser Phe Glu Val
1 5
<210>29
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>29
Lys Ile Phe Gly Ser Leu Ala Phe Leu
1 5
<210>30
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>30
Ile Ile Ser Ala Val Val Gly Ile Leu
1 5
<210>31
<211>8
<212>PRT
<213>智人(Homo sapiens)
<400>31
Thr Leu Gly Ile Val Cys Pro Ile
1 5
<210>32
<211>131
<212>PRT
<213>噬菌体AP205
<400>32
Met Ala Asn Lys Pro Met Gln Pro Ile Thr Ser Thr Ala Asn Lys Ile
1 5 10 15
Val Trp Ser Asp Pro Thr Arg Leu Ser Thr Thr Phe Ser Ala Ser Leu
20 25 30
Leu Arg Gln Arg Val Lys Val Gly Ile Ala Glu Leu Asn Asn Val Ser
35 40 45
Gly Gln Tyr Val Ser Val Tyr Lys Arg Pro Ala Pro Lys Pro Glu Gly
50 55 60
Cys Ala Asp Ala Cys Val Ile Met Pro Asn Glu Asn Gln Ser Ile Arg
65 70 75 80
Thr Val Ile Ser Gly Ser Ala Glu Asn Leu Ala Thr Leu Lys Ala Glu
85 90 95
Trp Glu Thr His Lys Arg Asn Val Asp Thr Leu Phe Ala Ser Gly Asn
100 105 110
Ala Gly Leu Gly Phe Leu Asp Pro Thr Ala Ala Ile Val Ser Ser Asp
115 120 125
Thr Thr Ala
130
<210>33
<211>131
<212>PRT
<213>人工序列
<220>
<223>噬菌体AP205突变体
<400>33
Met Ala Asn Lys Thr Met Gln Pro Ile Thr Ser Thr Ala Asn Lys Ile
1 5 10 15
Val Trp Ser Asp Pro Thr Arg Leu Ser Thr Thr Phe Ser Ala Ser Leu
20 25 30
Leu Arg Gln Arg Val Lys Val Gly Ile Ala Glu Leu Asn Asn Val Ser
35 40 45
Gly Gln Tyr Val Ser Val Tyr Lys Arg Pro Ala Pro Lys Pro Glu Gly
50 55 60
Cys Ala Asp Ala Cys Val Ile Met Pro Asn Glu Asn Gln Ser Ile Arg
65 70 75 80
Thr Val Ile Ser Gly Ser Ala Glu Asn Leu Ala Thr Leu Lys Ala Glu
85 90 95
Trp Glu Thr His Lys Arg Asn Val Asp Thr Leu Phe Ala Ser Gly Asn
100 105 110
Ala Gly Leu Gly Phe Leu Asp Pro Thr Ala Ala Ile Val Ser Ser Asp
115 120 125
Thr Thr Ala
130
<210>34
<211>5
<212>PRT
<213>人工序列
<220>
<223>HBcAg肽
<400>34
Gly Gly Lys Gly Gly
1 5
<210>35
<211>152
<212>PRT
<213>人工序列
<220>
<223>HBcAg变体
<400>35
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ala Ala Leu Tyr Arg Asp Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Asp
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Thr Asn Leu Glu Asp Gly Gly
65 70 75 80
Lys Gly Gly Ser Arg Asp Leu Val Val Ser Tyr Val Asn Thr Asn Val
85 90 95
Gly Leu Lys Phe Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr
100 105 110
Phe Gly Arg Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp
115 120 125
Ile Arg Thr Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser
130 135 140
Thr Leu Pro Glu Thr Thr Val Val
145 150
<210>36
<211>185
<212>PRT
<213>人工序列
<220>
<223>HBcAg变体
<400>36
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Ser
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Asn Asn Leu Glu Asp Pro Ala
