CN105131051B - 合成的吡喃葡萄糖脂佐剂 - Google Patents
合成的吡喃葡萄糖脂佐剂 Download PDFInfo
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- CN105131051B CN105131051B CN201510353412.8A CN201510353412A CN105131051B CN 105131051 B CN105131051 B CN 105131051B CN 201510353412 A CN201510353412 A CN 201510353412A CN 105131051 B CN105131051 B CN 105131051B
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Abstract
Description
本申请是申请日为2010年06月04日、中国申请号为201080034214.0、发明名称为“合成的吡喃葡萄糖脂佐剂”的发明申请的分案申请。
相关申请的引用
本申请根据35U.S.C.§119(e)要求于2009年6月5日提交的第61/184,703号美国临时专利申请的权益,其中该临时申请通过引用整体并入本文。
发明背景
发明领域
本发明涉及药物和疫苗组合物领域。更具体地,本文描述的实施方案涉及药物和疫苗组合物,以及相关的预防和治疗方法,其中所述组合物包含如本文所述的吡喃葡萄糖脂佐剂(GLA)。
相关领域描述
高级生物体的免疫系统已被表征为将外源物(或“非己”物)和亲近或“自身”组分区分,这使得外源物引发免疫反应而对“自身”组分忽略或耐受。免疫反应传统上被表征为体液反应或细胞介导反应,其中在体液反应中由称为浆细胞的分化型B淋巴细胞产生抗原特异性抗体,在细胞介导反应中不同类型的T淋巴细胞起到通过多种机制清除抗原的作用。例如,能识别特异性抗原的CD4+辅助T细胞可以通过释放诸如细胞因子的可溶性介质募集免疫系统的其它细胞来作出应答以参与免疫反应。同样,也能识别特异性抗原的CD8+细胞毒素T细胞可以通过结合到携带抗原的细胞或微粒并破坏或损伤所述细胞或颗粒来作出应答。通常为了在宿主中诱导期望免疫反应的目的,提供多种不 同制剂的某些疫苗,这在免疫学领域是已知的。
通过向宿主给予疫苗来引发特异性免疫反应的几种方法包括:用热灭活的或活的诸如病毒、细菌或某些真核病原体的弱毒感染性病原体进行免疫;用能够指导遗传物质表达的无毒性传染物进行免疫,其中所述遗传物质编码免疫反应所针对的一种或多种抗原;以及用包含从特定病原体中分离的免疫原(诸如蛋白)的亚单位疫苗进行免疫,从而产生针对所述病原体的免疫。(参见,例如,Liu,1998Nature Medicine4(5suppl.):515.)对于某些抗原,可有一种或多种类型的理想免疫,这些方法中没有一种对所述理想免疫特别有效,包括开发在免疫学上保护宿主免受人类免疫缺陷病毒或其它感染性病原体、癌症、自体免疫疾病或其它临床病症中的有效疫苗。
长期认为肠细菌脂多糖(LPS)是免疫系统的有效刺激物,尽管它在佐剂中的用途已经由于其毒性效应而被缩减。Ribi等人已经描述了LPS的无毒衍生物,即通过从还原端葡糖胺中移除核糖类基团和磷酸根而产生的单磷酰脂质A(MPL)(1986,Immunology andlmmunopharmacology of Bacterial Endotoxins(细菌内毒素的免疫学和免疫药物学),Plenum Publ.Corp.,NY,p407-419)。
MPL的另一种去毒形式是从二糖骨架的3-位去除酰基链而得到的,并且其被称为3-O-脱酰基单磷酰脂质A(3D-MPL)。它可以通过GB 2122204B中教导的方法来纯化和制备,文献GB 2122204B也公开了双磷酰脂质A及其3-O-脱酰基变体的制备。例如,已经以具有直径小于0.2μm的小粒度乳剂形式来制备3D-MPL,且其制备方法在WO94/21292中公开。包含单磷脂酰脂质A和表面活性剂的水性制剂已在WO9843670A2中描述。
可以从细菌源中纯化和加工欲被配制在佐剂组合中的细菌脂多糖衍生佐剂,或可选择地,它们可以是合成的。例如,在1986Ribi等人(上述)描述了纯化的单磷酰脂质A,在GB2220211和第4,912,094号美国专利中描述了衍生自沙门氏菌属(Salmonella sp.)的3-O-脱酰基单磷酰脂质A或3-O-脱酰基双磷酰脂质A。已经描述了3D-MPL和β(1-6)二糖葡糖胺以及其它纯化的和合成的脂多糖类(WO 98/01139;第 6,005,099号美国专利和EP 0 729 473B1,Hilgers等人,1986Int.Arch.Allergy Immunol.,79(4):392-6;Hilgers等人,1987,Immunology,60(1);141-6;以及EP 0 549 074 B1)。3D-MPL和来自智利皂荚树(QuillajaSaponaria Molina)树皮的皂苷佐剂的组合在EP 0 761 231 B中描述。WO 95/17210公开了佐剂乳剂体系,其基于由免疫刺激物QS21配制的鲨烯、α-生育酚和聚氧乙烯山梨醇酐单油酸酯(TWEENTM-80),并且任选地包括3D-MPL。尽管易得到这种组合,但使用来自天然产物的佐剂伴随着高生产成本、批间不一致性、大规模生产有关的困难,以及在任何给定制剂的组合构成中存在杂质的不确定性。
因此,对改良的疫苗存在需要,特别是对有益地包含高纯度、化学成分明确(chemically defined)的佐剂组分的疫苗存在需要,所述疫苗表现出批间一致性且可以在工业规模上有效地制备而不引入不期望或结构不确定的污染物。本发明提供了这种疫苗的组合物和方法,并提供了其它相关的优势。
发明简述
本发明在若干方面涉及化合物、组合物以及方法,其有利地应用某些合成的吡喃葡萄糖脂佐剂(GLA)作为免疫调节剂或佐剂。因此,根据本文所述发明的一个方面,提供具有下式(I)结构的GLA化合物或其药物可接受的盐:
其中L1、L2、L3、L4、L5、L6、L7、L8、L9、L10、Y1、Y2、Y3、Y4、R1、R2、R3、R4、R5、R6如本文所定义。
本发明的GLA化合物在期望诱导特异性或非特异性免疫反应的广泛治疗应用方面具有效用。例如,在本发明的某些方面,提供了与抗原结合的包含本文所列的一种或多种GLA化合物的疫苗组合物。这种疫苗组合物有利地用于在有需要的个体中激发抗原特异性免疫反应的方法。在本发明的其它方面,提供包含本文所列的一种或多种GLA化合物的药物组合物,其中所述组合物基本上不含抗原。这种药物组合物可以有利地用于在有需要的个体中激发非特异性免疫反应的方法,例如用于传染病、季节性鼻炎等的治疗。
参照下面的详细描述和附图,本发明的这些和其它方面会将变得显而易见。此外,本文提及的、更为详细地描述本发明某方面的各种参考文献都以其整体通过引用方式并入本文。
附图的若干视图的简要说明
图1表示在用包含抗原和GLA的本发明组合物接种小鼠之后,在体内诱导的IFN-γ细胞因子产生。
图2A-2F表示在用包含抗原和GLA的本发明组合物接种小鼠之后,在体内诱导的抗体反应。
图3表示本发明示例性GLA化合物(化合物IX)在不同浓度下所观察到的NF-kB增强。
图4A-4D表示本发明示例性GLA化合物(化合物IX)在不同浓度下的免疫刺激细胞因子(MIP-1b和TNFa)的诱导。
发明详述
已知单磷酰脂A(MPL)和其它相关佐剂通过充当Toll样受体(TLR)的激动剂而至少部分地调节其作用。本发明的吡喃葡萄糖脂佐剂(GLA)化合物基于与TLR受体刺激相关的3D结构方面的考虑而进行合理地设计。更特别地,根据本发明,通过选择性地对本发明的GLA化合物的酰基链长度进行限定以便其在化合物三维结构中形成“平”的底部,可在TLR受体的结合位点内实现更好的配合,由此实现更高的TLR刺激和免疫刺激性能。另外,本发明GLA化合物的溶解度(例如, 在水性溶液中)由于酰基链长度缩短而有利地改善,由此促进形成高效且有效的化合物制剂。另外,因为将酰基链长度缩短而使分子沿分子底部在三维上变“平”,因此该化合物能够更加有效地并入例如用于脂质体制剂的载体。
更进一步,本发明的化合物提供了有利的效能与毒性比的性质。例如,可以在广泛且相对高范围的剂量上使用本发明的化合物以获得所需的活性水平(例如,佐剂活性),但同时对人类细胞和人类患者基本上保持无毒,例如,由在一定范围的浓度内从人细胞产生的肿瘤坏死因子水平所检测到的,本发明化合物迅速上升且趋平,不同于诸如脂多糖的其它毒性更大的TLR4激动剂。该基于细胞的检测能够预测更低的炎性标记,类似于在人类药理学的不良事件中所涉及的C-反应性蛋白。本发明化合物的有利的效能与毒性比的性质尤其重要,例如,当向对细胞因子耐受性更差的儿童给予时可以更低,或当在针对庞大人口(其中对于对TLR激动具有不同反应性的人群而言,更高水平的反应将转化为更一致的临床结果)的剂型中使用该化合物时。类似地,因为靶剂量更加宽泛,因此注册审批将更为简化,而且当活性药物成分的范围不需要严格控制在耐受水平时制备变得简化。
因此,本发明在其多个实施方案中提供了包含如本文所描述的合成GLA化合物的化合物、疫苗组合物、佐剂组合物、药物组合物和相关剂型以及方法。GLA化合物代表合成的免疫调节剂,其相对于现有技术中的佐剂、尤其相对于天然产物佐剂,能够基本上以均质的形式制备。而且,与天然产物衍生的佐剂不同,本发明的GLA化合物能够通过大规模的合成化学制造来进行高效且经济地制备。因为从确定的起始物质对合成的佐剂进行化学合成以得到化学成分明确的产物,所以,所述合成的佐剂表现出批次与批次间的性质和数量上的一致性,本发明的所述GLA化合物具有包括改善的产品质量控制在内的优势。
如本文所描述的,GLA化合物、组合物以及用于它们应用的方法在一些实施方案中包括GLA本身与药物上可接受的载体或赋形剂在包括“辅佐”的免疫佐剂活性(例如非特异性免疫刺激活性)中的用途,其中给予个体GLA可以完全独立于给予个体一种或多种抗原,和/或在 时间上和/或空间上与给予个体一种或多种抗原分离,所述抗原针对于所期望的个体免疫反应(例如,抗原特异性反应)的引发或增强。其它的实施方案包括GLA在疫苗组合物中的应用,所述组合物也包括一种或多种由所述疫苗引发或增强的免疫反应所针对的抗原。
如本文所述,在某些相关实施方案中,这些疫苗组合物也包括一种或多种Toll样受体(TLR)激动剂和/或一个或多个的选自辅佐剂、咪唑并喹啉免疫反应调节剂和双茎环免疫调节剂(dSLIM)中的一种或多种。在其它相关实施方案中,本文提供的疫苗组合物可以包含GLA和一种或多种重组表达构建体,每一个构建体都包含可操作连接于编码抗原的核酸序列的启动子,所述抗原针对期望的个体免疫反应的引发或增强。
GLA
如上文所述,因为GLA是化学合成的佐剂,所以其可以以基本上均一的形态制备,其对于GLA分子而言,所涉及的GLA制剂的纯度为至少80%、优选至少85%、更优选至少90%、更优选至少95%以及仍更优选至少96%、97%、98%或99%。
本发明的GLA化合物具有下式(I)或其药物可接受的盐:
其中:
L1、L2、L3、L4、L5和L6为相同或不同的,并且其独立地为-O-、-NH-或-(CH2)-;
L7、L8、L9和L10为相同或不同的,并且其独立地不存在或 为-C(=O)-;
Y1为酸官能团;
Y2和Y3为相同或不同的,并且其独立地为-OH、-SH或酸官能团;
Y4为-OH或-SH;
R1、R3、R5和R6为相同或不同的,并且其独立地为C8-13烃基;以及
R2和R4为相同或不同的,并且其独立地C6-11烃基。
如本文所用,上述术语具有如下含义:
“烃基”指直链或支链的、非环状或环状的、不饱和或饱和的脂肪烃,其包含1至20个碳原子,并且在某些优选的实施方案中,包含11至20个碳原子。代表性的饱和直链烃基包括甲基、乙基、正-丙基、正-丁基、正-戊基、正-己基等,包括十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基等;而饱和的支链烃基包括异丙基、仲丁基、异丁基、叔-丁基、异戊基等。代表性的饱和环状烃基包括环丙基、环丁基、环戊基、环己基等;而不饱和的环状烃基包括环戊烯基、环己烯基等。环状烃基在本文也被称为“碳环(homocycles)”或“同素环(homocyclic rings)”。不饱和的烃基在相邻的碳原子之间包含至少一个双键或叁键(分别被称为“烯基”或“炔基”)。代表性的直链和支链烯基包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、异丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基等;而代表性的直链和支链炔基包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基等。
“C8-13烃基”和“C6-11烃基”指如上所定义的烃基,其分别包含8-13个或6-11个碳原子。
“酸官能团”指能够在水性介质中给予质子的官能团(例如 酸)。在给予质子之后,所述酸官能团成为带负电的种类(即酸官能团的共轭碱)。酸官能团的实例包括但不限于:-OP(=O)(OH)2(磷酸根)、-OS(=O)(OH)2(硫酸根)、-OS(OH)2(亚硫酸根)、-C(=O)OH(羧酸根)、-OC(=O)CH(NH2)CH2C(=O)OH(天冬氨酸根)、-OC(=O)CH2CH2C(=O)OH(琥珀酸根)以及 -OC(=O)CH2OP(=O)(OH)2(羧甲基磷酸根)。
在更优选的实施方案中,本发明提供式(I)的GLA化合物,其中L5和L6均为-O-且L7、L8、L9和L10各自为-C(=O)-,并且所述GLA化合物具有如下的式(II):
在更具体的实施方案中,本发明提供式(II)的GLA化合物,其中R1、R3、R5和R6各自为Cx烃基,其中x为常量且选自8-13的整数,并且R2和R4均为Cx-2烃基,并且所述GLA化合物具有如下的式(III):
在其它更具体的实施方案中,本发明提供式(III)的GLA化合物,其中x选自10-12的整数。
在其它更具体的实施方案中,本发明提供式(III)的GLA化合物, 其中x为11,且所述GLA化合物具有如下的结构(IV):
还在其它的具体实施方式中,本发明提供式(II)的GLA化合物,其中Y1为-OP(=O)(OH)2且Y2、Y3和Y4各自为-OH,并且所述GLA化合物具有如下的式(V):
在其它的具体实施方式中,本发明提供式(II)的GLA化合物,其中L1和L3均为-O-且L2和L4均为-NH-,并且所述GLA化合物具有如下的式(VI):
还在更具体的实施方式中,本发明提供式(II)的GLA化合物,其中Y1为-OP(O)(OH)2,Y2、Y3和Y4各自为-OH,L1和L3均为-O-,且L2和L4均为-NH-,并且所述GLA化合物具有如下的式(VII):
还在其它的具体实施方式中,本发明提供式(II)的GLA化合物,其中Y1为-OP(O)(OH)2,Y2、Y3和Y4各自为-OH,L1和L3均为-O-,L2和L4均为-NH-,R1、R3、R5和R6各自为Cx烃基,其中x为常量且选自8-13的整数,并且R2和R4均为Cx-2烃基,并且所述GLA化合物具有如下的式(VIII):
在式(VIII)的更具体的实施方式中,x为11,且本发明提供具有如下结构(IX)的GLA化合物:
GLA化合物
如上文所述,本发明提供GLA化合物。本发明的GLA化合物可以通过已知的有机合成技术而制备,包括在实施例中更具体地描述的方法。通常,结构(I)的GLA化合物可以通过以下反应方案而制备,其中除非另有说明,所有取代基如上文所定义。
反应方案1
通常能够根据反应方案1来制备代表性的GLA化合物的糖骨架,其中G1、G2、G3、G4、G5、G6、G7、G8、G9和G10为相同或不同,且独立地为适合的保护基团或氢。能够购买或者根据本领域技术人员所已知的方法来制备诸如(i)的适合的糖。使用本领域技术人员所已知的方法能够充分保护糖(i)的官能团以得到(ii)。为此,本领域技术人员将认识到可以采用适当的允许选择性脱保护糖官能团的正交保护基团法。适合的保护基团包括但不限于甲硅烷基醚、苄基醚、烯丙氧基羰基、缩醛、芴甲氧羰基(Fmoc)、叠氮化物等。G1的脱保护产生游离的醇(iii),其随后能够使用诸如CCl3CN/NaH的适当耦合条件与被保护的糖(iv)相耦合以得到所需的糖骨架(v)。
反应方案2
通常能够根据反应方案2进行制备代表性的GLA化合物尾端(tail piece),其中L5和L6均为-O-且L7、L8、L9和L10各自为-C(=O)-,其中G11表示适合的保护基团。能够购买或根据本领域技术人员所已知的方法来制备结构(vi)的酸化合物。与诸如甲基氢丙二酸酯的适合试剂的反应(vi)产生酮酸酯(vii)。(vii)的还原产生醇(viii)。本领域技术人员将认识到在适当的条件下,(vii)的酮基可以按照实施例中所示例的进行立体特异性还原。(viii)的皂化产生了酸(ix),其随后能够被保护以产生(x)。用酰基氯(xi)处理(x)产生(xii),对其脱保护产生(xiii)。通过本领域技术人员已知的方法将化合物(ix)和(xiii)两者转变为适当保护的酰基氯衍生物,并且与如下反应方案3所表示的GLA化合物糖骨架连接。尽管反应方案2表示了包含R1和R2的GLA化合物尾端的合成,但应该理解的是通过类似方法也可以制备包含其他烃基(例如R3、R4、R5和R6)的其它尾端。通过类似方法还可以制备具有不同的L5、L6、L7、L8、L9和L10基团的其它尾端。
反应方案3
通常根据反应方案3能够制备代表性的GLA化合物,其中G12和G13为相同或不同的,且独立地表示适合的保护基团。将(v)的G5保护基团去除随后与酰基氯(xiv)反应产生(xv)。类似地,将G8保护基团从(xv)去除,随后与酰基氯(xvi)反应产生(xvii)。将(xvii)脱保护并与酰基氯(xviii)反应产生(xix)。将G9去除并与(xx)反应随后产生被保护的GLA化合物(xxi)。将(xxi)完全脱保护产生结构(II)的化合物。尽管反应方案3描述了结构(II)化合物的合成,本领域技术人员将认识到可采用类似的方法来产生结构(I)的任何化合物。另外,本领域的技术人员还将认识到通过选择适当的保护基团,最终的脱保护将产生所需的化合物。
通常本发明的化合物可用作游离碱或游离酸。另外,本发明的化合物可以以酸加成盐或碱加成盐的形式使用。可通过本领域已知的方法来制备本发明的游离氨基化合物的酸加成盐,且可由有机酸和无机酸形成。适合的有机酸包括马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、甲基磺酸、乙酸、草酸、丙酸、酒石酸、水杨酸、柠檬酸、葡萄糖酸、乳酸、扁桃酸、肉桂酸、天冬氨酸、硬脂酸、棕榈酸、乙醇酸、谷氨酸和苯磺酸。适合的无机酸包括盐酸、氢溴酸、硫酸、磷酸和硝酸。
类似地,本发明的酸性化合物的碱加成盐可以通过本领域已知的方法进行制备,且可以由有机碱和无机碱形成。适合的有机碱包括但不限于三乙胺和吡啶。适合的无机碱包括但不限于氢氧化钠、氢氧化钾、碳酸钠、碳酸钾和氨。因此,术语结构(I)的“药物可接受的盐”意图包含任何及所有可接受的盐形式。