65 70 75 80
Ser Arg Asp Leu Val Val Asn Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95
Ile Arg Gln Leu Leu Trp Phe His Ile Ser Ser Leu Thr Phe Gly Arg
100 105 110
Glu Thr Val Leu Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125
Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140
Glu Thr Thr Val Val Arg Arg Arg Asp Arg Gly Arg Ser Pro Arg Arg
145 150 155 160
Arg Thr Pro Ser Pro Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Arg
165 170 175
Arg Ser Gln Ser Arg Glu Ser Gln Cys
180 185
<210>37
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>37
Glu Ala Ala Gly Ile Gly Ile Leu Thr Val
1 5 10
<210>38
<211>10
<212>PRT
<213>智人(Homo sapiens)
<400>38
Glu Leu Ala Gly Ile Gly Ile Cys Thr Val
1 5 10
<210>39
<211>10
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸ISS
<400>39
gacgatcgtc 10
<210>40
<211>19
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸G3-6
<400>40
ggggacgatc gtcgggggg 19
<210>41
<211>20
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸G4-6
<400>41
gggggacgat cgtcgggggg 20
<210>42
<211>21
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸G5-6
<400>42
ggggggacga tcgtcggggg g 21
<210>43
<211>22
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸G6-6
<400>43
gggggggacg atcgtcgggg gg 22
<210>44
<211>24
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸G7-7
<400>44
ggggggggac gatcgtcggg gggg 24
<210>45
<211>26
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸G8-8
<400>45
ggggggggga cgatcgtcgg gggggg 26
<210>46
<211>28
<211>DNA
<213>人工序列
<220>
<223>寡核苷酸G9-9
<400>46
gggggggggg acgatcgtcg gggggggg 28
<210>47
<211>30
<212>DNA
<213>人工序列
<220>
<223>寡核苷酸G6
<400>47
ggggggcgac gacgatcgtc gtcggggggg 30
<210>48
<211>23
<212>DNA
<213>人工序列
<220>
<223>CpG-2006,通过磷酸二酯键连接的脱氧核苷酸
<400>48
tcgtcgtttt gtcgttttgt cgt 23
<210>49
<211>21
<212>DNA
<213>人工序列
<220>
<223>CyCpGpt,通过磷酸二酯键连接的脱氧核苷酸
<400>49
tccatgacgt tcctgaataa t 21
<210>50
<211>20
<212>DNA
<213>人工序列
<220>
<223>B-CpGpt,通过磷酸二酯键连接的脱氧核苷酸
<400>50
tccatgacgt tcctgacgtt 20
<210>51
<211>20
<212>DNA
<213>人工序列
<220>
<223>B-CpG
<400>51
tccatgacgt tcctgacgtt 20
<210>52
<211>19
<212>DNA
<213>人工序列
<220>
<223>NKCpG
<400>52
ggggtcaacg ttgaggggg 19
<210>53
<211>21
<212>DNA
<213>人工序列
<220>
<223>CyCpG-rev-pt,通过磷酸二酯键连接的脱氧核苷酸
<400>53
attattcagg aacgtcatgg a 21
<210>54
<211>30
<212>DNA
<213>人工序列
<220>
<223>g10gacga-PO(G10-PO)
<400>54
gggggggggg gacgatcgtc gggggggggg 30
<210>55
<211>30
<212>DNA
<213>人工序列
<220>
<223>g10gacga-PS(G10-PS),通过磷酸二酯键连接的脱氧核苷酸
<400>55
gggggggggg gacgatcgtc gggggggggg 30
<210>56
<211>62
<212>DNA
<213>人工序列
<220>
<223>(CpG)20OpA