另外,前药也包括在本发明的内容中。前药为任何共价结合的载体,当将这种前药给予患者时,其在体内释放结构(I)的化合物。通常通过修饰官能团来制备前药,其方法是通过常规操作或在体内使修饰断裂,从而产生母体化合物。例如,前药包括本发明的化合物,其中羟基、氨基或巯基与任何当给予患者时裂解以形成羟基、氨基或巯基的基团连接。因此,前药的代表性的实例包括(但不限于)结构(I)的化合物的醇和胺官能团的乙酸、甲酸和苯甲酸衍生物。另外,对于羧酸 (COOH)而言,可以采用酯,诸如甲酯、乙酯等。
对于立体异构体,结构(I)的化合物可以具有手性中心且可以以外消旋体、外消旋混合物以及单独的对映体或非对映体的形式出现。本发明包含所有这样的异构体形式,包括其混合物。另外,结构(I)的化合物的一些结晶形式可以作为多晶型存在,其包括在本发明中。另外,一些结构(I)的化合物也可与水或其它有机溶剂形成溶剂化物。类似地,这样的溶剂化物包括在本发明的范围内。
抗原
在本文描述的疫苗组合物和应用GLA的方法的某些实施方案中使用的抗原可以是期望的个体内免疫反应的引发或增强所针对的任一靶抗原决定部位、分子(包括生物分子)、分子复合物(包括含有生物分子的分子复合物)、亚细胞集群、细胞或组织。通常,术语抗原指目标多肽抗原。然而,如本文所用,抗原也可以指编码目标多肽抗原的重组构建体(例如,表达构建体)。在某些优选实施方案中,所述抗原可以是或可以来自与感染、癌症、自身免疫疾病、过敏症、哮喘症或任何其它疾病状态(其中,抗原特异性免疫反应的激活是理想的或有益的)相关的感染性病原体和/或抗原决定部位、生物分子、细胞或组织,或者与其在免疫学上交叉反应。
优选地,在某些实施方案中,本发明的疫苗制剂包含能够引发针对人类或其它哺乳动物病原体的免疫反应的抗原或抗原组合物,所述抗原或抗原组合物可以包括来自病毒的组成,诸如来自HIV-1(如tat,nef,gp120或gp160)、人类疱疹病毒(如gD或其衍生物或来自HSV1或HSV2的诸如ICP27的即刻早期蛋白)、巨细胞病毒(特别是人类的)(诸如gB或其衍生物)、轮状病毒(包括活力减弱病毒)、爱泼斯坦-巴尔氏病毒(诸如gp350或其衍生物)、水痘带状疱疹病毒(诸如gpI,II和IE63),或者来自诸如乙型肝炎病毒(例如乙型肝炎表面抗原或其衍生物)、甲型肝炎病毒、丙型肝炎病毒以及戊型肝炎病毒的肝炎病毒,或者来自其它的病毒病原体,诸如副粘病毒:呼吸道合胞病毒(诸如F和G蛋白或其衍生物)、副流感病毒、麻疹病毒、腮腺炎病毒、人乳头瘤 病毒(例如HPV6、11、16、18等)、虫媒病毒(例如黄热病毒、登革热病毒、蜱传脑炎病毒、日本脑炎病毒)或流感病毒(全活或灭活病毒、在鸡胚或MDCK细胞内生长的裂解流感病毒,或完整的流感病毒体(如由Gluck,Vaccine,1992,10,915-920所描述的)或者是其纯化的或重组的蛋白,诸如HA,NP,NA或M蛋白或者其组合)。
在某些其它的优选实施方案中,本发明的疫苗制剂包含能够引发针对人类或其它哺乳动物病原体的免疫反应的抗原或抗原组合物,所述抗原或抗原组合物可以包括来自一种或多种细菌病原体的组成,所述病原体例如奈瑟菌属某些种(Neisseria spp),包括淋病奈瑟菌(N.gonorrhea)和脑膜炎奈瑟菌(N.meningitides)(例如荚膜多糖和其轭合物、转铁蛋白结合蛋白、乳铁蛋白结合蛋白、PiIC、黏附素);化脓链球菌(S.pyogenes)(例如M蛋白或其片段、C5A蛋白酶、脂磷壁酸),无乳链球菌(S.agalactiae),变异链球菌(S.mutans):杜克雷嗜血杆菌(H.ducreyi);莫拉菌属某些种(Moraxella spp),包括粘膜炎莫拉菌(Mcatarrhalis),也称为粘膜炎布兰汉球菌(Branhamella catarrhalis)(例如高和低分子量的黏附素及透明质酸酶);博德特菌属某些种(Bordetella spp),包括百日咳博德特菌(B.pertussis)(例如百日咳杆菌粘附素、百日咳毒素或其衍生物,丝状血凝素,腺苷酸环化酶,菌毛)、副百日咳博德特菌(B.parapertussis)以及支气管败血性博德特菌(B.bronchiseptica);分枝杆菌属某些种(Mycobacterium spp),包括肺结核分枝杆菌(M.tuberculosis)(例如ESAT6,抗原85A、-B或-C)、牛型分枝杆菌(M.bovis)、麻风分枝杆菌(M.leprae)、鸟分枝杆菌(M.avium)、副结核分枝杆菌(M.paratuberculosis)、耻垢分枝杆菌(M.smegmatis);军团菌属某些种(Legionella spp),包括嗜肺军团菌(L.pneumophila);埃希氏菌属某些种(Escherichia spp),包括肠毒素性大肠埃希菌(enterotoxic E.coli)(例如定居因子、不耐热毒素或其衍生物、耐热毒素或其衍生物)、肠出血性大肠埃希菌(enterohemorragic E.coli)、肠致病性大肠埃希菌(enteropathogenic E.coli)(例如志贺毒素样毒素或其衍生物);弧菌属某些种(Vibrio spp),包括霍乱弧菌(V.cholera)(例如霍乱毒素或其衍生物);志贺菌属某些种(Shigella spp),包括索内氏志 贺菌(S.sonnei)、痢疾志贺菌(S.dysenteriae)、福氏志贺菌(S.flexnerii);耶尔森菌属某些种(Yersiniaspp),包括小肠结肠炎耶尔森菌(Y.enterocolitica)(例如Yop蛋白)、鼠疫耶尔森菌(Y.pestis)、假结核耶尔森菌(Y.pseudotuberculosis);弯曲菌属某些种(Campylobacterspp),包括空肠弯曲菌(C.jejuni)(例如毒素、黏附素和透明质酸酶)和结肠弯曲菌(C.coli);沙门菌属某些种(Salmonella spp),包括伤寒沙门菌(S.typhi)、副伤寒沙门菌(S.paratyphi)、猪霍乱沙门菌(S.choleraesuis)、肠炎沙门菌(S.enteritidis);李斯特菌属某些种(Listeria spp.),包括单核细胞增生李斯特菌(L.monocytogenes);螺杆菌属某些种(Helicobacter spp),包括幽门螺杆菌(H.pylori)(例如尿素酶、过氧化氢酶、空泡毒素);假单胞菌属某些种(Pseudomonas spp),包括铜绿假单胞菌(P.aeruginosa);葡萄球菌属某些种(Staphylococcus spp.),包括金黄色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis);肠球菌属某些种(Enterococcus spp.),包括粪肠球菌(E.faecalis)、屎肠球菌(E.faecium);梭菌属某些种(Clostridium spp.),包括破伤风梭菌(C.tetani)(例如破伤风毒素及其衍生物)、肉毒梭菌(C.botulinum)(例如肉毒菌毒素及其衍生物)、艰难梭菌(C.difficile)(例如梭菌毒素类A或B及其衍生物);芽孢杆菌属某些种(Bacillusspp.),包括炭疽芽孢杆菌(B.anthracis)(例如肉毒菌毒素及其衍生物);棒杆菌属某些种(Corynebacterium spp.),包括白喉棒杆菌(C.diphtheriae)(例如白喉毒素及其衍生物);疏螺旋体属某些种(Borrelia spp.),包括伯氏疏螺旋体(B.burgdorferi)(例如OspA、OspC、DbpA、DbpB)、伽氏疏螺旋体(B.garinii)(例如OspA、OspC、DbpA、DbpB)、嘎氏疏螺旋体(B.afzelii)(例如OspA、OspC、DbpA、DbpB)、安德森疏螺旋体(B.Andersonii)(例如OspA、OspC、DbpA、DbpB)、赫姆斯疏螺旋体(B.hermsii);埃立克体属某些种(Ehrlichia spp.),包括马埃立克体(E.equi)以及人类粒细胞埃立克体病(Human Granulocytic Ehrlichiosis)作用剂;立克次体属某些种(Rickettsia spp),包括立氏立克次体(R.rickettsii);衣原体属某些种(Chlamydia spp.)包括沙眼衣原体(C.trachomatis)(例如MOMP,肝素结合蛋白)、肺炎衣原体(C.pneumoniae)(例如MOMP,肝素结合蛋白)、鹦鹉热衣原体 (C.psittaci);钩端螺旋体属某些种(Leptospira spp.),包括问号状钩端螺旋体(L.interrogans);密螺旋体属某些种(Treponema spp.),包括苍白球密螺旋体(T.pallidum)(例如罕见的外膜蛋白)、牙密螺旋体(T.denticola)、猪痢疾密螺旋体(T.hyodysenteriae);或其他细菌病原体。
在某些其它的优选实施方案中,本发明的疫苗制剂包含能够引发针对人类或其它哺乳动物病原体的免疫反应的抗原或抗原组合物,所述抗原或抗原组合物可以包含来自一种或多种寄生虫的组成(参见,例如,John,D.T.和Petri,W.A.,Markell and Voge'sMedical Parasitology第9版,2006,WB Saunders,Philadelphia;Bowman,D.D.,Georgis’Parasitology for Veterinarians-第8版,2002,WB Saunders,Philadelphia),例如:疟原虫属某些种(Plasmodium spp.),包括恶性疟原虫(P.falciparum);弓形虫属某些种(Toxoplasma spp.),包括刚地弓形虫(T.gondii)(例如SAG2、SAG3、Tg34);内阿米巴属某些种(Entamoeba spp.),包括溶组织内阿米巴(E.histolytica);巴贝虫属某些种(Babesiaspp.),包括田鼠巴贝虫(B.microti);锥虫属某些种(Trypanosoma spp.),包括克氏锥虫(T.cruzi);贾第虫属某些种(Giardia spp.),包括蓝氏贾第虫(G.lamblia);利什曼虫某些种(Leishmania spp.),包括硕大利什曼虫(L.major);肺囊虫属某些种(Pneumocystisspp.),包括卡氏肺囊虫(P.carinii);毛滴虫属某些种(Trichomonas spp.),包括鞘毛滴虫(T.vaginalis);或者所述抗原或抗原组合物可以包含来自能够感染哺乳动物的蠕虫的组成,诸如:(i)线虫感染(包括但不限于:蠕形住肠线虫(Enterobius vermicularis)、似蚓蛔线虫(Ascaris lumbricoides)、毛首鞭形线虫(Trichuris trichuria)、美洲板口线虫(Necator americanus)、十二指肠钩口线虫(Ancylostoma duodenale)、班氏吴策线虫(Wuchereria bancrofti)、马来布鲁线虫(Brugia malayi)、旋盘尾丝虫(Onchocercavolvulus)、麦地那龙线虫(Dracanculus medinensis)、旋毛形线虫(Trichinellaspiralis)以及粪类圆线虫(Strongyloides stercoralis));(ii)吸虫感染(包括但不限于:曼森血吸虫(Schistosoma mansoni)、埃及血吸虫(Schistosoma haematobium)、日本血吸虫(Schistosoma japonicum)、湄公河裂体吸虫(Schistosoma mekongi)、华枝睾吸虫(Opisthorchis sinensis)、并殖吸虫属(Paragonimus sp)、肝片形吸虫(Fasciolahepatica)、大拟片吸虫(Fasciola magna)、片形吸虫(Fasciola gigantica));以及(iii)绦虫感染(包括但不限于牛肉绦虫(Taenia saginata)和猪肉绦虫(Taenia solium))。因此,某些实施方案可以涉及的疫苗组合物所包括的抗原来自血吸虫属某些种(Schistosomaspp.)、曼氏血吸虫(Schistosoma mansonii)、埃及血吸虫(Schistosoma haematobium)和/或日本血吸虫(Schistosoma japonicum);或者来自酵母,诸如包括白假丝酵母(C.albicans)的假丝酵母属(Candida spp.)、包括新型隐球酵母(C.neoformans)的隐球酵母属(Cryptococcus spp.)。
对于结核分枝杆菌(M.tuberculosis),其它优选的特异性抗原例如Th Ra12、TbH9、Tb Ra35、Tb38-1、Erd 14、DPV、MTI、MSL、mTTC2和hTCC1(WO 99/51748)。结核分枝杆菌(M.tuberculosis)的蛋白还包括融合蛋白及其变体,其中结核分枝杆菌(M.tuberculosis)的至少两种、优选三种多肽融合成较大的蛋白。优选的融合物包括Ra12-TbH9-Ra35、Erd14-DPV-MTI、DPV-MTI-MSL、Erd14DPV-MTI-MSL-mTCC2、Erd14-DPV-MTI-MSL、DPV-MTI-MSL-mTCC2、TbH9-DPV-MTI(WO 99151748)。
衣原体的某些优选的抗原包含例如高分子量蛋白(HWMP)(WO99/17741)、ORF3(EP366 412)、CT622、CT610、pmpD、UVEB以及推定的膜蛋白(Pmps)。疫苗制剂的其它衣原体抗原可以选自在WO99128475中描述的组。优选的细菌疫苗所包含的抗原来自:链球菌属某些种(Streptococcus spp),包括肺炎链球菌(S.pneumoniae)(例如荚膜多糖及其轭合物、PsaA、PspA、PdB、链球菌溶血素、胆碱结合蛋白)和蛋白抗原肺炎链球菌溶血素(Biochem BiophysActa,1989,67,1007;Rubins等人,Microbial Pathogenesis(微生物致病机理),25,337-342);以及其突变的去毒衍生物(WO 90/06951;WO 99/03884)。其它优选的细菌疫苗所包含的抗原来自嗜血菌属(Haemophilus spp.),包括:B型流感嗜血杆菌(H.influenzae typeB)(例如PRP及其轭合物);不可分型流感嗜血杆菌,例如OMP26、高分子量黏附素、P5、P6、蛋白质D和脂蛋白D以及丝束蛋白和丝束蛋白衍生肽(第5,843,464号美国专利) 或多重拷贝变体或其融合蛋白。
乙型肝炎表面抗原衍生物在本领域是公知的,并且其包括在欧洲专利申请EP-A414 374、EP-A-0304 578和EP 198474中所描述的那些PreS1、Pars2 S表面抗原。在一个优选方面,本发明的疫苗制剂包含HIV-1抗原、gp120,特别是在CHO细胞中表达时。在另外的实施方案中,本发明的疫苗制剂包含本文上面限定的gD2t。
在本发明优选的实施方案中,含有要求保护的佐剂的疫苗包含的抗原来自被认为是生殖器疣病因的人类乳头瘤病毒(HPV)(HPV 6或HPV 11及其它),以及是宫颈癌病因的HPV病毒(HPV16、HPV18及其它)。生殖器疣预防或治疗性疫苗的特别优选形式包含L1颗粒和壳粒以及包含选自HPV6和HPV11蛋白E6、E7、L1和L2中的一个或多个抗原的融合蛋白。融合蛋白的某些优选形式包括WO 96/26277中所公开的L2E7以及GB 9717953.5(PCT/EP98/05285)中所公开的蛋白D(1/3)-E7。优选的HPV宫颈感染或癌症的预防性或治疗性疫苗组合物可以包含HPV 16或18的抗原。例如,L1或L2抗原单体,或者L1或L2抗原共同表达为病毒样颗粒(VLP),或者单独的L1蛋白在VLP或壳粒结构中单独表达。这些抗原、病毒样颗粒和壳粒本身是已知的。参见例如WO94/00152、WO94/20137、WO94/05792和WO93/02184。
其它早期蛋白可以单独地被包括或者作为诸如E7、E2或优选例如F5的融合蛋白;特别优选的实施方案包括包含L1E7融合蛋白的VLP(WO 96/11272)。特别优选的HPV16抗原包含与蛋白D载体融合的早期蛋白E6或E7以从HPV16形成蛋白D-E6或E7融合物或其组合;或者包含E6或E7与L2的组合(WO 96/11272)。可选择地,HPV16或18的早期蛋白E6和E7可以在单分子、优选蛋白D-E6/E7融合物中表达。这类疫苗可任选地包含朝向HPV18的E6和E7蛋白的任一者或两者,优选以蛋白D-E6或蛋白D-E7融合蛋白或蛋白D E6/E7融合蛋白的形式。本发明的疫苗可以还包含来自其它HPV菌株的抗原,优选来自HPV 31或33菌株。
本发明的疫苗还包含来自导致疟疾的寄生虫的抗原。例如,来自恶性疟原虫(Plasmodia falciparum)的优选抗原包括RTS,S和TRAP。 RTS是杂交蛋白,其基本上包含恶性疟原虫(P.falciparum)的环子孢子(CS)蛋白的全部C-末端部分,所述C-末端部分通过乙型肝炎表面抗原的preS2部分的四个氨基酸连接于乙型肝炎病毒表面(S)抗原。其完整结构在PCT/EP92/02591号国际专利申请中公开,该国际申请公布号为WO 93/10152,要求第9124390.7号英国专利申请的优先权。当在酵母中表达时,RTS作为脂蛋白颗粒而产生,且当它与来自HBV的S抗原共表达时,它产生了称为RTS,S的混合颗粒。
在以WO 90/01496公布的PCT/GB89/00895号国际专利申请中描述了TRAP抗原。本发明的优选实施方案是疟疾疫苗,其中抗原制剂包含RTS,S和TRAP抗原的组合。可能为多级疟疾疫苗组分的候选物的其它疟原虫抗原是恶性疟原虫(P.faciparum)MSP1、AMA1、MSP3、EBA、GLURP、RAP1、RAP2、钳合蛋白、PfEMPI、Pf332、LSA1、LSA3、STARP、SALSA、PfEXP1、Pfs25、Pfs28、PFS27125、Pfs16、Pfs48/45、Pfs230以及在疟原虫属某些种中的它们的类似物。
因此,本文公开的某些实施方案涉及的抗原来自至少一种感染型病原体,例如细菌、病毒或真菌,这包括:放线细菌,诸如结核分支杆菌和麻风分支杆菌或另外的分支杆菌;细菌,诸如沙门菌属(Salmonella)、奈瑟球菌属(Neisseria)、疏螺旋体属(Borrelia)、衣原体属(Chlamydia)或博德特菌属(Bordetella)的成员;病毒,诸如单纯疱疹病毒、人类免疫缺陷病毒(HIV)、猫免疫缺陷病毒(FIV)、巨细胞病毒、水痘带状疱疹、肝炎病毒、爱泼斯坦-巴尔氏病毒(EBV)、呼吸道合胞病毒、人乳头状瘤病毒(HPV)以及巨细胞病毒;HIV,诸如HIV-1或HIV-2;真菌,诸如曲霉菌(Aspergillus)、芽生菌(Blastomyces)、球孢菌(Coccidioides)和肺孢子菌(Pneumocysti),或者酵母,包括假丝酵母(Candida)种,诸如白色念珠菌(C.albicans)、光滑念珠菌(C.glabrata)、克柔假丝酵母(C.krusei)、葡萄牙念珠菌(C.lusitaniae)、热带念珠菌(C.tropicalis)、近平滑念珠菌(C.parapsilosis);诸如原生动物的寄生虫,例如疟原虫(Plasmodium)种,包括恶性疟原虫(P.falciparum)、间日疟原虫(P.vivax)、三日疟原虫(P.malariae)和卵圆疟原虫(P.ovale);或者其它寄生虫,例如棘阿米巴(Acanthamoeba)、溶组织内阿米巴 (Entamoeba histolytica)、管圆线虫(Angiostrongylus)、曼氏血吸虫(Schistosoma mansonii)、埃及吸血虫(Schistosomahaematobium)、日本血吸虫(Schistosoma japonicum)、隐孢子虫(Cryptosporidium)、钩虫属(Ancylostoma)、溶组织内阿米巴(Entamoeba histolytica)、结肠内阿米巴(Entamoebacoli)、迪斯帕内阿米巴(Entamoeba dispar)、哈特曼内阿米巴(Entamoeba hartmanni)、波氏内阿米巴(Entamoeba polecki)、班氏吴策线虫(Wuchereria bancrofti)、贾第虫(Giardia)以及利什曼虫(Leishmania)的一种或多种。
例如,在含GLA的疫苗实施方案中包含来自疏螺旋体属(Borrelia sp.)的抗原,所述抗原可以包括核酸、病原体来源的抗原或抗原制剂、重组产生的蛋白或肽以及嵌合融合蛋白。一种这样的抗原为OspA。OspA可以借助其在宿主细胞内的生物合成而成为载脂形式的完全成熟的蛋白(Lipo-OspA),或者可选择地成为非载脂的衍生物。这种非载脂衍生物包括非载脂NS1-OspA融合蛋白和另一种MDP-OspA,其中非载脂NS1-OspA融合蛋白具有流感病毒的非结构蛋白(NS1)的前81个N-末端氨基酸以及完整的OspA蛋白,并且另一种MDP-OspA为携带3个附加N-末端氨基酸的OspA的非载脂形式。
用于鉴别患有或疑似有患本文所述感染性病原体感染危险的个体的组合物和方法在本领域是已知的。
例如,细菌结核分支杆菌(Mycobacterium tuberculosis)导致肺结核(TB)。细菌通常侵袭肺部,但也可以侵袭肾脏、脊柱和脑。如果不能恰当地治疗,TB疾病可以是致死性的。当感染的人打喷嚏或咳嗽时,这种疾病可以在人与人之间播散。在2003年,美国报道的TB病例超过了14,000例。
尽管结核通常可以采用长期的抗生素治疗来控制,但这种治疗不足以预防该疾病的播散并对抗生素抗性菌株的潜在选择方面存在担忧。感染的个体在一段时间内可以是无症状的,但有传染性。此外,尽管依从治疗方案是至关重要的,但患者行为难以监测。一些患者不能完成治疗过程,这导致了无效治疗且发展了耐药性(例如第7,087,713号美国专利)。
目前,活菌疫苗是诱导针对肺结核的保护性免疫的最有效的方法。用于这一目的最常见的分支杆菌(Mycobacterium)是卡介菌(Bacillus Calmette-Guerin)(BCG),即牛型分支杆菌的无毒力株。然而,BCG的安全性和功效是争议的来源,并且有些国家,如美国并不给全民接种。通常使用皮肤测试来完成诊断,其包括结核菌素PPD(蛋白纯化的衍生物)的皮内暴露。抗原特异性T细胞反应导致了注射后48、72小时在注射部位的可测硬结,这标示分支杆菌抗原的暴露。然而,敏感性和特异性一直是该测试的难题,并且接种了BCG的个体不能与受感染的患者区分开(例如,第7,087,713号美国专利)。
尽管巨噬细胞已表现出作为肺结核杆菌免疫的主要效应器,但T细胞是这类免疫的主要诱导物。T细胞在防止肺结核杆菌感染中的重要作用通过AIDS患者中频发肺结核而示例,这归因于与人类免疫缺陷病毒(HIV)感染有关的CD4T细胞的耗竭。已表明,分支杆菌反应性CD4T细胞是γ干扰素(IFN-γ)的有效产生物,其也已被进一步表明触发小鼠体内巨噬细胞的抗分支杆菌效应。尽管不太清楚IFN-γ在人体内的作用,但已有研究表明1,25-二羟基-维生素D3单独地或与IFN-γ或肿瘤坏死因子-α结合地激活人类巨噬细胞以抑制肺结核分支杆菌感染。此外,已知IFN-γ刺激人类巨噬细胞以产生1,25-二羟基-维生素D3。类似地,已表明,IL-12在激发对肺结核分支杆菌感染的抗性中发挥作用。对肺结核分支杆菌感染的免疫学的综述,参见Chan and Kaufmann,in Tuberculosis:Pathogenesis,Protection and Control(肺结核:发病机理、保护和控制),Bloom(ed.),ASMPress.Washington,D.C.(1994)。
诊断肺结核或诱导针对抗肺结核的保护性免疫的现有的化合物和方法包括多肽和编码这种多肽的DNA分子的应用,所述多肽含有一种或多种分支杆菌蛋白的至少一种免疫原部分。包含这种多肽或DNA序列以及适当的检测试剂的诊断试剂盒可以用于检测患者和生物样本中的分支杆菌感染。也提供了针对这种多肽的抗生素。此外,这种化合物可以配制于疫苗和/或药物组合物中,用于抗分支杆菌感染的免疫。(第6,949,246号和第6,555,653号美国专利)。
二十世纪60年代,在世界上很多地方都消灭了疟疾,但这种疾病仍持续存在,并出现了抗现有药物的新致病株。疟疾在90多个国家是主要的公共卫生问题。10例疟疾中有9例出现在撒哈拉以南非洲。超过1/3的世界人口正面临危险,且每年有3.5亿至5亿人感染疟疾。今年有4千5百万的孕妇面临感染疟疾的危险。在那些已经被感染的个体中,每年有超过1百万的被感染个体死于可预防的疾病。那些死亡者中主要是非洲的儿童。
疟疾通常是在人被受感染的雌疟蚊叮咬时传播。蚊子必须通过汲取已经感染疟疾的人的血而被感染后才能传播疟疾。疟疾由寄生虫导致,且该病的临床症状包括发热和流感样不适,诸如寒战、头痛、肌肉疼痛和疲倦。这些症状可以伴有恶心、呕吐和腹泻。疟疾也可以导致由红细胞损失而引起的贫血和黄疸。由一种类型的疟疾,即恶性疟原虫(Plasmodium falciparum)的感染如果不能及时治疗的话,可能导致肾衰、惊厥、意识模糊、昏迷和死亡。
个体中疟疾的体外诊断方法是已知的,其包括将从个体采集的组织或生物学流体与分子或多肽组合物接触(在允许体外免疫反应在所述组合物与可存在于组织或生物流体中的抗体之间发生的条件下)并且放置在形成的抗原抗体复合物的体外检测中(参见,例如第7,087,231号美国专利),其中所述分子或多肽组合物包括一个或多个多肽序列,其携带由恶性疟原虫(Plasmodium falciparum)的感染活性而产生的蛋白中的一个或多个T抗原决定部位的全部或部分。
已经描述了重组恶性疟原虫(Plasmodium falciparum)(3D7)AMA-1胞外区的表达和纯化。先前的方法已经产生了高纯化的蛋白,其保留了天然分子的折叠和二硫化物桥接。重组的AMA-1可以用作诊断试剂以及用于抗体制备,并且作为蛋白单独用于或作为疫苗的一部分用于预防疟疾。(第7,029,685号美国专利)
本领域已经描述了编码种属特异性的间日疟原虫(P.vivax)疟疾肽抗原的多核苷酸,所述抗原是分泌入感染后的易感哺乳动物宿主血浆内的蛋白或蛋白片段,随之产生针对这些抗原的单克隆或多克隆抗体。所述肽抗原、单克隆抗体和/或多克隆抗体在用于诊断疟疾的测定 中利用,以及被用于确定是否间日疟原虫(Plasmodium vivax)是导致感染的种属(第6,706,872号美国专利)。也已经报道了种属特异性的间日疟原虫疟疾肽抗原,其是分泌入感染后的敏感哺乳动物宿主血浆内的蛋白或蛋白片段,随之产生针对这些抗原的单克隆或多克隆抗体。所述肽抗原、单克隆抗体和/或多克隆抗体在用于诊断疟疾的测定中被利用,以及被用于确定是否间日疟原虫(Plasmodium vivax)是导致感染的种属(参见,例如第6,231,861号美国专利)。
通过产生高纯度蛋白的方法也已经表达了重组的恶性疟原虫(Plasmodiumfalciparum)(3D7)AMA-1胞外区,其保留了天然分子的折叠和二硫化合物桥接。所述重组的AMA-1用作诊断试剂,对于在抗体产生中的用途,其用作疫苗(第7,060,276号美国专利)。同样已知的是重组恶性疟原虫(Plasmodium falciparum)(3D7)MSP-142的表达和纯化,其保留了天然分子的折叠和二硫化合物桥接。重组的MSP-142用作诊断试剂,对于在抗体产生中的用途,其用作疫苗(第6,855,322号美国专利)。
因此根据这些和相关的公开内容,已知检测人类疟疾感染的诊断方法,以鉴定患有或疑似有患疟疾感染性病原体感染危险的个体。具体地,例如,将血液样本与含3-乙酰基嘧啶腺嘌呤二核苷酸(APAD)、底物(例如,乳酸盐或乳酸)以及缓冲液的试剂结合。该试剂被设计为检测由疟疾寄生虫产生的独特的糖分解酶的存在。已知该酶是寄生虫乳酸脱氢酶(PLDH)。使用上述试剂,很容易区别PLDH与宿主LDH。所述试剂与寄生虫感染的血液样本的结合导致APAD的还原。然而,APAD不被宿主LDH还原。然后可以通过包括光谱、荧光测定、电泳或比色分析的多种技术来检测还原的APAD。以上述方式检测还原的APAD提供了疟疾感染的阳性指示(例如第5,124,141号美国专利)。在另一种诊断疟疾的方法中,包含特征性氨基酸序列的多肽源自恶性疟原虫抗原GLURP,并可在检测样本中由针对所述多肽或与其反应的特异性抗体所识别。(第5,231,168号美国专利)
利什曼病是世界范围内的寄生虫病,在印度次大陆、非洲和拉丁美洲频繁流行,并且是世界卫生组织疫苗开发的优先对象。不同疾病 的复合,利什曼寄生虫导致了内脏器官的致命感染以及严重的皮肤病。利什曼病最具破坏性的形式中的一种是鼻和嘴的毁容性感染。利什曼病例的数量越来越多,并且目前在许多地区以难于控制。作为HIV感染的结果,利什曼病在一些发达地区也处于上升状态,特别是在南欧。可利用的药物是有毒性的、昂贵的,并需要长期的每日注射。
利什曼虫是栖息于免疫系统的巨噬细胞或白血细胞的原生动物寄生虫。这种寄生虫通过小型吸血昆虫(沙蝇)的叮咬而传播,所述昆虫由于栖息于地球上的广大地区,因此难以控制。
内脏利什曼病是该病三种临场表现中最危险的。据估计每年发生约500,000例内脏形式(黑热病或“致死疾病”)的新病例。超过200百万的人目前处于感染内脏利什曼病的危险中。超过90%的内脏利什曼病例发生在印度、孟加拉国、苏丹、巴西和尼泊尔。大多数死亡发生在儿童中。患有皮肤形式的那些人通常是永久地遗留下丑容。
利什曼虫感染难以诊断,并且通常涉及组织活检样本的组织病理学分析。然而已经开发了几种血清学和免疫学诊断测定。(第7,008,774号美国专利;Senaldi等人,(1996)J.Immunol.Methods 193:95;Zijlstra等人,(1997)Trans.R.Soc.Trop.Med.Hyg.91:671673;Badaro等人,(1996)J.Inf.Dis.173:758 761;Choudhary,S.等人,(1992)J.Comm.Dis.24:32 36;Badaro,R.等人,(1986)Am.J.Trop.Med.Hyg.35:72 78;Choudhary,A.,等人,(1990)Trans.R.Soc.Trop.Med.Hyg.84:363 366;以及Reed,S.G.,等人,(1990)Am.J.Trop.Med.Hyg.43:632 639)。前鞭毛体释放代谢产物进入培养基以产生条件培养基。这些代谢产物对宿主产生免疫性。参见Schnur,L.F.等人,(1972)Isrl.J.Med.Sci.8:932942;Sergeiev,V.P.等人,(1969)Med.Parasitol.38:208 212;El-On,J.等人,(1979)Exper.Parasitol.47:254 269;以及Bray,R.S.等人,(1966)Trans.R.Soc.Trop.Med.Hyg.60:605 609;第6,846,648号美国专利、第5,912,166号美国专利、第5,719,263号美国专利、第5,411,865号美国专利。
世界范围内大约有4千万人感染导致AIDS的病毒HIV。每年约3千万人死于该病,他们中的95%是在发展中国家。每年有接近5百万 的人感染HIV。目前在撒哈拉以南的非洲人经受该病的负担最重,但它正在向诸如印度、中国和俄罗斯的其它国家快速传播。这种流行病在少数人口中更快速地增长。在美国,从1981年起,已经报道了超过950,000例的AIDS。AIDS袭击处于生产年纪的人们。由于生物学和社会原因,妇女患HIV/AIDS的危险增加。
AIDS由人类免疫缺陷病毒(HIV)导致,所述病毒杀死和破坏人体免疫系统的细胞,并且渐进地破坏人体对抗感染和某些癌症的能力。HIV最普遍的传播是通过与受感染的伴侣进行无保护的性交。对这一问题最有力的解决方案是预防病毒的传播。实现该目的的一条途径是制备安全、有效和负担得起的HIV疫苗。在世界范围内,处于高危HIV感染的患者中不到五分之一采取了有效的预防。
诊断HIV感染的方法是已知的,包括通过患者样本的病毒培养、确定的核酸序列的PCR,以及对患者血清中抗-HIV抗体的存在的抗体测试(参见例如,第6,979,535号、第6,544,728号、第6,316,183号、第6,261,762号、第4,743,540号美国专利)。
根据本文公开的某些其它实施方案,疫苗组合物和相关制剂以及应用方法可以包括来自癌细胞的抗原,其可以用于癌症的免疫治疗学治疗。例如,佐剂制剂可以利用肿瘤排斥抗原,诸如对前列腺癌、乳腺癌、结肠直肠癌、肺癌、胰腺癌、肾癌或黑色素瘤癌的排斥抗原。示例性的癌症或癌细胞来源的抗原包括MAGE 1、3和MAGE 4或诸如在WO99/40188中公开的那些其它MAGE抗原、PRAME、BAGE、Lage(也被称为NY Eos 1)SAGE和HAGE(WO 99/53061)或GAGE(Robbins和Kawakami,1996Current Opinions in Immunology 8,pps628-636;Vanden Eynde等人,International Journal of Clinical&Laboratory Research(1997&1998);Correale等人(1997),Journal of the National Cancer Institute 89,p.293。癌抗原的这些非限定性实例表达于诸如黑色素瘤、肺癌、肉瘤和膀胱癌的多种肿瘤类型中。参见,例如第6,544,518号美国专利。
依照某些目前公开的实施方案,适于与GLA一起使用的其它肿瘤特异性抗原包括但不限于肿瘤特异性或肿瘤相关性神经节苷脂类,如 GM2和GM3或其与载体蛋白的轭合物;或者在GLA疫苗组合物中使用的用于引发或增强抗癌症免疫反应的抗原可以是自身肽激素,诸如可用于许多癌症治疗的全长促性腺激素释放激素(GnRH,WO95/20600),即一种10个氨基酸长的短肽。在另一个实施方案中,使用了前列腺抗原,例如前列腺特异性抗原(PSA)、PAP、PSCA(例如,Proc.Nat.Acad.Sci.USA 95(4)1735-17401998)、PSMA或在优选实施方案中称为前列腺酶的抗原。(例如,Nelson,等人,Proc.Natl.Acad.Sci.USA(1999)96:3114-3119;Ferguson,等人Proc.Natl.Acad.Sci.USA1999.96,3114-3119;WO 98/12302;第5,955,306号美国专利;WO98/20117;第5,840,871号和第5,786,148号美国专利;WO/004149。从WO98/137418和WO/004149中可知其它的前列腺特异性抗原。另一种是STEAP(PNAS 9614523 14528 7-12 1999)。
用于本发明背景下的其它肿瘤相关抗原包括:Plu-1(J Biol.Chem274(22)15633-15645,1999)、HASH-1、HasH-2、Cripto(Salomon等人Bioessays 199,21:61-70,第5,654,140号美国专利)以及Criptin(第5,981,215号美国专利)。此外,与癌症治疗疫苗特别相关的抗原也包括酪氨酸酶和存活素。
本文公开的涉及包含癌抗原的含GLA疫苗组合物的实施方案可以用于对抗由肿瘤相关抗原表达所表征的任何癌症,诸如HER-2/neu表达或其他癌症特异性或癌症相关的抗原。
在患有或疑似有患癌症危险的个体中对癌症的诊断可以通过众多本领域公认的方法学中的任一种来完成,这可以依赖于多种因素而变化,所述因素包括临床表现、癌症的进展程度、癌症类型或其它因素。癌症诊断学的实例包括:患者样本(例如,血液、皮肤活检、其它组织活检、手术样本等)的组织病理学检测、组织细胞化学检测、免疫组织细胞化学检测和免疫组织病理学检测,对确定的遗传(例如,核酸)标记的PCR检测,对循环的癌相关抗原或携带所述抗原的细胞的血清学检测,或对确定的特异性抗体的血清学检测,或者本领域技术人员熟悉的其它方法。参见,例如,第6,734,172号、第6,770,445号、第6,893,820号、6,979,730号、第7,060,802号、第7,030,232号、第6,933,123 号、第6,682,901号、第6,587,792号、第6,512,102号、第7,078,180号、第7,070,931号美国专利;JP5-328975;Waslylyk等人,1993Eur.J Bioch.211(7):18。
本发明的某些实施方案的疫苗组合物和方法还可用于预防或治疗自身免疫疾病,其包括疾病、疾病状态或病症,其中宿主或个体的免疫系统不利地介导针对“自身”组织、细胞、生物分子(例如,肽、多肽、蛋白、糖蛋白、脂蛋白、蛋白脂质、脂质、糖脂、诸如RNA和DNA的核酸、低聚糖、多聚糖、蛋白聚糖、糖胺聚糖等等,以及个体细胞和组织的其它分子组分)或抗原决定部位(例如,特异性免疫界定识别结构,诸如由抗体可变区互补性决定区(CDR)或由T细胞受体CDR所识别的那些)的免疫反应。
因此自身免疫疾病的特征在于涉及细胞或抗体的异常免疫反应,其在任一种情形下都针对正常的自组织。哺乳动物的自身免疫疾病能通常分类为两种不同类型中的一种:细胞介导的疾病(即,T-细胞)或抗体介导的病症。细胞介导的自身免疫疾病的非限定性实例包括多发性硬化、风湿性关节炎、桥本甲状腺炎、I型糖尿病(幼年起病型糖尿病)和自身免疫性葡萄膜视网膜炎。抗体介导的自身免疫病症包括但不限于重症肌无力、全身性红斑狼疮(或SLE)、格雷夫斯病、自身免疫性溶血性贫血、自身免疫性血小板减少症、自身免疫性哮喘、冷球蛋白血症、血栓性血小板减少性紫癜、原发性胆汁性肝硬化和恶性贫血。与全身性红斑狼疮有关的抗原是小核核糖核酸蛋白(snRNP);与格雷夫斯病有关的抗原是促甲状腺激素受体、甲状腺球蛋白和甲状腺上皮细胞的其它组分(Akamizu等人,1996;Kellerman等人,1995;Raju等人,1997以及Texier等人,1992);与天疱疮有关的抗原是类钙粘蛋白天疱疮抗原,例如桥粒芯糖蛋白3和其它黏附分子(Memar等人,1996:Stanley,1995;Plott等人,1994;以及Hashimoto,1993);以及与血栓性血小板减少性紫癜有关的抗原是血小板抗原。(参见,例如第6,929,796号美国专利;Gorski等人(Eds.),Autoimmunity(自身免疫),2001,Kluwer Academic Publishers,Norwell,MA;Radbruch和Lipsky,P.E.(Eds.)CurrentConcepts in Autoimmunity and Chronic Inflammation(自 身免疫和慢性炎症的现代观点)(Curr.Top.Microbiol,and Immunol.(微生物学和免疫学的现代观点))2001,Springer,NY.)