<400>56
cgcgcgcgcg cgcgcgcgcg cgcgcgcgcg cgcgcgcgcg aaatgcatgt caaagacagc 60
at 62
<210>57
<211>61
<212>DNA
<213>人工序列
<220>
<223>Cy(CpG)20
<400>57
tccatgacgt tcctgaataa tcgcgcgcgc gcgcgcgcgc gcgcgcgcgc gcgcgcgcgc 60
g 61
<210>58
<211>83
<212>DNA
<213>人工序列
<220>
<223>Cy(CpG)20-OpA
<400>58
tccatgacgt tcctgaataa tcgcgcgcgc gcgcgcgcgc gcgcgcgcgc gcgcgcgcgc 60
gaaatgcatg tcaaagacag cat 83
<210>59
<211>253
<212>DNA
<213>人工序列
<220>
<223>dsCyCpG-253
<400>59
ctagaactag tggatccccc gggctgcagg aattcgattc atgacttcct gaataattcc 60
atgacgttgg tgaataattc catgacgttc ctgaataatt ccatgacgtt cctgaataat 120
tccatgacgt tcctgaataa ttccatgacg ttcctgaata attccatgac gttcctgaat 180
aattccatga cgttcctgaa taattccatg acgttcctga aaattccaat caagcttatc 240
gataccgtcg acc 253
<210>60
<211>9
<212>PRT
<213>智人(Homo sapiens)
<400>60
Lys Ala Val Tyr Asn Phe Ala Thr Met
1 5
Claims (54)
1.一种增强动物免疫应答的组合物,包括:
(a)病毒样颗粒;
(b)免疫刺激核酸;
其中所述免疫刺激核酸(b)与所述病毒样颗粒(a)结合;
并且其中所述免疫刺激核酸是含非甲基化的CpG的低聚核苷酸;
(c)至少一种抗原,其中所述抗原与所述病毒样颗粒(a)混合或偶合;和
(d)至少一种toll样受体(TLR)配体,并且其中所述配体是TLR4的配体。
2.权利要求1的组合物,其中所述TLR配体(d)与所述VLP混合。
3.权利要求1的组合物,其中所述激活TLR 4的配体(d)选自:
(a)LPS;
(b)单磷酰脂A;
(c)gp96;
(d)热激蛋白;和
(e)防卫素。
4.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸包括序列:
5′X1X2CGX3X4 3′,
其中X1,X2,X3,和X4为任意核苷酸。
5.权利要求4的组合物,其中所述核苷酸X1,X2,X3,和X4中至少一种有磷酸主链修饰。
6.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸包括选自如下的序列:
(a)TCCATGACGTTCCTGAATAAT(SEQ ID NO:49);
(b)TCCATGACGTTCCTGACGTT(SEQ ID NO:51);
(c)GGGGTCAACGTTGAGGGGG(SEQ ID NO:52);
(d)GGGGGGGGGGGACGATCGTCGGGGGGGGGG(SEQ ID NO:54);和
(e)″dsCyCpG-253″(SEQ ID NO:59)。
7.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸是由选自如下的序列组成的:
(a)TCCATGACGTTCCTGAATAAT(SEQ ID NO:49);
(b)TCCATGACGTTCCTGACGTT(SEQ ID NO:51);
(c)GGGGTCAACGTTGAGGGGG(SEQ ID NO:52);
(d)GGGGGGGGGGGACGATCGTCGGGGGGGGGG(SEQ ID NO:54);和
(e)″dsCyCpG-253″(SEQ ID NO:59)。
8.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸的CpG基序是回文序列的一部分。
9.权利要求8的组合物,其中所述回文序列为GACGATCGTC(SEQ ID NO:39)。
10.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸包括下列序列:GGGGGGGGGGGACGATCGTCGGGGGGGGGG(SEQ ID NO:54)。
11.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸是由下列序列组成的:GGGGGGGGGGGACGATCGTCGGGGGGGGGG(SEQ ID NO:54)。
12.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸在磷酸主链上含有一个或多个硫代磷酸修饰或所述低聚核苷酸磷酸主链各个磷酸部分均为硫代磷酸修饰。
13.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸不是被磷酸二酯主链上硫代磷酸修饰稳定化的。
14.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸被包装进所述病毒样颗粒内。
15.权利要求9的组合物,其中所述回文序列在其3′-末端和5′-末端侧翼连接有10个乌嘌呤核苷。
16.权利要求9的组合物,其中所述回文序列在其N-末端侧翼连接有最少3个和至多9个乌嘌呤核苷,和其中所述回文序列在其C-末端侧翼连接最少6个和最多9个鸟嘌呤核苷。
17.权利要求9的组合物,其中所述含非甲基化CpG的低聚核苷酸的核酸序列选自:
(a)GGGGACGATCGTCGGGGGG(SEQ ID NO:40);
(b)GGGGGACGATCGTCGGGGGG(SEQ ID NO:41);
(c)GGGGGGACGATCGTCGGGGGG(SEQ ID NO:42);
(d)GGGGGGGACGATCGTCGGGGGG(SEQ ID NO:43);
(e)GGGGGGGGACGATCGTCGGGGGGG(SEQ ID NO:44);
(f)GGGGGGGGGACGATCGTCGGGGGGGG(SEQ ID NO:45);
(g)GGGGGGGGGGACGATCGTCGGGGGGGGG(SEQ ID NO:46);和
(h)GGGGGGCGACGACGATCGTCGTCGGGGGGG(SEQ IDNO:47)。
18.权利要求9的组合物,其中所述回文序列在其5′-末端侧翼连接有最少4个和最多9个乌嘌呤核苷,和其中所述回文序列在其3′-末端侧翼连接有最少6个和最多9个乌嘌呤核苷。
19.权利要求9的组合物,其中所述回文序列在其5′-末端侧翼连接最少5个和最多8个乌嘌呤核苷,和其中所述回文序列在其3′-末端侧翼连接有最少6个和最多8个鸟嘌呤核苷。
20.权利要求9的组合物,其中所述含非甲基化CpG的低聚核苷酸的核酸序列为SEQ ID NO:45。
21.权利要求1的组合物,其中所述含非甲基化CpG的低聚核苷酸包括6到100个核苷酸。
22.权利要求1的组合物,其中所述的含非甲基化CpG的低聚核苷酸包括6到40个核苷酸。
23.权利要求1的组合物,其中所述的含非甲基化CpG的低聚核苷酸包括20到40个核苷酸。
24.权利要求1的组合物,其中含非甲基化CpG的低聚核苷酸是合成低聚核苷酸
25.权利要求1的组合物,其中所述配体(d)是LPS。
26.权利要求1的组合物,其中所述病毒样颗粒(a)是重组病毒样颗粒。
27.权利要求1的组合物,其中所述病毒样颗粒包括重组蛋白,其中所述重组蛋白选自:
(a)RNA噬菌体重组蛋白;
(b)麻疹病毒重组蛋白;
(c)辛德比斯病毒重组蛋白;
(d)轮状病毒重组蛋白;
(e)口蹄疫病毒重组蛋白;
(f)逆转录病毒重组蛋白;
(g)诺沃克病毒重组蛋白;
(h)阿尔发病毒重组蛋白;
(i)人乳头状瘤病毒重组蛋白;
(j)多瘤病毒重组蛋白;
(k)噬菌体重组蛋白;
(l)乙肝病毒重组蛋白;
(m)Qβ-噬菌体重组蛋白;
(n)GA-噬菌体重组蛋白
(o)fr-噬菌体重组蛋白;
(p)AP 205-噬菌体重组蛋白;
(q)Ty重组蛋白;和
(r)从(a)到(p)中任何重组蛋白的片断。
28.权利要求1的组合物,其中所述重组病毒颗粒是乙肝病毒核心蛋白或BK病毒VP1蛋白。
29.权利要求1的组合物,其中所述病毒样颗粒包括RNA-噬菌体的重组蛋白或其片断。
30.权利要求29的组合物,其中所述RNA噬菌体选自:
(a)噬菌体Qβ;
(b)噬菌体R17;
(c)噬菌体fr;
(d)噬菌体GA;
(e)噬菌体SP;
(f)噬菌体MS2;
(g)噬菌体M11;
(h)噬菌体MX1;
(i)噬菌体NL95;
(j)噬菌体f2;
(k)噬菌体PP7;和
(l)噬菌体AP205。
31.权利要求1的组合物,其中所述病毒样颗粒包括RNA噬菌体的重组蛋白或其片断,其中所述RNA噬菌体是噬菌体Qβ。
32.权利要求1的组合物,其中所述病毒样颗粒包括RNA噬菌体的重组蛋白或其片断,其中所述RNA噬菌体是噬菌体AP205。
33.权利要求1的组合物,其中所述病毒样颗粒包括至少一个第一附着位点,且其中所述抗原(c)还包括至少一个第二附着位点,选自:
(a)抗原或抗原决定簇上非天然存在的附着位点;和
(b)所述抗原或抗原决定簇上天然存在的附着位点;且其中所述第二附着位点能与所述第一附着位点缔合。
34.权利要求33的组合物,其中还包括氨基酸连接体,其中所述氨基酸连接体包括所述第二附着位点。
35.权利要求33的组合物,其中还包括氨基酸连接体,其中所述氨基酸连接体是由所述第二附着位点组成的。
36.权利要求1的组合物,其中所述抗原(c)选自:
(a)多肽;
(b)脂蛋白;和
(c)糖蛋白。
37.权利要求1的组合物,其中所述抗原(c)是重组抗原。
38.权利要求1的组合物,其中所述抗原(c)从天然来源中分离得到。
39.权利要求38的组合物,其中所述天然来源选自:
(a)花粉提取物;
(b)粉尘提取物;
(c)尘螨提取物;
(d)真菌提取物;
(e)哺乳动物表皮提取物;
(f)羽毛提取物;
(g)昆虫提取物;
(h)食物提取物,
(i)毛发提取物;
(j)唾液提取物,和
(k)血清提取物。
40.权利要求1的组合物,其中所述抗原(c)衍生自:
(a)病毒;
(b)细菌;
(c)寄生虫;
(d)朊病毒;
(e)肿瘤;
(f)自身分子;
(g)非肽半抗原分子;
(h)变态反应原;和
(i)荷尔蒙。
41.权利要求1的组合物,其中所述抗原(c)是肿瘤抗原。
42.权利要求41的组合物,其中所述肿瘤抗原选自:
(a)Her2;
(b)GD2;
(c)EGF-R;
(d)CEA;
(e)CD52;
(f)人黑素瘤蛋白gp100;
(g)人黑素瘤蛋白melan-A/MART-1;
(h)酪氨酸酶;
(i)NA17-A nt蛋白;
(j)MAGE-3蛋白;
(k)p53蛋白;
(l)HPV16 E7蛋白;和
(m)从(a)到(l)中的任何肿瘤抗原的抗原片断。
43.权利要求1的组合物,其中所述抗原(c)是变态反应原。
44.权利要求43的组合物,其中所述变态反应原衍生自:
(a)花粉提取物;
(b)粉尘提取物;
(c)尘螨提取物;
(d)真菌提取物;
(e)哺乳动物表皮提取物;
(f)羽毛提取物;
(g)昆虫提取物;
(h)食物提取物,
(i)毛发提取物;
(j)唾液提取物,和
(k)血清提取物。
45.权利要求43的组合物,其中所说变态反应原选自:
(a)树;
(b)草;
(c)室内粉尘;
(d)室内尘螨;
(e)曲霉菌;
(f)动物毛发;
(g)动物羽毛;
(h)蜂毒;