自身免疫在80多种不同疾病中发挥作用,包括1型糖尿病、多发性硬化、狼疮、风湿性关节炎、硬皮病和甲状腺疾病。对于大多数自身免疫疾病,缺乏对发病率的有力的量化评估。20世纪90年代末完成的最新研究表明自身免疫疾病是美国第三位最常见的主要疾病;且最常见的自身免疫疾病影响了超过8千5百万美国人。该流行疾病的目前估值是美国人口的5%到8%。大多数自身免疫疾病倾向于传染女性。对于获得自身免疫疾病,女性可能是男性的2.7倍以上。女性更易感自身免疫疾病;男性看起来比女性具有更高水平的天然杀伤细胞活性。(Jacobsen等人,Clinical Immunology and Immunopathology,84:223-243,1997.)
当免疫系统将自身组织错认为异物而启动不恰当的攻击时,自身免疫疾病发生。机体可受到自身免疫疾病不同方式的影响,包括例如,内脏(克罗恩氏疾病)和脑部(多发性硬化)。已知自身抗体攻击自身细胞或自身组织以损伤它们的功能,并由此导致自身免疫疾病,并且已知在自身免疫疾病真正发生(例如,临床体征和症状的出现)之前,可在患者的血清中检测出自身抗体。因此自身抗体的检测允许早期发现或识别自身免疫疾病的存在或发展为自身免疫疾病的风险。基于这些发现,已经发现了针对自身抗原的多种自身抗体,并且在临床检验中已经检测了针对自身抗原的自身抗体(例如,第6,919,210号、第6,596,501号、第7,012,134号、第6,919,078号美国专利),而其它的自身免疫诊断可能涉及相关代谢产物的检测(例如,第4,659,659号美国专利)或免疫活性(例如,第4,614,722和5,147,785、4,420,558、5,298,396、5,162,990、4,420,461、4,595,654、5,846,758、6,660,487号美国专利)。
在某些实施方案中,本发明的组合物特别适用于治疗老人和/或免疫抑制的个体,包括肾透析个体、化疗和/或放疗个体、接受移植者等。这些个体通常表现出对疫苗较弱的免疫反应,因此使用本发明的组合物能够增强在这些个体中实现免疫反应。
在其它实施方案中,在本发明组合物中使用的一种抗原或多种抗 原包括与呼吸系统疾病有关的抗原,诸如由细菌感染(例如,肺炎球菌感染)导致或加剧的那些疾病,从而预防和治疗诸如慢性阻塞性肺疾病(COPD)的疾病状态。COPD的生理学定义是在患有慢性支气管炎和/或肺气肿的患者中存在不可逆或部分可逆的呼吸道阻塞(Am J Respir CritCare Med.1995Nov;152(5Pt 2):S77-121)。COPD的恶化经常是由细菌(例如,肺炎球菌)感染而引起的(Clin Microbiol Rev.2001Apr;14(2):336-63)。在具体实施方案中,本发明的组合物包含与肺炎链球菌疫苗(Wyeth)组合的如本文所述的GLA佐剂。
还在另一实施方案中,包含本文所述的GLA的本发明组合物用于治疗过敏性疾病状况。例如,在具体实施方案中,所述组合物用于过敏症脱敏治疗。这类治疗涉及用逐渐增加剂量的使人过敏的物质刺激免疫系统,其中所述物质配制在包含GLA的组合物中。在具体实施方案中,所述组合物用于治疗对食物产品、花粉、螨虫、猫或有刺昆虫(例如,蜜蜂、大黄蜂、小黄蜂、胡蜂、蚁蜂、火蚁)的过敏症。
TLR
如本文所述,本发明的某些实施方案涉及包括药物组合物的疫苗组合物和免疫佐剂组合物,除本发明的GLA化合物以外,其还包含一种或多种钟样受体激动剂(TLR激动剂)。钟样受体(TLR)包括固有免疫系统的细胞表面跨膜受体,其赋予宿主细胞早期识别多种保守的微生物分子结构的能力,所述分子结构例如可以存在于众多感染性病原体内或表面。(例如,Armant等人,2002Genome Biol.3(8):reviews(综述)3011.1-3011.6;Fearon等人,1996Science 272:50;Medzhitov等人,1997Curr.Opin.Immunol.9:4;Luster2002Curr.Opin.Immunol.14:129;Lien等人2003Nat.Immunol.4:1162;Medzhitov,2001Nat.Rev.Immunol.1:135;Takeda等人,2003Ann Rev Immunol.21:335;Takeda等人2005Int.Immunol.17:1;Kaisho等人,2004Microbes Infect.6:1388;Datta等人,2003J.Immunol.170:4102)。
诱导TLR-介导的信号转导以通过天然免疫系统加强免疫反应的启动可受TLR激动剂影响,所述TLR激动剂占用细胞表面TLR。例 如,脂多糖(LPS)可以为通过TLR2或TLR4的TLR激动剂(Tsan等人,2004 J.Leuk.Biol.76:514;Tsan等人,2004Am.J.Physiol.CellPhysiol.286:C739;Lin等人,2005 Shock 24:206);聚(肌苷-胞苷)(polyl:C)可以为通过TLR3的TLR激动剂(Salem等人,2006 Vaccine 24:5119);CpG序列(含有未甲基化的胞嘧啶-鸟嘌呤或诸如CpG 7909的“CpG”二核苷酸基序的寡聚脱氧核苷酸,Cooper等人,2005 AIDS19:1473;CpG10101 Bayes等人Methods Find Exp Clin Pharmacol 27:193;Vollmer等人Expert Opinion on Biological Therapy 5:673;Vollmer等人,2004Antimicrob.AgentsChemother.48:2314;Deng等人,2004 J.Immunol.173:5148)可以是通过TLR9的TLR激动剂(Andaloussi等人,2006Glia54:526;Chen等人,2006 J.Immunol.177:2373);肽聚糖可以是TLR2和/或TLR6的激动剂(Soboll等人,2006Biol.Reprod.75:131;Nakao等人,2005J.Immunol.174:1566);3M003(4-氨基-2-(乙氧基甲基)-α,α-二甲基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-乙醇水合物,分子量318Da,得自3M Pharmaceuticals,St.Paul,MN,其也是相关化合物3M001和3M002的来源;Gorden等人,2005 J.Immunol.174:1259)可以是TLR7激动剂(Johansen 2005 Clin.Exp.Allerg.35:1591)和/或TLR8激动剂(Johansen2005);鞭毛蛋白可以是TLR5激动剂(Feuillet等人,2006Proc.Nat.Acad.Sci.USA 103:12487);以及丙肝抗原可以作为通过TLR7和/或TLR9的TLR激动剂(Lee等人,2006Proc.Nat.Acad.Sci.USA 103:1828;Horsmans等人,2005Hepatol.42:724)。其它的TLR抗原是已知的(例如,Schirmbeck等人,2003 J.Immunol.171:5198),且依照目前描述的某些实施方案可以使用其它的TLR抗原。
例如,根据背景知识(参见,例如第6,544,518号美国专利),已知含未甲基化的CpG二核苷酸(“CpG”)的免疫刺激型寡核苷酸可以作为当通过全身和粘膜途径进行给药时的佐剂(WO 96/02555,EP 468520,Davis等人,J.Immunol,1998.160(2):870-876;McCluskieand Davis,J.Immunol.,1998,161(9):4463-6)。CpG是存在于DNA中的胞嘧啶-鸟嘌呤二核苷酸基序的缩写。由Krieg,Nature 374,p546 1995阐明CG基序在免疫刺激中的重要作用。详细的分析已表明CG基序必须是在某一 序列背景下,且这些序列在细菌DNA中是常见的,但在脊椎动物DNA中罕见。所述免疫刺激序列通常是:嘌呤,嘌呤,C,G,嘧啶,嘧啶;其中所述二核苷酸CG基序不是甲基化的,但已知其它未甲基化CpG序列具有免疫刺激性,且可以用于本发明的某些实施方案中。当CpG配制于疫苗中时,它可以在游离溶液中连同游离抗原一起给药(WO96/02555;McCluskie和Davis,见上述),或与抗原共价共轭(第WO98/16247号PCT公布),或者与诸如氢氧化铝的载体进行配制(例如,Davis等人.见上述,Brazolot-Millan等人,Proc.Natl.Acad.Sci.,USA,1998,95(26),15553-8)。
用于本发明的佐剂或疫苗的优选寡核苷酸优选包含由至少三个、更优选至少6个或更多个核苷酸而分开的两个或多个二核苷酸CpG基序。本发明的寡核苷酸通常是脱氧核苷酸。在优选的实施方案中,寡核苷酸中的核苷酸间为二硫代磷酸酯或更优选为硫代磷酸键,尽管磷酸二酯和其它的核苷酸间键都在本发明的范围内,包括带有混合核苷酸间键合的寡核苷酸。在第5,666,153号、第5,278,302号美国专利和WO95/26204中描述了产生硫代磷酸寡核苷酸或二硫代磷酸酯的方法。
优选的寡核苷酸的实例具有在下述公开文献中公开的序列;对于某些本文公开的实施方案,所述序列优选包含硫代磷酸修饰的核苷酸间键合:
CPG 7909:Cooper等人,“CPG 7909 adjuvant improves hepatitis B virusvaccine seroprotection in antiretroviral-treated HIV-infected adults.(CPG7909佐剂在抗逆转录病毒治疗的HIV感染的成年人中改善乙型肝炎病毒疫苗的血清保护).”AIDS,2005 Sep 23;19(14):1473-9。
CpG 10101:Bayes等人,“Gateways to clinical trials(临床试验途径)”Methods Find.Exp.Clin.Pharmacol.2005Apr;27(3):193-219。
Vollmer J.,“Progress in drug development of immunostimula-tory CpGoligodeoxynucleotide ligands for TLR9(TLR9的免疫刺激性CpG寡聚脱氧核苷酸配体的药物开发进展)”Expert Opinion on Biological Therapy.2005 May;5(5):673-682。
可选择的CpG寡核苷酸可以包括上文引用的公开文献中所描述 的优选序列变体,其不同在于它们具有无逻辑(inconsequential)的核苷酸序列置换、插入、删除和/或添加。本发明的某些实施方案中使用的CpG寡核苷可以通过本领域已知的任何方法而合成(例如EP 468520)。可以利用自动合成器方便地合成这些寡核苷酸。所述寡核苷酸通常是脱氧核苷酸。在优选的实施方案中,寡核苷酸中的核苷酸间键为二硫代磷酸酯,或更优选地为硫代磷酸键,尽管磷酸二酯也在目前涉及的实施方案的范围内。也涉及包含不同核苷酸间键合的寡核苷酸,例如,混合的硫代磷酸磷酸二酯。也可以使用稳定寡核苷酸的其它核苷酸间键。
辅佐剂
本文提供的某些实施方案包括包含药物组合物的疫苗组合物和免疫佐剂组合物,所述药物组合物包含除GLA化合物以外的至少一种辅佐剂,该辅佐剂指具有佐剂活性但不同于GLA的这种组合物组分。具有所述佐剂活性的辅佐剂所包括的成份在给予诸如人类(例如人类患者)、非人类的灵长类、哺乳动物或具有识别免疫系统的另一种高等真核生物体的个体时,能够改变(即,以统计学显著的方式增加或降低;以及在某些优选的实施方案中,增强或增加)免疫反应的效能和寿命。(参见,例如,Powell和Newman,“Vaccine design-TheSubunit and Adjuvant Approach(疫苗设计-亚单位和佐剂方法)”,1995,Plenum Press,New York)。在本文公开的某些实施方案中,GLA和期望的抗原,以及任选地一种或多种辅佐剂可以因此改变,例如引发或增强针对期望的抗原的免疫反应,所述抗原可以随GLA同时给药或者可以在时间和/或空间上(例如,在不同的解剖学部位)分开给药,但某些发明实施方案并不旨在限制于此,因此还涉及在不包含指定抗原的组合物中的GLA给药,但所述组合物还可以包含一种或多种TLR激动剂、辅佐剂、咪唑并喹啉免疫反应调节剂以及双茎环免疫调节剂(dSLIM)。
因此如上所述,辅佐剂包含除了GLA之外具有佐剂作用的组成,诸如皂苷和皂苷类似物,包括QS21和QS21类似物(参见,例如第5,057,540号美国专利;EP 0 362 279 B1;WO95/17210)、明矾、诸如番 茄素的植物碱、诸如(但不限于)皂苷的清洁剂、聚山梨醇酯80、司盘85和硬脂酰酪氨酸、一种或多种细胞因子(例如,GM-CSF、IL-2、IL-7、IL-12、TNF-α、IFN-γ)、咪唑并喹啉免疫反应调节剂以及双茎环免疫调节剂(dSLIM,例如,Weeratna等人,2005Vaccine 23:5263)。
在例如美国专利6,544,518,Lacaille-Dubois,M and Wagner H.(1996Phytomedicine 2:363-386),第5,057,540号美国专利,Kensil,Crit Rev Ther DrugCarrier Syst,1996,12(1-2):1-55和EP 0 362 279 B1中教授了包括皂苷的清洁剂。包含Quil A部分(皂苷)的称为免疫刺激复合物(ISCOMS)的微粒结构是溶血的,且已经疫苗的制备中使用(Morein,B.,EP 0 109 942 B1)。已报道这些结构具有佐剂活性(EP 0 109942B1;WO 96/11711)。这些溶血皂苷QS21和QS17(Quil A的HPLC纯化部分)已被描述为有效的系统佐剂,且在第5,057,540号美国专利和EP 0 362 279 B1中公开了它们的制备方法。这些参考文献中也描述了作为系统疫苗的有效佐剂的QS7(Quil-A的非溶血部分)的用途。在Kensil等人(1991.J.Immunology 146:431-437)中进一步描述了QS21的用途。QS21和聚山梨醇酯或环式糊精的组合也是已知的(WO99/10008)。在WO 96/33739和WO 96/11711中描述了包含诸如QS21和QS7的QuilA部分的微粒佐剂系统。已经用于系统接种疫苗研究的其它皂苷包括来自诸如丝石竹属(Gypsophila)和肥皂草属(Saponaria)的其它植物品种的那些(Bomford等人,Vaccine,10(9):572-577,1992)。
七叶树皂角素是与在本文公开的实施方案的佐剂组合物中使用的皂苷有关的另一种清洁剂。七叶树皂角素在默克索引(第12版:第3737条目)中被描述为皂苷的混合物,其存在于马栗树(horse chestnut tree),即欧洲七叶树(Aesculus hippocastanum)的籽中。描述了它通过层析和纯化(Fiedler,Arzneimittel-Forsch.4,213(1953)),以及通过离子交换树脂(Erbring等人,第3,238,190号美国专利)而分离。七叶树皂角素部分(也称为七叶皂甙)已经被纯化并已显示出具有生物学活性(Yoshikawa M,等人(Chem Pharm Bull(Tokyo)1996August;44(8):1454-1464))。毛地黄皂苷是另一种清洁剂,也在默克索引(第12版,第3204条目)中被描述为皂苷,其来自毛地黄(Digitalis purpurea)的籽,并依照Gisvold 等人,J.Am.Pharm.Assoc,1934,23,664和Rubenstroth-Bauer,Physiol.Chem.,1955,301,621所描述的方法而纯化。
根据本文公开的某些实施方案而应用的其它辅佐剂包括嵌段共聚物或生物可降解聚合物,其涉及本领域相关技术人员熟悉的一类聚合化合物。可以包括在GLA疫苗组合物内或GLA免疫佐剂内的嵌段共聚物或生物可降解聚合物的实例包括L121(BASFCorp.,Mount Olive,NJ;参见,例如,Yeh等人,1996Pharm.Res.13:1693;第5,565,209号美国专利)、CRL1005(例如,Triozzi等人,1997Clin Canc.Res.3:2355)、聚乳酸-羟基乙酸共聚物(PLGA)、聚(乳酸)(PLA)、聚-(D,L-丙交酯-共-乙交酯)(PLG)以及polyl:C。(参见例如,Powell和Newman,“Vaccine design-The Subunit and Adjuvant Approach(疫苗设计-亚单位和佐剂方法)”,1995,Plenum Press,New York)
某些实施方案涉及包括油的GLA疫苗和GLA免疫佐剂,所述油在某些此类实施方案中可以促进辅佐剂活性,并且在其它的此类实施方案中可以附加地或选择地提供药物上可接受的载体或赋形剂。已知许多合适的油,并且基于本公开,可以对其进行选择以包含在疫苗组合物和免疫佐剂组合物中。示例且非限制地,此类油的实例包括角鲨烯、角鲨烷、矿物油、橄榄油、胆固醇和二缩甘露醇单油酸酯。
诸如咪唑并喹啉免疫反应调节剂的免疫反应调节剂在本领域也是已知的,并可以作为辅佐剂包括在目前公开的某些实施方案中。某些优选的咪唑并喹啉免疫反应调节剂包括(作为非限定性实例)雷西莫特(R848)、咪喹莫特和嘎德莫特(gardiquimod)(Hemmi等人,2002 Nat.Immunol.3:196;Gibson等人,2002Cell.Immunol.218:74;Gorden等人,2005J.Immunol.174:1259);这些和其它的咪唑并喹啉免疫反应调节剂在适当的条件下,也可以具有本文描述的TLR激动剂活性。其它的免疫反应调节剂是核酸类双茎环免疫调节剂(dSLIM)。可以在Schmidt等人,2006 Allergy 61:56;Weihrauch等人2005 Clin CancerRes.11(16):5993-6001;Modern Biopharmaceuticals,J.(Editor).JohnWiley&Sons,December 6,2005.(第183至约200页讨论了dSLIM)中,以及从Mologen AG(Berlin,FRG:[2006年8月18日在 http://www.mologen.com/English/04.20-dSLIM.shtml的在线检索]中发现所涉及的在目前公开的某些实施方案中使用的dSLIM的具体实例。
如上文所述,与本文所述的与GLA一起使用的辅佐剂的一种类型可以是铝辅佐剂,其通常被称为“明矾”。明矾辅佐剂基于下述:羟基氧化铝、磷酸羟铝,或各种专利盐(proprietary salts)。使用明矾辅佐剂的疫苗可以包括用于破伤风菌株、HPV、甲型肝炎病毒、脊髓灰质炎病毒的疫苗以及本文描述的其它抗原。铝辅佐剂是有优势的,因为它们具有良好的安全记录、能放大抗体应答、稳定抗原并且对于大规模生产相对简单。(Edelman2002 Mol.Biotechnol.21:129-148;Edelman,R.1980 Rev.Infect.Dis.2:370-383.)
可以与GLA结合以有效免疫刺激的其它辅佐剂包括皂苷和皂苷类似物,包括QS21以及产生相似作用且在本文称为QS21类似物的结构相关化合物。QS21已被公认为是优选的辅佐剂。QS21可以包含来自智利皂荚树(Quillaja Saponaria Molina)的树皮、经HPLC纯化的非毒性部分。在第5,057,540号美国专利中公开了QS21的制备。(还可参见第6,936,255,7,029,678和6,932,972号美国专利)
在某些实施方案中,GLA也可以与被称为ISCOMS的“免疫刺激复合物”结合(例如第6,869,607、6,846,489、6,027,732、4,981,684号美国专利),包括皂苷来源的,其可以从例如Iscotec(Stockholm,Sweden)和CSL Ltd.(Parkville,Victoria,Australia)商购。
重组表达构建体
依照本文公开的某些实施方案,GLA疫苗组合物可以含有至少一种重组表达构建体,其包含可操作连接于编码抗原的核酸序列的启动子。在某些其它实施方案中,重组表达构建体存在于诸如腺病毒、腺相关病毒、疱疹病毒、慢病毒、痘病毒或逆转录病毒载体的病毒载体中。制备和使用这些表达构建体和载体的组合物和方法是本领域已知的,例如依照Ausubel等人(Eds.),Current Protocols in Molecular Biology(新编分子生物学实验指南),2006 John Wiley&Sons,NY,用于表达本文所提供的多肽抗原。通常可以在例如第6,844,192、 7,037,712、7,052,904、7,001,770、6,106,824、5,693,531、6,613,892、6,875,610、7,067,310、6,218,186、6,783,981、7,052,904、6,783,981、6,734,172、6,713,068、5,795,577和6,770,445号美国专利以及别处找到在某些目前公开的实施方案中使用的重组表达构建体的非限定性实例,以及适用于本文所提供的多肽抗原表达的教导。
免疫反应
本发明因此提供了在能够启动免疫反应的宿主内改变(即,例如,相对于本领域技术人员熟悉的适当对照,以统计学显著的方式增强或降低)免疫反应的组合物。正如本领域普通技术人员已知的,免疫反应可以是宿主免疫状态的任何积极的改变,其可包括参与维持和/或调节宿主免疫状态的一种或多种组织、器官、细胞或分子的结构或功能的任何改变。通常,可以通过多种公知参数的任一种来检测免疫反应,这些参数包括但不限于在体内或体外对下述进行检测:可溶性免疫球蛋白或抗体;诸如细胞因子、淋巴因子、趋化因子、激素、生长因子等的可溶性介质以及其它的可溶性小肽、碳水化合物、核苷和/或脂质介质;由免疫系统中细胞改变的功能或结构特性而测定的细胞激活状态的变化,例如细胞增殖、改变的运动性、诸如特异性基因表达或溶细胞行为的专用活性诱导;免疫系统细胞的细胞分化,包括改变的表面抗原表达谱或凋亡的启动(程序性细胞死亡);或者任何其它可以检测免疫反应存在的标准。
例如,免疫反应通常被认为是通过宿主免疫系统的细胞和组织在分子和细胞水平上自身结构和异已结构之间的区分,但本发明不应局限于此。例如,免疫反应还可以包括由自身分子、细胞或组织的免疫识别导致的免疫系统状态变化,这可以伴随着诸如免疫系统组分典型调节的许多正常状态,或者可以存在于诸如在自身免疫和退行性疾病中观测到的不适当自身免疫反应的病理学疾病状态。作为另一个实例,除了上调特定免疫系统活性的诱导(诸如抗体和/或细胞因子产生,或者细胞介导的免疫刺激)外,免疫反应还可以包括可测免疫的抑制、消弱或任何其它的下调,这可以受所选择的抗原、抗原给药途径、特异 耐受诱导或其它因素的影响。
可以通过本领域普通技术人员易于熟悉的许多公知的免疫学测试中的任一种来建立由本发明疫苗诱导的免疫反应的检测。这些测试包括,但不必限于在体内或体外对下述进行检测:可溶性抗体;诸如细胞因子、淋巴因子、趋化因子、激素、生长因子等的可溶性介质以及其它的可溶性小肽、碳水化合物、核苷和/或脂质介质;由免疫系统中细胞改变的功能或结构特性而确定的细胞激活状态变化,例如细胞增殖、改变的运动性、诸如特异性基因表达或溶细胞行为的专用活性诱导;免疫系统细胞的细胞分化,包括改变的表面抗原表达谱或凋亡的启动(程序性细胞死亡)。进行这些和类似测试的操作步骤是公知的,并且可以在例如Lefkovits(Immunology Methods Manual:The Comprehensive Sourcebook ofTechniques(免疫学方法手册:全面的技术读物资料),1998;也可参见Current Protocolsin Immunology(免疫学实验指南);还可参见,例如,Weir,Handbook of ExperimentalImmunology(实验免疫学手册),1986 Blackwell Scientific,Boston,MA;Mishell andShigii(eds.)Selected Methods in Cellular Immunology(细胞免疫学方法精选),1979Freeman Publishing,San Francisco,CA;Green和Reed,1998Science 281:1309和其中所引用的参考文件)中找到。
抗原反应性T细胞增殖的检测可以通过多种已知技术而实现。例如,T细胞增殖能通过测量DNA合成的速率而检测,并且抗原特异性能通过控制暴露于候选抗原反应性T细胞的刺激物(例如,特异性期望的抗原-脉冲抗原提呈细胞或对照抗原-脉冲抗原提呈细胞)而测定。受刺激而增殖的T细胞表现出增加的DNA合成速率。测量DNA合成速率的典型方式是,例如,通过具有氚化胸腺嘧啶的T细胞脉冲标记培养物,所述氚化胸腺嘧啶是掺入新合成的DNA的核苷前体。掺入的氚化胸腺嘧啶的量可以用液体闪烁分光光度计来测定。检测T细胞增殖的其它方式包括测量白介素-2(IL-2)产生的增加、Ca2+通量或诸如3-(4,5-二甲基噻唑-2-基)-2,5-联苯-四唑的染料摄取。另外,可以测量淋巴因子(诸如干扰素-γ)的合成,或者可以量化能对特定抗原反应的T细胞的相对数目。
例如,可以通过采用诸如放射免疫测定(RIA)、酶联免疫吸附测定(ELISA)、平衡透析或包括蛋白免疫印迹的固相免疫印迹法的体外方法,分析来自用本发明疫苗处理的宿主的样本(例如,包含免疫球蛋白的样本,诸如血清、血浆或血液)从而实施抗原特异性抗体产生的测定。在优选的实施方案中,ELISA测定还可以包括用对抗原特异性的固相单克隆抗体进行靶抗原的抗原捕获固定,例如,以增加该测定的敏感性。例如,使用从商业途径容易获得的方法、装置和试剂(例如Sigma,St.Louis,MO;还参见R&D Systems 2006 Catalog,R&DSystems,Minneapolis,MN),通过酶联免疫吸附测定(ELISA)也可以容易地检测可溶性介质(例如,细胞因子、趋化因子、淋巴因子、前列腺等)的详尽细节。
许多其它的免疫学参数可以使用本领域公知的常规测定来监测。这些可以包括,例如,抗体依赖性细胞介导的细胞毒性(ADCC)测定、继发性体外抗体反应、利用已确立的标记物抗原系统进行各种外周血细胞或淋巴样单核细胞亚群的流式免疫细胞荧光测定分析、免疫组织化学或其它相关的测定。例如,可以在Rose等人(Eds.),Manual of ClinicalLaboratory Immunology,5th Ed.(临床实验室免疫学手册,第5版),1997American Societyof Microbiology,Washington,DC中找到的这些和其它测定。
因此,应认为本文所提供的疫苗和佐剂组合物能够引发或增强宿主的至少一种免疫反应,所述免疫反应选自TH1-型T淋巴细胞反应、TH2-型T淋巴细胞反应、细胞毒T淋巴细胞(CTL)反应、抗体反应、细胞因子反应、淋巴因子反应、趋化因子反应以及炎症反应。在某些实施方案中,免疫反应可以包含下述中的至少一种:一种或多种细胞因子的产生,其中所述细胞因子选自干扰素-γ(IFN-γ)、肿瘤坏死因子-α(TNF-α);一种或多种白介素的产生,其中所述白介素选自IL-1、IL-2、IL-3、IL-4、IL-6、IL-8、IL-10、IL-12、IL-13、IL-16、IL-18和IL-23;一种或多种趋化因子的产生,其中所述趋化因子选自MIP-1α、MIP-1β、RANTES、CCL4和CCL5;以及选自记忆性T细胞反应、记忆性B细胞反应、效应T细胞反应、细胞毒性T细胞反应以 及效应B细胞反应的淋巴细胞反应。参见,例如WO 94/00153;WO95/17209;WO 96/02555;U.S.6,692,752;U.S.7,084,256;U.S.6,977,073;U.S.6,749,856;U.S.6,733,763;U.S.6,797,276;U.S.6,752,995;U.S.6,057,427;U.S.6,472,515;U.S.6,309,847;U.S.6,969,704;U.S.6,120,769;U.S.5,993,800;U.S.5,595,888;Smith等人,1987 J BiolChem.262:6951;Kriegler等人,1988Cell 53:4553;Beutler等人,1986Nature 320:584;U.S.6,991,791;U.S.6,654,462;U.S.6,375,944。
药物组合物
药物组合物通常包含至少一种本发明的GLA化合物,且还可以包含本文提供的与药物上可接受的载体、赋形剂或稀释剂结合的一种或多种组分,例如所述组分选自抗原、TLR激动剂、辅佐剂(任选地包括细胞因子、咪唑并喹啉免疫反应调节剂和/或dSLIM)和/或重组表达构建体。
因此,在某些方面,本发明涉及GLA“单治疗”,其中如本文所述的GLA被配制于基本上没有其它抗原的组合物中,并被给予个体以刺激免疫反应,例如非特异性免疫反应,由此治疗或预防疾病或其它疾病状态,例如用于治疗生物体引起的感染,用于治疗季节性鼻炎等。在一个实施方案中,例如,本发明的组合物和方法采用了用于激活个体免疫反应的GLA化合物。在另一实施方案中,GLA为喷雾形式,其任选地以试剂盒形式而提供。
GLA可以优选配制于稳定的乳剂中。在一个特定的实施方案中,例如,在基本上没有其它抗原的稳定乳剂中提供了包含本发明GLA化合物的组合物。
在某些其它实施方案中,药物组合物是包含GLA和抗原的疫苗组合物,并且还可以包含本文所提供的与药物上可接受的载体、赋形剂或稀释剂结合的一种或多种组分,所述组分选自TLR激动剂、辅佐剂(包括例如细胞因子、咪唑并喹啉免疫反应调节剂和/或dSLIM)等和/或重组表达构建体。
示例的载体在所使用的剂量和浓度下对受方无毒。对于GLA加核 酸类疫苗,或者对于包含GLA和抗原的疫苗,每千克体重通常给予约0.001μg至约100mg,通常是通过皮内、皮下、肌肉内或静脉内途径或通过其它途径而给予。
在更具体的实施方案中,剂量为约0.001μg/kg至约1mg/kg。在另一个具体的实施方案中,剂量为约0.001μg/kg至约50μg/kg。在另一个具体的实施方案中,剂量为约0.001μg/kg至约15μg/kg。
在另一具体的实施方案中,所给予的GLA的量为约0.01μg/剂量至约5mg/剂量。在另一个具体的实施方案中,所给予的GLA的量为约0.1μg/剂量至约1mg/剂量。在另一个具体的实施方案中,所给予的GLA的量为约0.1μg/剂量至约100μg/剂量。在另一个具体的实施方案中,所给予的GLA为约0.1μg/剂量至约10μg/剂量。
对本领域的技术人员显而易见地是,给药的数量和频率依赖于宿主的反应。治疗用途的“药物上可接受的载体”是药学领域公知的,且在例如在Remingtons Pharmaceutical Sciences(雷明顿药物科学),Mack Publishing Co.(A.R.Gennaroedit.1985)中所描述的。例如,可以使用生理学pH值的无菌盐水和磷酸缓冲盐水。可以在药物组合物中提供防腐剂、稳定剂、染料以及甚至调味剂。例如,苯甲酸钠、山梨酸和对羟基苯甲酸酯可以作为防腐剂而添加。同上在1449。此外,可以使用抗氧化剂和悬浮剂。同上。
“药物上可接受的盐”指本发明化合物的盐,其来自这类化合物和有机酸或无机酸(酸加成盐)或者有机或无机碱(碱加成盐)的组合。本发明的组合物可以以游离碱或盐的形式使用,同时两种形式都认为是在本发明的范围内。
药物组合物可以是允许向患者给予该组合物的任何形式。例如,所述组合物可以是固体、液体或气体(气溶胶)的形式。给药的典型途径包括,但不限于,口服、局部、肠胃外(例如舌下或经颊)、舌下、直肠、阴道以及鼻内(例如作为喷雾剂)。本文使用的术语肠胃外包括离子导入的(例如U.S.7,033,598、7,018,345、6,970,739)、超声波导入的(例如,U.S.4,780,212、4,767,402、4,948,587、5,618,275、5,656,016、5,722,397、6,322,532、6,018,678)、热性的(例如U.S.5,885,211、 6,685,699)、被动透皮的(例如U.S.3,598,122、3,598,123、4,286,592、4,314,557、4,379,454、4,568,343、5,464,387、第2232892号英国专利的说明书、U.S.6,871,477、6,974,588、6,676,961)、微针的(例如U.S.6,908,453、5,457,041、5,591,139、6,033,928)给药,且还包括皮下注射、静脉内、肌肉内、胸骨内、海绵窦内、鞘内、外耳道内(intrameatal)、尿道内注射或输注方法。在特定的实施方案中,本文描述的组合物(包括疫苗和药物组合物)通过选自离子导入、微气穴(microcavitation)、超声波导入或微针的技术而皮内给药。
将药物组合物进行配制以使在将组合物给予患者时其中包含生物可利用的活性成分。给予患者的组合物采用一个或多个剂量单位的形式,其中,例如,药片可以是单一剂量单位,并且为气溶胶形式的本发明的一种或多种化合物的容器可以持有多个剂量单位。
对于口服给药,可以存在赋形剂和/或粘合剂。实例为蔗糖、高岭土、甘油、淀粉糊精、藻酸钠、羧甲基纤维素和乙基纤维素。可以存在着色剂和/或调味剂。可以使用包衣壳。
组合物可以是液体形式,例如酏剂、糖浆、溶液、乳剂或悬浮剂。作为两个实例,所述液体可以口服给药或通过注射而递送。当旨在口服给药时,优选的组合物包含甜味剂、防腐剂、染色/着色剂以及增味剂中的一种或多种。在旨在由注射而给药的组合物中,可以包括表面活性剂、防腐剂、润湿剂、分散剂、悬浮剂、缓冲液、稳定剂和等渗剂中的一种或多种。
本文使用的液体药物组合物,无论为溶液、悬浮液形式或其它类似形式,都可以包括下述载体或赋形剂中的一种或多种:无菌稀释液,例如注射用水、盐水溶液、优选生理盐水、林格液、等渗氯化钠,不挥发性油,例如角鲨烯、角鲨烷、矿物油、二缩甘露醇单油酸酯、胆固醇和/或可以作为溶剂或悬浮介质的合成单和二甘油酯,聚乙二醇、丙三醇、丙二醇或其它溶剂;抗菌剂,例如苯甲醇或尼泊金甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;诸如乙酸盐、柠檬酸盐或磷酸盐的缓冲液以及诸如氯化钠或葡萄糖的张度调节剂。肠胃外制剂可以封装在安瓿、一次性注射器或由玻璃或 塑料制成的多次剂量瓶内。可注射的药物组合物优选是无菌的。
在特定的实施方案中,本发明的药物或疫苗组合物包含小于0.2μm的稳定水性悬浮液,且还包含选自磷脂、脂肪酸、表面活性剂、清洁剂、皂苷、氟化脂质(fluorodatedlipids)等的至少一种组分。
在另一实施方案中,本发明的组合物以能被雾化的方式而配制。
还可以期望在疫苗或药物组合物中包含诸如递送载体的其它组分,所述递送载体包括但不限于铝盐、油包水型乳剂、生物可降解油载体、水包油型乳剂、生物可降解微胶囊以及脂质体。上文也描述了在这类载体中使用的其它免疫刺激物质(辅佐剂)的实例,并且其可以包括N-乙酰胞壁酰-L-丙氨酸-D-异谷酰胺(MDP)、葡聚糖、IL-12、GM-CSF、γ干扰素和IL-12。
尽管在本发明的药物组合物中可以使用本领域的技术人员已知的任何合适的载体,但载体的类型将根据给药方式以及是否需要持续释放而变化。对于肠胃外给药,例如皮下注射,载体优选包含水、盐水、乙醇、脂肪、蜡或缓冲液。对于口服给药,可以采用上述载体的任一种或固体载体,例如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖和碳酸镁。也可以将生物可降解的微球体(例如聚乳酸交酯(polylactic galactide))作为本发明药物组合物的载体。例如在第4,897,268和5,075,109号美国专利中公开了合适的生物可降解的微球体。对此,优选微球体大于约25微米。
药物组合物(包括GLA疫苗和GLA免疫佐剂)也可以包含:诸如缓冲液的稀释液,诸如抗坏血酸的抗氧化剂,低分子量(少于约10个残基)的多肽,蛋白质,氨基酸,包括葡萄糖、蔗糖或糊精的碳水化合物,诸如EDTA的螯合剂,谷胱甘肽和其它稳定剂和赋形剂。中性缓冲盐水或与非特异性血清白蛋白混合的盐水是示例性的适当稀释液。优选地,使用适当的赋形剂溶液(例如,蔗糖)作为稀释液,可以将产品配制成冷冻干产物。
如上文所述,在某些实施方案中,本发明包括能递送编码期望抗原的核酸分子的组合物。这种组合物包括重组病毒载体(例如,逆转录病毒(参见WO 90/07936,WO 91/02805,WO 93/25234,WO 93/25698和 WO 94/03622)、腺病毒(参见Berkner,Biotechniqυes6:616-627,1988;Li等人,Hum.Gene Ther.4:403-409,1993;Vincent等人,Nat.Genet.5:130-134,1993;和Kolls等人,Proc.Natl.Acad.Sci.USA 97:215-219,1994)、痘病毒(参见第4,769,330号美国专利;第5,017,487号美国专利;和WO 89/01973))、络合到聚阳离子分子的重组表达构建体核酸分子(参见WO 93/03709)以及与脂质体有关的核酸(参见Wang等人,Proc.Natl.Acad.Sci.USA 84:7851,1987)。在某些实施方案中,DNA可以连接到杀死或灭活的腺病毒(参见Curiel等人,Hum.Gene Ther.3:147-154,1992;Cotton等人,Proc.Natl.Acad.Sci.USA 89:6094,1992)。其它合适的组合物包括DNA-配体(参见Wu等人,J.Biol.Chem.264:16985-16987,1989)和脂质-DNA组合(参见Felgner等人,Proc.Natl.Acad.Sci.USA 84:7413-7417,1989)。
除了直接的体内操作,也可以采用间接体内操作,其中将细胞从宿主取出,修饰并置入相同的宿主动物或其它的宿主动物。显然,本领域技术人员可以利用上述任何组合物以将编码抗原的核酸分子导入间接体内环境中的组织细胞。用于病毒、物理和化学的摄取方法的操作是本领域公知的。
因此,本发明用于增强或引发宿主、患者或细胞培养物中的免疫反应。如本文所用,术语“患者”指任何温血动物,优选人类。患者可以罹患传染性疾病、诸如乳腺癌的癌症或自身免疫疾病,或者可以是正常的(即,没有可检测的疾病和/或感染)。“细胞培养物”是包含免疫活性细胞或免疫系统的分离细胞(包括但不限于,T细胞、巨噬细胞、单核细胞、B细胞和树突状细胞)的任何制剂。这类细胞可以通过本领域普通技术人员公知的多种技术而分离(例如聚蔗糖-泛影葡胺密度离心法)。细胞可以(但不必须)从罹患癌症的患者中分离出,并且可以重新导入治疗后的患者。
在某些实施方案中,旨在肠胃外或口服给药的液体组合物应包含一定量的GLA疫苗组合物以获得合适的剂量。通常,该量是为组合物中抗原的至少0.01%重量比。当旨在口服给药时,该量可以在组合物重量的0.1%至约70%之间变化。优选地,口服组合物包含约4%至约 50%的抗原。优选地,制备组合物和制剂以使肠胃外剂量单位包含0.01%重量比至1%重量比的活性成分。