(l)动物产品;和
(j)植物产品。
46.权利要求1的组合物,其中所述抗原(c)选自:
(a)蜂毒磷脂酶A2;
(b)豕草花粉Amb a1;
(c)桦树花粉Bet vI;
(d)白面大黄蜂毒5 Dol m V;
(e)内尘螨Der p1;
(f)室内尘螨Der f2;
(g)室内尘螨Der 2;
(h)尘螨Lep d;
(i)真菌变态反应原Alt a1;
(j)真菌变态反应原Aspf 1;
(k)真菌变态反应原Aspf 16;和
(l)花生变态反应原。
47.权利要求1的组合物,其中所述抗原(c)是细胞毒性T细胞表位,Th细胞表位和所述表位中至少两种的联合,其中所述至少两种表位直接连接或通过连接序列连接。
48.权利要求47的组合物,其中所述细胞毒性T细胞表位选自:
(a)病毒表位;
(b)肿瘤表位;和
(c)变态反应表位。
49.权利要求1-48任一项的组合物在制备用于增强动物体内免疫反应的药物中的应用。
50.权利要求49的方法,其中所述动物是哺乳动物。
51.权利要求49的应用,其中所述动物是人。
52.权利要求49的应用,其中所述药物通过皮下、肌肉内、静脉内、鼻内方式导入所述动物,和直接导入淋巴结。
53.一种疫苗,包括免疫学有效量的权利要求1至48之任一的组合物与药学上可接受的稀释剂、载体或辅料。
54.根据权利要求1至48任一项的组合物在制备用于治疗选自变态反应、肿瘤、慢性病和慢性的病毒性疾病的疾病的药物中的应用。
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EP1425040A2 (en) * | 2001-09-14 | 2004-06-09 | Cytos Biotechnology AG | In vivo activation of antigen presenting cells for enhancement of immune responses induced by virus like particles |
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2004
- 2004-07-12 RU RU2006103853A patent/RU2375076C2/ru not_active IP Right Cessation
- 2004-07-12 JP JP2006518174A patent/JP2009513532A/ja active Pending
- 2004-07-12 CN CNB2004800159525A patent/CN100404070C/zh not_active Expired - Fee Related
- 2004-07-12 AT AT04763176T patent/ATE494910T1/de not_active IP Right Cessation
- 2004-07-12 EP EP04763176A patent/EP1644034B1/en not_active Not-in-force
- 2004-07-12 KR KR1020057022783A patent/KR20060031607A/ko not_active Application Discontinuation
- 2004-07-12 DE DE200460031017 patent/DE602004031017D1/de active Active
- 2004-07-12 AU AU2004255470A patent/AU2004255470B2/en not_active Ceased
- 2004-07-12 WO PCT/EP2004/007679 patent/WO2005004907A1/en active Application Filing
- 2004-07-12 CA CA 2527102 patent/CA2527102A1/en not_active Abandoned
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2003024481A2 (en) * | 2001-09-14 | 2003-03-27 | Cytos Biotechnology Ag | Packaging of immunostimulatory substances into virus-like particles: method of preparation and use |
Also Published As
Publication number | Publication date |
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RU2375076C2 (ru) | 2009-12-10 |
RU2006103853A (ru) | 2007-08-20 |
JP2009513532A (ja) | 2009-04-02 |
ATE494910T1 (de) | 2011-01-15 |
US20060251623A1 (en) | 2006-11-09 |
DE602004031017D1 (de) | 2011-02-24 |
AU2004255470B2 (en) | 2010-08-19 |
EP1644034A1 (en) | 2006-04-12 |
WO2005004907A1 (en) | 2005-01-20 |
AU2004255470A1 (en) | 2005-01-20 |
CN1802173A (zh) | 2006-07-12 |
CA2527102A1 (en) | 2005-01-20 |
KR20060031607A (ko) | 2006-04-12 |
EP1644034B1 (en) | 2011-01-12 |
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