药物组合物可以旨在局部给药,在这种情况下,载体可以适宜地包括溶液、乳剂、药膏或凝胶基质。所述基质,例如,可以包括下述中的一种或多种:矿脂、羊毛脂、聚乙二醇、蜂蜡、矿物油、诸如水和乙醇的稀释液、以及乳化剂和稳定剂。增稠剂可以存在于局部给药的药物组合物中。如果旨在透皮给药,组合物可以包括透皮贴片或离子导入装置。局部制剂可以包含约0.1%w/v至约10%w/v(每单位体积的重量)的抗原(例如GLA-抗原疫苗组合物)或GLA(例如免疫佐剂组合物;GLA可以从Avanti Polar Lipids,Inc.,Alabaster,AL处得到;例如产品号为699800)的浓缩物。
旨在直肠给药的组合物,可以采用例如栓剂的形式,其在直肠内溶化并释放药物。用于直肠给药的组合物可以包含作为合适的无刺激赋形剂的油脂性基质。这种基质包括但不限于羊毛脂、可可油和聚乙二醇。在本发明的方法中,疫苗组合物/佐剂可以通过使用插入物、珠粒、定时释放制剂、贴片或快速释放制剂而给药。
某些实施方案也涉及包含本文描述的GLA疫苗组合物和/或GLA免疫佐剂组合物的试剂盒,其可以在一种或多种容器中而提供。在一个实施方案中,GLA疫苗组合物和/或GLA免疫佐剂组合物的所有组分共同存在于单个容器内,但本发明的实施方案旨在不受此限制,并且还可以涉及两个或多个容器,其中,例如,GLA免疫佐剂组合物与抗原组分分离且互不接触。通过非限定的理论,认为在一些情况下,可以有利地进行GLA免疫佐剂组合物的单独给药,而在另一些情况下,可以有利地将这种给药与抗原给药在时间和/或空间(例如在不同的解剖部位)上分开,仍在另一些情况下,向个体给药是有益地传输本文所述的GLA疫苗组合物,并且其包含抗原和GLA二者以及还任选地包含本文所述的其它组分。
所述试剂盒实施方案的容器可以是任何合适的容器、器皿、小瓶、安瓿、管、杯、盒、瓶、长颈瓶、罐、盘、单孔或多孔设备的孔、贮液囊、槽等,或者其它装置,本文公开的组合物可以在所述其它装置 中放置、储存和/或转运并易于移走容纳物。通常,这种容器可由与目的用途相兼容的材料制成,并且从中可以容易地实现所包含的容纳物的回收。这种容器的优选实例包括玻璃和/或塑料密封的或可重新密封的管和安瓿,包括具有橡胶隔膜的那些或其他密封的装置,其通过使用针和注射器而与容纳物的收回相适应。例如,这类容器可以由玻璃或化学兼容的塑料或树脂制成,该玻璃或化学兼容的塑料或树脂可以由一种材料制成,也可以是涂覆有该材料,所述材料允许从容器中有效地回收材料和/或保护这种材料免受诸如紫外线或温度极限的降解条件的影响,或防止引入包括微生物污染物在内的不必要的污染物。容器优选地为无菌的或可灭菌的,并且由可与任何载体、赋形剂、溶剂、媒介物等兼容的材料制成,由此可用于悬浮或溶解本文所描述的疫苗组合物和/或免疫佐剂组合物和/或抗原和/或重组表达构建体等。
乳剂系统还可以用于配置本发明的组合物。例如,已描述了许多单相或多相乳剂系统。已经证明,水包油乳剂佐剂本身可用作辅助成分(EP 0 399 843B),还已描述了水包油乳剂和其他活性剂的组合作为疫苗佐剂(WO 95/17210;WO 98/56414;WO 99/12565;WO99/11241)。已描述了其它油性乳剂佐剂,例如油包水乳剂(第5,422,109号美国专利;EP 0480 982 B2)和水包油包水乳剂(第5.424,067号美国专利;EP 0480 981 B)。在本发明中使用的油性乳剂佐剂可以为天然或合成的,并可以为矿物或有机的。矿物油和有机油的实例很容易为本领域技术人员所理解。
在特定实施方案中,本发明的组合物包含水包油乳剂,其中GLA掺入油相中。在另一实施方案中,本发明组合物物包含水包油乳剂,其中GLA掺入油相中并存在另外的组分,诸如本文所描述的辅佐剂、TLR激动剂等。
为了使任何水包油组合物适于对人类给药,乳剂系统的油相优选包含一种可代谢油。术语可代谢油的含义为本领域所熟知。可代谢能被定义为“能够通过新陈代谢而转化”(Dorland's illustrated Medical Dictionary(道兰氏图解医学词典),W.B.SaundersCompany,25th edition(1974))。所述油可以是任何植物油、鱼油、动物油或合成油, 其对受体无害且能够通过新陈代谢而转化。坚果(例如花生油)、种子和谷物是植物油最常用的来源。合成油也是本发明中的一部分,可以包括商用油,例如及其他。
例如,角鲨烯(2,6,10,15,19,23-六甲基-2,6,10,14,18,22-二十四碳六烯)是一种不饱和油,其在鲨鱼肝油中大量存在且在橄榄油、麦芽油、米糠油和酵母中少量存在,并且其是在本发明中使用的特别优选的油。由于角鲨烯是胆固醇生物合成中的中间物(默克索引,第10版,第8619条目),因此它是可代谢的油。特别优选的油性乳剂是水包油乳剂,并且尤其是水包角鲨烯乳剂。另外,本发明中最优选的油性乳剂佐剂包含抗氧化剂,其优选地为α生育酚油(维生素E,EP 0 382 271 B1)。WO 95/17210和WO 99/11241公开了任选由免疫刺激剂QS21和/或3D-MPL(上文已讨论)配制的基于角鲨烯、α生育酚、吐温的乳剂佐剂。WO 99/12565公开了通过在油相中加入固醇而改进这些角鲨烯乳剂。另外,甘油三酯,诸如三辛精(C27H50O6)可以添加至油相中,以便稳定乳剂(WO 98/56414)。
存在于稳定的水包油乳剂中的油滴的尺寸优选为直径小于1微米,可在直径基本为30-600nm的范围内,优选基本为约30-500nm,且最优选基本为150-500nm,并且特别地,直径约为150nm,所述直径是用光子关联能谱法所测量。对此,为80%个数比的油滴应在优选的范围内,更优选超过90%个数比且最优选超过95%个数比的油滴位于所限定的尺寸范围内。在本发明油性乳剂中存在的组分量通常为2%至10%的诸如角鲨烯的油;2%至10%的α生育酚(若存在);以及0.3%至3%的诸如聚氧乙烯山梨醇酐单油酸酯的表面活化剂。优选地,油:α生育酚的比例等于或少于1,这样能提供更稳定的乳剂。司盘85也可以以约1%的水平存在。在某些情况下,本发明中的疫苗另外含有稳定剂是有利的。
水包油乳剂的制备方法为本领域技术人员所熟知。通常,该方法包括将油相与诸如PBS/吐温溶液的表面活性剂混合,随后用均质器均质化。例如,包括将混合物通过注射器针头一次、两次或更多次的方法将适于均质化少量的液体。同样地,在微射流均质器(microfluidizer)(M110S微流体仪,最大50个通道,在6巴的最大输入压(约为850巴的输出压)下持续2分钟)中的乳化过程适于制备较小或较大量的乳剂。这种调整可以通过常规实验而完成,其包括测量产生的乳剂直至实现制剂具有所需直径的油滴。
下面提供的实施例用于说明而非用于限制。
实施例
实施例1
2-叠氮基-2-脱氧-D-吡喃葡萄糖苷(2)
将叠氮化钠(2.78g,42.7mmol)溶解于水(7mL)和甲苯(7mL)中。在充分搅拌下将该混合物冷却至0℃。滴加三氟甲磺酸酐(4.57mL,27.2mmol),并将该混合物在0℃下搅拌30分钟。升温至10℃,并将该二相混合物搅拌2小时。滴加碳酸氢钠饱和水溶液直至没有气体逸出。将两相分离,并将水层用甲苯(2×7mL)萃取。在随后的重氮基转移反应中使用所合并的有机层。
将葡萄糖胺1(2.04g,9.45mmol)、碳酸氢钠(3.21g,38.22mmol)和五水合硫酸铜(II)(90.5mg,0.362mmol)溶解于水(12.3mL)。添加上述制备的三氟甲基叠氮化物(triflicazide)储备溶液(21mL),随后添加甲醇(81mL)以产生均质系统。在室温下充分搅拌该蓝色混合物。用TLC(茚三酮染色剂)监测胺的全部消耗过程,并且还通过该混合物从蓝色变为绿色的颜色变化进行标示。用严格控温在25℃以下的旋转蒸发仪在真空中去除溶剂。用硅胶层析(120g RediSep柱,0%到40%梯度的甲醇/二氯甲烷洗脱50分钟,85mL/min)纯化残留物,从而得到为无色液体的产物2(1.93g,99%)。1H NMR(300MHz,CD3OD)(非对应异构体1/1的混合物)δ5.18(d,J=3.4Hz,0.5H),4.51(d,J=8.0Hz, 0.5H),3.89-3.63(m,3H),3.32-3.26(m,2H),3.11-3.06(m,1H)。
实施例2
2-叠氮基-2-脱氧-4,6-O-苯亚甲基-D-吡喃葡萄糖苷(3)
向化合物2(2.00g,9.75mmol)的DMF(40mL)溶液添加苯甲醛二甲基缩醛(1.65g,10.8mmol)和樟脑磺酸(90mg)。将烧瓶连接至真空系统,并在油浴中将该混合物在50℃下加热。在3小时后,使用旋转蒸发仪该将该混合物浓缩。将该残留物再溶解于二乙醚(50mL)和Et3N(2mL),随后再溶解于饱和碳酸氢钠(50mL)。用二乙醚(3×50mL)萃取水层。将合并的有机萃取物在硫酸钠上干燥并过滤。在使用旋转蒸发仪去除溶剂后,用硅胶层析(120gRediSep柱,0%至100%梯度的乙酸乙酯/己烷洗脱50分钟,85mL/min)纯化残留物,从而得到为无色液体的产物3(2.58g,90%)。1H NMR(300MHz,CD3OD)δ7.49-7.32(m,5H),5.58(s,1H),4.64(d,J=3.8Hz,1H),4.25-341(m,5H),3.23-3.20(m,1H)。
实施例3
叔丁基二甲基甲硅烷基-2-叠氮基-4,6-O-苯亚甲基-2-脱氧-β-D-吡喃葡萄糖苷
(4)
在0℃下,向化合物3(1.45g,4.94mmol)和咪唑(768mg,11.3mmol)混合物的CH2Cl2(40mL)溶液添加叔丁基二甲基甲硅烷基氯化物 (820mg,5.44mmol)。在将该溶液搅拌过夜后,添加饱和碳酸氢钠(20mL),并且用二乙醚(3×30mL)萃取该混合物。在Na2SO4上干燥合并的有机层,过滤并真空浓缩。用快速柱层析(80g RediSep柱,0%至70%梯度的乙酸乙酯/己烷洗脱40分钟,60mL/min)纯化残留物,从而得到为无色固体的产物4(1.5g,74%)。1H NMR(300MHz,CDCl3)δ7.46-7.43(m,2H),7.35-7.32(m,3H),5.48(s,1H),4.59(d,J=7.6Hz,1H),4.23(dd,J=10.2,5.0Hz,1H),3.73(t,J=10.2Hz,1H),3.56-3.51(m,2H),3.31-3.28(m,2H),2.72(d,J=2.2Hz,1H),0.91(s,9H),0.14(s,3H),0.13(s,3H)。
实施例4
叔丁基二甲基甲硅烷基-3-O-烯丙氧基羰基-2-叠氮基-4,6-O-苯亚甲基-2-脱氧-
D-吡喃葡萄糖苷(5)
在0℃下,向化合物4(1.50g,3.68mmol)和四甲基乙二胺(TMEDA)(0.78mL,5.2mmol)的二氯甲烷(DCM)(50mL)溶液滴加氯甲酸烯丙酯(0.78mL,7.3mmol)。使混合物加热至室温,并在室温下搅拌该混合物10小时。将混合物由DCM(50mL)溶解并由NaHCO3饱和水溶液(2×100mL)和盐水(2×50mL)洗涤。在Na2SO4上干燥合并的有机层,过滤并真空浓缩。用快速柱层析(80g RediSep柱,0%至50%梯度的乙酸乙酯/己烷洗脱40分钟,60mL/min)纯化残留物,从而得到为无色固体的产物5(1.57g,87%)。Rf=0.40(己烷/乙酸乙酯,3/1,v/v)。1H NMR(300MHz,CDCl3)δ7.44-7.41(m,2H),7.35-7.32(m,3H),5.98-5.85(m,1H),5.48(s,1H),5.38-5.22(m,2H),4.88(t,J=11.4Hz,1H),4.72-4.64(m,3H),4.32-4.27(m,1H),3.81-3.65(m,2H),3.50-3.42(m,2H),0.94(s,9H),0.18(s,3H),0.17(s,3H)。
实施例5
叔丁基二甲基甲硅烷基-3-O-烯丙氧基羰基-2-叠氮基-6-O-苄基-2-脱氧-D-吡喃
葡萄糖苷(6)
在室温下,将化合物5(320mg,0.651mmol)和分子筛(200mg)的THF(5mL)悬浮液搅拌1小时,并随后添加NaCNBH3(246mg,3.91mmol)。将氯化氢溶液(2M,在乙醚中)滴加至该混合物,直至混合物变为酸性(~5mL,pH=5)。再另外搅拌0.5小时后,将反应混合物由固体NaHCO3骤冷,用二乙醚(100mL)稀释,并用NaHCO3饱和水溶液(2×100mL)和盐水(2×50mL)洗涤。在Na2SO4上干燥有机层,过滤,真空浓缩,并用快速柱层析(40g RediSep柱,0%至100%梯度的乙酸乙酯/己烷洗脱40分钟,40mL/min)纯化残留物,从而得到为无色固体的产物6(273mg,85%)。Rf=0.42(己烷/乙酸乙酯,4/1,v/v)。1H NMR(300MHz,CDCl3)δ7.39-7.34(m,5H),5.99-5.89(m,1H),5.40-5.26(m,2H),4.67-4.56(m,5H),3.72-3.70(m,3H),3.48-3.46(m,2H),3.37(dd,J=9.6,8.4Hz,1H),3.01(broad s,1H),0.94(s,9H),0.17(s,6H)。
实施例6
叔丁基二甲基甲硅烷基-3-O-烯丙氧基羰基-2-叠氮基-6-O-苄基-2-脱氧-4-O-
(1,5-二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-D-吡喃葡萄糖苷(7)
向化合物6(5.47g,11.1mmol)和1H-四唑(在乙腈溶液中为3%重量比,35.5mmol,104mL)的溶液添加N,N-二乙基-1,5-二氢-3H-2,4,3-苯并二恶磷环庚烷(benzodioxaphosphepin)-3-胺(5.3g,22mmol)。在室温下将反应混合物搅拌15分钟后,将其冷却至-20℃,在此温度下再搅拌10分钟,随后添加mCPBA(8.40g,50-55%重量比,24.4mmol)。在-20℃下将反应混合物搅拌20分钟,并真空浓缩。将残留物再溶解于DCM(30mL)并用NaHCO3饱和水溶液(40mL)洗涤。水层由DCM(3×50mL)萃取。将合并的有机层在Na2SO4上干燥,过滤并真空浓缩。将残留物用快速柱层析(120g RediSep柱,0%至100%梯度的乙酸乙酯/己烷洗脱60分钟,85mL/min)纯化,从而得到为淡黄色油状的产物7(4.85g,65%)。Rf=0.40(己烷/乙酸乙酯,1/1,v/v)。1H NMR(300MHz,CDCl3)δ7.35-7.18(m,9H),5.98-5.85(m,1H),5.41-5.05(m,6H),4.64(t,J=10.1Hz,1H),4.58-4.52(m,6H),3.83(d,J=9.0Hz,1H),3.72-3.61(m,2H),3.41(dd,J=10.5,7.4Hz,1H),0.92(s,9H),0.16(s,3H),0.15(s,3H)。
实施例7
叔丁基二甲基甲硅烷基-3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-二氢-
3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-(9-芴基甲氧基羰基氨基)-D-吡喃葡
萄糖苷(8)
将乙酸(0.30mL,5.2mmol)滴加至7(700mg,1.04mmol)和锌粉(676mg,10.4mmol)的DCM(15mL)搅拌悬浮液。将反应混合物在室温下搅拌4小时,之后将其用乙酸乙酯(50mL)稀释。通过过滤去除固体并用乙酸乙酯(2×10mL)洗涤。将合并的滤液用NaHCO3饱和水溶 液(2×40mL)和盐水(2×40mL)洗涤。将有机相干燥(MgSO4)并过滤,并将滤液真空浓缩以产生为淡黄色油状的粗中间体胺。Rf=0.21(己烷/乙酸乙酯,1/1,v/v)。在0℃下,将9-芴基甲氧基羰基氯化物(Fmoc-Cl)(323mg,1.25mmol)添加至粗胺和二异丙基乙胺(DIPEA)(0.22mL,1.3mmol)的DCM(15mL)搅拌溶液。将反应混合物加热并在室温下搅拌5小时,之后将其用DCM(40mL)稀释并用盐水(2×50mL)洗涤。将有机相干燥(MgSO4)并过滤。将滤液真空浓缩。将残留物用硅胶柱层析(40g RediSep柱,0%至100%梯度的乙酸乙酯/己烷洗脱30分钟,40mL/min)纯化,从而得到为白色固体的产物8(337mg,在两步法中为73%)。Rf=0.54(己烷/乙酸乙酯,1/1,v/v)。1H NMR(300MHz,CDCl3)δ7.78–7.20(m,17H),5.92-5.82(m,1H),5.49-5.16(m,8H),4.69-4.06(m,5H),4.49-4.28(m,2H),3.88-3.61(m,3H),3.60-3.51(m,2H),3.32(broad s,1H),0.94(s,9H),0.14(s,3H),0.10(s,3H)。
实施例8
3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-3H-2,4,3-苯
并二恶磷环庚烷-3-基)-2-(9-芴基甲氧基羰基氨基)-D-吡喃葡萄糖苷(9)
将氟化氢/吡啶(6mL,0.2mol)滴加至8(6.00g,6.88mmol)的THF(50mL)搅拌溶液。将该反应混合物在室温下搅拌12小时,之后将其用二乙醚(100mL)稀释,并随后用NaHCO3饱和水溶液(2×40mL)和盐水(2×40mL)洗涤。将有机相干燥(MgSO4)并过滤。将滤液真空浓缩。将残留物用硅胶柱层析(120g RediSep柱,0%至80%梯度的乙酸乙酯/己烷洗脱60分钟,85mL/min)纯化,从而得到为淡黄色油状的产物9(4.34g,83%)。1H NMR(300MHz,CDCl3)δ7.75-7.20(m,17H), 5.92-5.82(m,1H),5.27-5.06(m,9H),4.59-4.55(m,5H),4.41-4.39(m,1H),4.25-4.01(m,5H),3.85-3.65(m,2H)。
实施例9
叔丁基二甲基甲硅烷基-6-O-{3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-
二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-十二酰氧基-十四酰基
氨基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧基-十二酰基]-2-脱氧-
β-D-吡喃葡萄糖苷(11)
在室温下,将10(参见如下制备)(350mg,0.172mmol)、锌(1.3g,21mmol)和乙酸(0.70mL,12mmol)的DCM(20mL)悬浮液搅拌12小时。将该混合物用二乙醚稀释。将固体通过过滤而去除,并将残留物用二乙醚(2×10mL)洗涤。将合并的滤液用NaHCO3饱和水溶液(2×15mL)和盐水(2×15mL)洗涤。将有机相干燥(MgSO4)并过滤。将滤液真空浓缩,并将残留物用硅胶柱层析(12g RediSep柱,0%至60%梯度的乙酸乙酯/己烷洗脱35分钟,30mL/min)纯化,从而得到为淡黄色浆体的产物11(220mg,64%)。Rf=0.29(己烷/乙酸乙酯,5/2,v/v)。1HNMR(300MHz,CDCl3)δ7.37-7.24(m,20H),6.20(d,J=7.2Hz,1H),5.59(t,J=9.6Hz,1H),5.31(m,1H),5.12-4.97(m,6H),4.62-4.44(m,7H),4.05-3.24(m,9H),2.68-2.12(m,9H),1.64-1.59(m,13H),1.27(broad m,95H),0.94(m,25H),0.13(s,6H)。HRMS(m/z)(pos)计算为C117H193N2O20PSi,2005.37;求得2006.3729[M+H]+。
实施例10
叔丁基二甲基甲硅烷基-6-O-{3-O-烯丙氧基羰基-6-O-苄基-2-脱氧
-4-O-(1,5-二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-十
二酰氧基-十四酰基氨基]-β-D-吡喃葡萄糖基}-4-O-苄基-3-O-[(R)-3-苄氧基-十二酰
基]-2-[(R)-3-4-甲氧基苄氧基-十四酰基]-2-脱氧-β-D-吡喃葡萄糖苷(12)
在室温下,向胺11(93mg,0.046mmol)的DCM(10mL)溶液添加吡啶(21mg,0.27mmol)、(R)-3-(4-甲氧基苄氧基)十四酰基氯化物(参见如下制备,化合物35)(40mg,0.12mmol)和4-二甲基氨基吡啶(DMAP)(1mg),并将该混合物搅拌过夜。将该混合物转移至分液漏斗并用二乙醚(20mL)和饱和碳酸氢钠(20mL)稀释。将水层用二乙醚(3×20mL)萃取。将合并的有机萃取物用硫酸钠干燥,过滤并减压浓缩。将残留物用硅胶层析(12g RediSep柱,由0%至80%梯度的乙酸乙酯/己烷洗脱35分钟,30mL/min)纯化,从而得到为无色液体的产物12(81mg,74%)。Rf=0.34(己烷/乙酸乙酯,3/2,v/v)。1H NMR(300MHz,CDCl3)δ7.34-7.20(m,20H),6.89-6.86(m,4H),6.15(t,J=9.0Hz,1H),5.57-5.55(m,1H),5.31-4.99(m,8H),4.57-4.44(m,11H),4.06-3.33(m,15H),2.63-2.57(m,5H),2.33-2.27(m,9H),1.57(m,8H),1.27(broad m,112H),0.88-0.82(m,27H),0.08(s,3H),0.04(s,3H)。HRMS(m/z)(pos)计算为C139H227N2O23PSi,2351.62;求得2352.6343[M+H]+。
实施例11
脂质A(13a)
在室温下,将12(10mg,0.0042mmol)和钯黑(Pd-black)(15.0mg)的无水THF(5mL)悬浮液在H2(50psi)环境中震荡30小时。催化剂通过过滤而去除。将残留物用THF(2×1mL)洗涤。将溶液冷却至-40℃并用氨的甲醇溶液(0.1mL,7M)中和并且在真空中无加热浓缩。将残留物用层析(12g RediSep柱,用氯仿/甲醇/水8/2/0.1洗脱30分钟,30mL/min)纯化,从而得到为无色膜状的13a(4mg,54%)。将产物再溶解于水和甲醇(v/v,1/1,2mL)并冻干以获得为白色粉状的产物13a。1H NMR(500MHz,CDCl3)δ6.00-5.00(m,1H),4.50-3.50(m,2H),3.00-2.00(m,3H),2.00-1.00(m,50H),0.81(m,18H).MS(Multimode,neg)计算为C96H181N2O22P,1745.28;求得1745.0[M-H]–。
实施例12
脂质A(13b)
在室温下,将12(27mg,0.011mmol)和钯黑(41.0mg)的无水THF(12mL)悬浮液在H2(50psi)环境中震荡30小时。将催化剂通过过滤去除。将残留物用THF(2×3mL)洗涤。将溶液用三乙胺(TEA)(0.1mL)中和并无加热真空浓缩。将合并的滤液真空浓缩并用硅胶层析(12g RediSep柱,用氯仿/甲醇/水8/2/0.1洗脱30分钟,30mL/min)纯化,从而得到为无色膜状的13b(5mg,25%)。将产物再溶解于水和甲醇(v/v,1/1,2mL)并冻干以获得为白色粉状的产物13b。1H NMR(500MHz,CDCl3)δ5.17(broad,2H),4.23-3.62(m,5H),3.11-3.07(q,J=2.8Hz,2H),2.51-2.12(m,6H),1.56-1.00(m,69H),0.92-0.84(m,18H)。MS(Multimode,neg)计算为C96H181N2O22P,1745.28;求得1744.1[M–H]–。
实施例13
叔丁基二甲基甲硅烷基-6-O-[3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-
二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-(9-芴基甲氧基羰基氨基)-β-D-
吡喃葡萄糖基]-2-叠氮基-4-O-苄基-2-脱氧-β-D-吡喃葡萄糖苷(15)
将化合物9(89mg,0.12mmol)溶解于无水DCM(3mL)。添加三氯乙腈(1.0mL)随后添加氢化钠(1.0mg,60%的矿物油溶液)。在15分钟后,TLC标示9的存在,因此添加额外量的氢化钠(1mg,60%的矿物油溶液)。在15分钟后,TLC标示反应完成。将该混合物真空浓缩并装载于SiO2柱上,将其用Et3N预处理并用50%乙酸乙酯/己烷洗脱从而提供三氯亚氨逐乙酸酯中间体(76.9mg,71%),其不经进一步纯化而使用。将三氯亚氨逐乙酸酯(76.9mg,0.0852mmol)、接受体14(参见如下制备)(52.34mg,0.1277mmol)和分子筛(,500mg)的DCM(5.0mL)悬浮液在室温下搅拌1小时。将该混合物冷却(-60℃),并添加TMSOTf(1.54μL,0.0851mmol)。在将反应混合物搅拌30分钟后,将其用固体NaHCO3骤冷。将该固体通过过滤去除,并将滤液真空浓缩。将残留物用硅胶柱层析(己烷/乙酸乙酯,2:1(v/v))纯化,从而得到为无色固体的15(55mg,40%)。1H NMR(500MHz,CD3COCD3)δ7.86-7.22 (m,22H),6.98(d,J=9.0Hz,1H),5.85(m,1H),5.41(t,J=9.0Hz,1H),5.38-5.21(m,3H),5.10-5.02(m,3H),4.91(d,J=11.0Hz,2H),4.72-4.46(m,7H),4.23-4.15(m,4H),3.93-3.80(m,4H),3.69-3.66(m,1H),3.54(br s,3H),3.20(dd,J1=8.0Hz,J2=8.0Hz,1H),0.95(s,9H),0.17(s,6H);13C NMR(125MHz,CD3COCD3)δ207.00,156.61,155.51,145.22,144.82,142.06,142.01,139.98,139.57,136.68,136.62,133.02,132.94,129.85,129.83,129.15,129.05,128.95,128.91,128.82,128.61,128.49,128.41,128.21,128.17,128.0,127.92,126.19,126.09,125.98,120.79,118.60,118.52,101.41,97.57,78.78,78.10,76.84,75.98,75.88,75.43,75.30,75.17,74.70,74.07,70.63,69.76,69.64,69.27,69.15,69.10,69.02,68.97,67.73,67.17,57.29,54.94,26.11,18.51;HR MS(m/z)计算为C59H69N4O16PSi[M+H]+,1149.4293;求得1149.4238。
实施例14
叔丁基二甲基甲硅烷基-6-O-{3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-
二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-十二酰氧基-十四酰基
氨基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-2-脱氧-β-D-吡喃葡萄糖苷(16)
将1,8-二氮杂二环[5.4.0]十一-7-烯(220μL,1.47mmol)滴加至15(800mg,0.696mmol)的DCM(10mL)溶液。将反应混合物在室温下搅拌1小时,之后将其真空浓缩。将残留物用硅胶柱层析(DCM/甲醇,100:1至100:3(v/v))纯化,从而得到为无色浆体游离胺(648mg,99%)。 1H NMR(500MHz,CDCl3)δ7.36-7.17(m,14H),5.96-5.88(m,1H),5.40-5.06(m,7H),4.84-4.50(m,9H),4.21(d,J=13.5Hz,1H), 4.15-4.11(m,1H),3.82(m,1H),3.79-3.42(m,5H),3.34-3.19(m,2H),2.96-2.90(m,1H),2.34(d,J=4.5Hz,1H),0.90(s,9H),0.13(s,6H)。HRMS(m/z)计算为C44H59N4O14PSi[M+H]+,927.3613;求得927.3569。
将N,N-二环己基碳二亚胺(DCC)(230mg,1.11mmol)添加至(R)-3-十二酰基-四癸酸(参见如下制备,化合物40)(381mg,0.81mmol)的DCM(10mL)搅拌溶液。在将反应混合物搅拌10分钟后,添加游离胺(648mg,0.699mmol)的DCM(10mL)溶液,并继续搅拌另外的12小时。不溶物质通过过滤而去除,并用DCM(2×2mL)洗涤残留物。将合并的滤液真空浓缩,并将残留物用硅胶柱层析(己烷/乙酸乙酯,2:1(v/v))纯化,从而得到为白色固体的16(450mg,47%)。1H NMR(500MHz,CDCl3)δ7.35-7.17(m,14H),5.94-5.86(m,2H),5.47(t,J=9.0,10.5Hz,1H),5.37(d,J=2.5Hz,1H),5.34(d,J=2.5Hz,1H),5.24(d,J=13.5Hz,1H),5.13-4.97(m,6H),4.75(d,J=11.0Hz,1H),4.66-4.49(m,7H),4.00(d,J=17.0Hz,2H),3.83(d,J=10.5Hz,1H),3.75-3.56(m,4H),3.49-3.36(m,5H),3.20(m,1H),2.42-2.17(m,4H),1.93(d,J=11.5Hz,1H),1.70(m,2H),1.23(br s,36H),0.92(s,9H),0.89-0.86(m,6H),0.14(s,6H);HRMS(m/z)计算为C72H111N4O17PSi[M+H]+,1363.7529;求得1363.7487。
实施例15
叔丁基二甲基硅烷基-6-O-{3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-二
氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-十二酰氧基-十四酰基氨
基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧基-十四酰基]-2-脱氧-β-
D-吡喃葡萄糖苷(17)
在室温下,将(R)-3-苄氧基十四酸(参见如下制备,化合物33)(120mg,0.540mmol)和DCC(171mg,0.830mmol)的混合物的DCM(5mL)溶液搅拌10分钟,随后添加二糖16(451mg,0.331mmol)的DCM(5mL)溶液和DMAP(25mg,0.21mmol)。在室温下将反应混合物搅拌14小时,之后将固体通过过滤而去除。用DCM(2×4mL)洗涤残留物。真空浓缩合并的滤液,并将残留物用硅胶柱层析(己烷/乙酸乙酯,4:1(v/v))纯化,从而得到为白色固体的17(540mg,97%)。Rf=0.41(己烷/乙酸乙酯,2:1(v/v))。1H NMR(500MHz,CDCl3)δ7.33-7.15(m,19H),5.94-5.85(m,2H),5.47(t,J=9.5Hz,1H),5.37(d,J=17.5Hz,1H),5.22(d,J=10.0Hz,1H),5.10-4.95(m,7H),4.62-4.43(m,10H),4.0-3.96(m,3H),3.90-3.81(m,2H),3.74-3.67(m,3H),3.56-3.42(m,6H),3.33-3.27(m,1H),2.60-2.21(m,6H),1.24(br s,54H),0.91(s,9H),0.87-0.84(m,9H),0.14(s,6H).HRMS(m/z)计算为C93H143N4O19PSi[M+H]+,1679.9931;求得1679.9934。
实施例16
叔丁基二甲基甲硅烷基-6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-
3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-十二酰氧基-十四酰基氨基]-β-D-吡喃葡
萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧基-十四酰基]-2-脱氧-β-D-吡喃葡萄糖苷
(18)
向17(1.66g,0.980mmol)、n-BuNH2(0.19mL,1.97mmol)和HCOOH(74.5μL,1.98mmol)的THF(20mL)溶液添加四(三苯基膦)钯(228mg,0.198mmol)。在将反应混合物在室温下搅拌20分钟后,将其用DCM(40mL)稀释,依次用水(40mL)、NaHCO3饱和水溶液(2×40mL)和盐水(40mL)洗涤。将有机相干燥(MgSO4)并过滤。将该滤液真空浓缩。将残留物用硅胶柱层析(己烷/乙酸乙酯,4:3(v/v))纯化,从而得到化合物18(1.43g,91%)。Rf=0.5(己烷/乙酸乙酯,1:1(v/v))。1H NMR(500MHz,CDCl3)δ7.33-7.11(m,19H),6.2(d,J=7.5Hz,1H),5.46(t,J=9.0Hz,1H),5.04-4.90(m,9H),4.55-4.38(m,8H),3.92(d,J=10.0Hz,1H),3.84-3.76(m,1H),3.75-3.7(m,4H),3.53-3.44(m,2H),3.43-3.32(m,2H),3.25-3.20(m,1H),2.61-2.10(m,12H),1.23(br s,54H),0.90(s,9H),0.88-0.84(m,9H),0.12(s,6H)。HRMS(m/z)计算为C89H139N4O17PSi[M+H]+,1595.972;求得1595.9713。
实施例17
叔丁基二甲基甲硅烷基-6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-
3H-2,4,3-苯并二恶磷环庚烷-3基)-2-[(R)-3-十二酰氧基-十四酰基氨基]-3-O-[(R)-3-
(p-甲氧基)苄氧基十四酰基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧
基-十四酰基]-2-脱氧-β-D-吡喃葡萄糖苷(19)
在室温下,将(R)-3-(p-甲氧基)苄氧基-十四酸(参见如下制备,化合物34,424mg,1.16mmol)和DCC(369mg,1.79mmol)的DCM(15mL)溶液搅拌10分钟,且添加醇18(1.43g,0.896mmol)的DCM(10mL)溶液和DMAP(54.72mg,0.4479mmol)。将反应混合物再搅拌14小时,之后固体通过过滤而去除并用DCM(2×5mL)洗涤。将合并的滤液真空浓缩。将残留物用硅胶柱层析(己烷/乙酸乙酯,4:1(v/v))纯化,从而得到为白色固体的19(1.15g,66%)。Rf=0.46(己烷/乙酸乙酯,2:1(v/v))。1H NMR(500MHz,CDCl3)δ7.38-6.79(m,23H),5.73(d,J=8.0Hz,1H),5.55(t,J=9.5Hz,1H),5.20-4.88(m,8H),4.66-4.47(m,12H),4.33(d,J=12.5Hz,1H),4.0-3.66(m,12H),3.61-3.40(m,5H),3.36-3.27(m,3H),2.67(d,J=6.0Hz,2H),2.60-2.22(m,6H),1.27(br s,72H),0.93(s,9H),0.92-0.87(m,12H),0.16(s,6H)。HRMS(m/z)计算为C111H173N4O20PSi[M+H]+,1942.2228;求得1942.2289。
实施例18
叔丁基二甲基甲硅烷基-6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-
3H-2,4,3-苯并二恶磷环庚烷-3基)-2-[(R)-3-十二酰氧基-十四酰基氨基]-3-O-[(R)-3-
十四酰氧基-十四酰基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧基-十
四酰基]-2-脱氧-β-D-吡喃葡萄糖苷(10)
向19(1.15g,0.592mmol)的DCM和H2O(11mL,10:1(v/v))混合物的搅拌溶液添加2,3-二氯-5,6-二氰基-1,4-苯并醌(DDQ)(202mg,0.890mmol)。将反应混合物在室温下搅拌1小时,之后将其用DCM稀释。将该混合物用盐水(20mL)洗涤,干燥(MgSO4),并真空浓缩。将残留物用硅胶柱层析(己烷/乙酸乙酯,3:1(v/v))纯化,从而得到为无色浆体的醇(1.01g,94%)。Rf=0.50(己烷/乙酸乙酯,5:3(v/v))。将十四酰氯化物(0.74mL,2.7mmol)加入该醇(1.01g,0.554mmol)和吡啶(0.35mL,4.33mmol)的DCM(20mL)溶液。在将反应混合物在室温下搅拌12小时后,将其用DCM稀释并用NaHCO3饱和水溶液(2×40mL)和盐水(40mL)洗涤。将该有机相干燥(MgSO4)并过滤。将滤液真空浓缩。将残留物用硅胶柱层析(己烷/乙酸乙酯,4:1(v/v))纯化,从而得到为白色固体的10(680mg,57%)。Rf=0.46(己烷/乙酸乙酯,5:2(v/v))。 1H NMR(500MHz,CDCl3)δ7.37-7.24(m,19H),6.23(d,J=7.5Hz,1H),5.58(t,J1=J2=9.5Hz,1H),5.32-5.27(m,1H),5.16-4.99(m,6H),4.78-4.44(m,7H),4.03(d,J=10.5Hz,1H),3.99-3.20(m,10H),2.65-2.21(m,10H),1.61-1.51(m,10H),1.27(br s,94H),1.21(br s,25H),0.12(s,6H)。
实施例19
叔丁基二甲基甲硅烷基-6-O-{3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-
二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-癸酰氧基-十四酰基氨
基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-2-脱氧-β-D-吡喃葡萄糖苷(20)
用与合成化合物16(实施例14)相似的方式,使用DCC(430mg,2.08mmol)、所需的脂质(Compound 40,实施例36,630mg,1.59mmol)和三乙胺(161mg,1.59mmol),将化合物15(1.23g,1.07mmol)酰化,从而提供为无色油状的20(1.05g,81%)。1H NMR(500MHz,CDCl3)δ7.35-7.17(m,14H),5.91-5.86(m,2H),5.47(t,J=9.0,10.5Hz,1H),5.34(d,J=17Hz,1H),5.24(d,J=10.5Hz,1H),5.10-4.98(m,8H),4.75(d,J=11.5Hz,1H),4.66-4.49(m,8H),4.00(d,J=11.0Hz,2H),3.83(d,J=11.0Hz,1H),3.75-3.69(m,2H),3.49-3.36(m,4H),3.20(m,1H),2.40-2.26(m,4H),1.24(br s,32H),0.92(s,9H),0.89-0.86(m,6H),0.14(s,6H);MS(多态,pos)m/z=1307[M+H]+。
实施例20
叔丁基二甲基甲硅烷基-6-O-{3-O-烯丙氧基羰基-6-O-苄基-2-脱氧-4-O-(1,5-
二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-癸酰氧基-十四酰基氨
基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧基-十四酰基]-2-脱氧-β-
D-吡喃葡萄糖苷(21)
以与合成化合物17(实施例15)相似的方式,使用DCC(453mg,2.20mmol)、所需的脂质(477mg,1.43mmol)和N,N-二甲基-4-氨基吡 啶(67mg,0.548mmol),将化合物20(1.43g,1.18mmol)酰化,从而提供为无色油状的21(1.60g,83%)。1H NMR(500MHz,CDCl3)δ7.33-7.15(m,19H),5.94-5.85(m,2H),5.48(t,J=9.0Hz,1H),5.34(d,J=17.5Hz,1H),5.22(d,J=10.0Hz,1H),5.12-4.96(m,7H),4.63-4.46(m,11H),3.97(d,J=10.5Hz,1H),3.89-3.85(m,2H),3.74-3.68(m,3H),3.55-3.52(m,2H),3.47-3.41(m,1H),3.28(m,1H),2.61-2.22(m,8H),1.59-1.52(m,6H),1.98(m,2H),1.23(br s,44H),0.90(s,9H),0.88-0.84(m,9H),0.12(s,6H);MS(多态,pos)m/z=1625[M+H]+。
实施例21
叔丁基二甲基甲硅烷基-6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-
3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-十二酰氧基-十四酰基氨基]-β-D-吡喃葡
萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧基-十四酰基]-2-脱氧-β-D-吡喃葡萄糖苷
(22)
以与合成化合物18(实施例16)相似的方式将化合物21(1.60g,0.985mmol)进行反应。因此,四(三苯基膦)钯(227mg,0.196mmol)、甲酸(74μL,1.97mmol)和正丁基胺(144mg,1.97mmol)提供了为黄色固体的22(1.25g,82%)。1H NMR(500MHz,CDCl3)δ7.33-7.15(m,19H),6.20(d,J=7.5Hz,1H),5.38-4.95(m,6H),4.86(d,J=8.0Hz,1H),4.60-4.46(m,10H),3.97-3.71(m,8H),3.68-3.48(m,5H),3.31-3.27(m,3H),2.62-2.55(m,2H),2.50-2.42(m,3H),2.40-2.22(m,5H),1.23(br s,44H),0.90(s,9H),0.88-0.84(m,9H),0.12(s,6H);MS(多态,pos)m/z=1539[M+H]+。
实施例22
叔丁基二甲基甲硅烷基-6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-
3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-癸酰氧基-十四酰基氨基]-3-O-[(R)-3-
(p-甲氧基)苄氧十四酰基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧
基-十四酰基]-2-脱氧-β-D-吡喃葡萄糖苷(23)
以与合成化合物19(实施例17)相似的方式,使用DCC(335mg,1.62mmol)、所需的脂质(化合物34,实施例32,386mg,1.06mmol)和N,N-二甲基-4-氨基吡啶(50mg,0.41mmol)对化合物22(1.25g,0.811mmol)进行酰化,从而提供为无色油状的23(440mg,29%)。1H NMR(500MHz,CDCl3)δ7.38-6.79(m,23H),5.71(d,J=7.5Hz,1H),5.55(t,J=9.5Hz,1H),5.06-4.85(m,9H),4.66-4.45(m,12H),3.97(d,J=11.0Hz,1H),3.90-3.69(m,9H),3.60-3.55(m,3H),3.37-3.29(m,2H),2.65(d,J=7.5Hz,2H),2.61-2.55(m,1H),2.48-2.42(m,1H),2.35-2.21(m,3H),2.11-2.05(m,1H),1.62-1.59(m,8H),1.27(br s,62H),0.93(s,9H),0.92-0.87(m,12H),0.16(s,6H);MS(多态,pos)m/z=1886[M+H]+。
实施例23
叔丁基二甲基甲硅烷基-6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-
3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-癸酰氧基-十四酰基氨基]-3-O-[(R)-3-癸
酰氧基-十四酰基]-β-D-吡喃葡萄糖基}-2-叠氮基-4-O-苄基-3-O-[(R)-3-苄氧基-十四酰
基]-2-脱氧-β-D-吡喃葡萄糖苷
(24)
在进行靶A的中间体10的步骤之后,首先使用DDQ(80mg,0.35mmol)将化合物23(446mg,0.236mmol)脱保护。随后以与合成靶A的化合物10相似的方式,使用癸酰氯化物(185mg,0.970mmol)和吡啶(123mg,1.55mmol),将该中间体(343mg,0.194mmol)酰化,从而提供为无色油状的24(343mg,76%)。1H NMR(500MHz,CDCl3)δ7.39-7.22(m,14H),6.15(d,J=7.5Hz,1H),5.54(t,J=9.5Hz,1H),5.28-5.24(m,1H),5.14-4.96(m,8H),4.60-4.45(m,10H),3.99(d,J=10.5Hz,1H),3.90-3.85(m,1H),3.80-3.65(m,4H),3.55(m,3H),3.46-3.39(m,1H),3.32-3.27(m,1H),2.66-2.53(m,3H),2.46-2.41(m,1H),2.35-2.18(m,7H),1.61-1.51(m,10H),1.26(br s,78H),0.95(s,9H),0.92-0.90(m,15H),0.19(s,3H),0.18(s,3H)。
实施例24
叔丁基二甲基甲硅烷基-6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-
3H-2,4,3-苯并二恶磷环庚烷-3-基)-2-[(R)-3-癸酰氧基-十四酰基氨基]-3-O-[(R)-3-癸
酰氧基-十四酰基]-β-D-吡喃葡萄糖基}-4-O-苄基-3-O-[(R)-3-苄氧十四酰基]-2-[(R)-
3-苄氧基-十四酰基氨基]-2-脱氧-β-D-吡喃葡萄糖苷(25)
在室温下,将24(296mg,0.154mmol)、锌(100mg,1.52mmol)和乙酸(53μL,0.93mmol)的DCM(10mL)悬浮液搅拌12小时,之后将其用乙酸乙酯(25mL)稀释。将固体通过过滤而去除并用乙酸乙酯(2×25mL)洗涤,并且将合并的滤液用NaHCO3饱和水溶液(2×100mL)和盐水(200mL)洗涤。将有机相干燥(Na2SO4)并过滤。将滤液真空浓缩。将残留物用硅胶柱层析(己烷/乙酸乙酯,2.5:1(v/v))纯化,从而得到为淡黄色浆体的胺(245mg,84%)。1H NMR(500MHz,CDCl3)δ7.39-7.22(m,14H),6.15(d,J=7.5Hz,1H),5.54(t,J=9.5Hz,1H),5.29-5.23(m,1H),5.13-4.93(m,8H),4.62-4.30(m,9H),4.00(d,J=10.5Hz,1H),3.88-3.65(m,6H),3.56-3.53(m,2H),3.46-3.41(m,1H),2.66-2.58(m,4H),2.54-2.45(m,2H),2.35-2.17(m,7H),1.64-1.42(m,12H),1.26(br s,78H),0.87(s,24H),0.13(s,6H)。
将胺添加至(R)-3-苄氧十四酰基氯化物(228mg,0.646mmol)、DMAP(15.79mg,0.1292mmol)和吡啶(83μL,1.0mmol)的DCM(5.0mL)搅拌溶液。将反应混合物搅拌14小时。将该混合物用CH2Cl2稀释并用饱和NaHCO3/盐水洗涤,用Na2SO4干燥并真空浓缩。将残留物用硅胶TLC层析(己烷/乙酸乙酯,3.5:1(v/v))纯化,从而得到为白色固体的25(450mg,>100%)。Rf=0.54(己烷/乙酸乙酯,2:1(v/v))。1H NMR(500MHz,CDCl3)δ7.39-7.22(m,19H),6.14-6.10(m,2H),5.57(t,J=9.5Hz,1H),5.29-5.24(m,1H),5.13-4.93(m,7H),4.61-4.41(m,10H),4.00(d,J=10.5Hz,1H),3.89-3.79(m,8H),3.72-3.66(m,4H),3.57-3.35(m,3H),2.73-2.57(m,10H),2.39-2.15(m,10H),1.71-1.64(m,7H),1.26(br s,93H),0.88(s,24H),0.83(s,9H)。
实施例25
6-O-{6-O-苄基-2-脱氧-4-O-(1,5-二氢-3-氧代-3λ5-3H-2,4,3-苯并二恶磷环庚
烷-3-基)-2-[(R)-3-癸酰氧基-十四酰基氨基]-3-O-[(R)-3-癸酰氧基-十四酰基]-β-D-吡
喃葡萄糖基}-4-O-苄基-3-O-[(R)-3-苄氧基-十四酰基]-2-[(R)-3-苄氧基-十四酰基氨
基]-2-脱氧-α-D-吡喃葡萄糖(26)
将氟化氢/吡啶(1.12mL,43.1mmol)滴加至25(450mg,0.204mmol)的THF(5mL)搅拌溶液。将反应混合物在室温下搅拌14小时。将该混合物用乙酸乙酯(100mL)稀释并用NaHCO3饱和水溶液(2×80mL)和盐水洗涤。将有机相干燥(Na2SO4)并过滤。将滤液真空浓缩。将残留物用硅胶柱层析(己烷/乙酸乙酯,3:1至4:3(v/v))纯化,从而得到为白色固体的26(180mg,42%)。1H NMR(500MHz,CDCl3)δ7.39-7.19(m,19H),6.31(d,J=7.0Hz,1H),6.24(d,J=9.5Hz,1H),5.57-5.48(m,2H),5.40(t,J=9.5Hz,1H),5.28-5.21(m,1H),5.14-4.96(m,8H),4.68-4.41(m,12H),4.23-4.19(m,1H),4.13-4.06(m,1H),3.94-3.66(m,9H),3.38-3.28(m,2H),2.67-2.58(m,3H),2.44-2.20(m,11H),1.58(br s,12H),1.26(br s,93H),0.91-0.81(m,18H)。
实施例26
(3R)-((2R,3S,4R,5S)-3-((R)-3-(癸酰氧基)十四烷基氨基)-2-(((3S,4R,5S)-
3,6-二氢-5-((R)-3-羟基十四烷基氨基)-4-((R)-3-羟基十四酰氧基)四氢-2H-吡喃-2-
基)甲氧基)-6-(羟甲基)-5-(磷酰氧基)四氢-2H-吡喃-4-基)3-(癸酰氧基)十四烷酸酯
(IX)
将化合物26(180mg,0.0858mmol)溶解于无水THF(15mL)中。将钯黑(0.225g)加入该混合物,并在50psi的氢气环境中氢化过夜。将该混合物通过硅藻土床过滤。将滤液冷却至-40℃,并加入氨的甲醇溶液(1.8mL,4M)。将该混合物无加热真空浓缩。将残留物用硅胶层析纯化,其中用氯仿/甲醇/水(80:20:1(v/v))的混合物洗脱,从而得到所需化合物(IX)(102mg,73%)。用TLC分析且1H NMR表明存在油脂且出现模糊的封闭流动点(runningspot)(TLC在CH2Cl2/CMA(4:1)中)。将残留物装载于层析(12g RediSep柱,用5个柱体积(CV)的等梯度CH2Cl2洗脱,用10CV的25%梯度的CMA洗脱,用10CV的等度CMA洗脱,用10CV的100%梯度的CMA洗脱,用10CV的100%等度CMA洗脱,20mL/min),从而得到所需产物(57mg,25%)。合并且浓缩的馏分的TLC分析还表明在所需产物的上方仍存在少量的杂质流动。将残留物用硅胶层析(两根串联的12g RediSep柱,与上述相同的梯度)再纯化,从而提供用TLC纯化的8.9mg所需产物以及溶解在甲醇/水/氯仿中且冻干后的11.9mg微量掺杂产物。总产率(20.8mg,14%),其为灰白色固体。Rf=0.40CMA。1H NMR(500MHz,CDCl3)δ5.40-5.30(br s,2H),4.10-4.00(m,4H),3.70-3.60(m,4H),2.83-2.76(m,1H),2.75-2.20(m,13H),2.10-1.90(broad,9H),1.40-1.00(broad,106H),0.90-0.70(broad,18H)。MS(多态,Neg)m/z=1632[M–H]–。
实施例27
甲基3-氧代十四烷酸酯(29)
向乙醇镁(10.82g,94.61mmol)的1,4-二氧杂环乙烷(100mL)的悬浮液添加甲基丙二酸氢(25.0g,189mmol)的1,4-二氧杂环乙烷(100mL)溶液。将所得的浆体搅拌过夜。将该混合物真空浓缩。在单独的烧瓶中,将月桂酸(28,20.85g,104.1mmol)溶解于1,4-二氧杂环乙烷(50mL)并在室温下添加CDI(16.88g,104.1mmol)的1,4-二氧杂环乙烷(150mL)溶液。将所得的溶液搅拌过夜。随后将该混合物转移至甲基丙二酸镁烧瓶。将所得的悬浮液回流过夜。将该混合物真空浓缩。将残留物再溶解于DCM(300mL)并通过硅胶塞(10g)过滤。减压蒸发溶剂。将残留物用硅胶柱层析(360g RediSep柱,0%至30%梯度的乙酸乙酯/己烷洗脱80分钟,100mL/min)纯化,从而得到为淡黄色浆体的产物29(17g,61%)。
实施例28
(R)-甲基3-羟基十四烷酸酯(30)
将甲基3-氧代十四烷酸酯(29,29.0g,113mmol)在甲醇(120mL)中的浆体在300mL高压反应器玻璃套管中用N2净化10分钟。添加二氯-R-2,2’-双(二苯基膦基)-1,1’-二萘基钌(897mg,1.10mmol)。将该混合物置于Parr 5500系列紧凑反应器中。用H2(60psi)填充反应器并排放3次。用H2(60psi)填充反应器并搅拌(1200rpm)且加热至50℃并持续20小时。将反应器冷却至室温,且将所得的橙色溶液真空浓缩。将残留物用硅胶层析(120g RediSep柱,0%到40%梯度的乙酸乙酯/己烷洗脱60分钟,85mL/min)纯化,从而提供为白色固体的产物30(28.5g,97%的产率)。
实施例29
(R)-甲基3-(苄氧基)十四烷酸酯(31)
在0℃下,向化合物30(2.8g,10.83mmol)和苄基三氯亚氨逐乙酸酯(3.4g,14mmol)的DCM(100mL)溶液滴加三氟甲磺酸(0.24mL,2.7mmol)。将所得的混合物在0℃下搅拌6小时并加热至室温。将该混合物用NaHCO3饱和溶液(300mL)和水(300mL)洗涤并将该有机层用Na2SO4干燥。干燥剂通过过滤而去除,并使用旋转蒸发仪将溶剂去除。将残留物用硅胶层析(80g RediSep柱,0%至30%梯度的乙酸乙酯/己烷洗脱60分钟,60mL/min)纯化,从而得到为无色液体的产物31(1.2g,32%)。1H NMR(300MHz,CDCl3)δ7.30-7.05(m,5H),4.51(s,2H),3.90-3.80(m,1H),3.70(s,3H),2.58-2.45(m,2H),1.80-1.60(m,2H),1.50-1.20(m,18H),0.85(t,J=5.8Hz,3H)。
实施例30
(R)-3-(苄氧基)十四酸(33)
将酯31(1.3g,3.73mmol)溶解于THF/MeOH/CH3CN混合物(v/v/v,1/1/1,90mL)。添加一水氢氧化锂(235mg,5.6mmol)的水(30mL)溶液,并将该混合物搅拌过夜。将溶剂量真空浓缩至约30mL。向剩余的水性溶液中加入1M盐酸以使pH值降低至3。将水层用二乙醚(3×40mL)萃取。将合并的有机萃取物用硫酸钠干燥。将干燥的试剂通过过滤去除,并使用旋转蒸发仪去除溶剂。将残留物用硅胶层析(40g RediSep柱,0%至50%梯度的乙酸乙酯/己烷洗脱40分钟,40mL/min)纯化,从而得到为无色液体的产物33(990mg,79%)。1H NMR(300MHz,CDCl3)δ7.30-7.05(m,5H),4.51(s,2H),3.90-3.80(m,1H),2.58-2.45(m,2H),1.80-1.60(m,2H),1.50-1.20(m,18H),0.85(t,J=5.8Hz,3H)。
实施例31
(R)-甲基3-(4-甲氧基苄氧)十四烷酸酯(32)
向化合物30(3.50g,12.9mmol)和4-甲氧基苄基三氯亚氨逐乙酸酯(4.65g,17.3mmol)的DCM(100mL)溶液添加樟脑磺酸(450mg,1.92mmol)。在室温下将该混合物搅拌过夜。将该混合物用NaHCO3饱和溶液(300mL)和水(300mL)洗涤并用Na2SO4干燥。将干燥剂通过过滤去除并使用旋转蒸发仪去除溶剂。将残留物用硅胶层析(120g RediSep柱,0%至30%梯度的乙酸乙酯/己烷洗脱70分钟,85mL/min)纯化,从而得到为无色液体的产物32(4.01g,81%)。
实施例32
(R)-3-(4-甲氧基苄氧基)十四酸(34)
将酯32(4.01g,10.4mmol)溶解于THF/MeOH/CH3CN混合物(v/v/v,1/1/1,90mL)。添加一水氢氧化锂(874mg,20.8mmol)的水溶液(30mL),并将该混合物搅拌过夜。将溶剂量真空浓缩至约30mL。向剩余的水溶液添加盐酸(1M)以将pH值降低至3。将水层用乙醚(3×40mL)萃取。将合并的有机萃取物用硫酸钠干燥。将干燥剂通过过滤去除并使用旋转蒸发仪去除溶剂。将残留物用硅胶层析(120g RediSep柱,0%至50%梯度的乙酸乙酯/己烷洗脱60分钟,85mL/min)纯化, 从而得到为无色液体的产物34(3.37g,89%)。1H NMR(300MHz,CDCl3)δ7.22(d,J=6.1Hz,2H),6.82(d,J=6.1Hz,2H),4.46(s,2H),3.81(m,1H),3.75(s,3H),2.65-2.49(m,2H),1.80-1.60(m,2H),1.50-1.20(m,18H),0.85(t,J=5.8Hz,3H)。
实施例33
(R)-3-(4-甲氧基苄氧基)十四酰基氯化物(35)
向酸34(500mg,1.37mmol)的DCM(5mL)溶液添加二甲基甲酰胺(DMF)(100mg,1.37mmol),并将所得的混合物冷却至-10℃。滴加草酰氯(174mg,1.37mmol)的DCM(5mL)溶液。使溶液加热至室温,持续1小时。在TLC分析后表明没有酸存在,将该混合物真空浓缩并且可以不经过进一步纯化而使用。
实施例34
(R)-2-氧代-2-苯基乙基3-羟基十四烷酸酯(37)
在室温下,向(R)-3-羟基十四酸(36,参见如下制备)(9.55g,39.1mmol)和三乙胺(5.90g,58.6mmol)的乙酸乙酯(500mL)溶液添加2-溴苯乙酮(7.90g,39.1mmol)。将该混合物在室温下搅拌14小时。将沉淀物通过过滤去除并将滤液真空浓缩。将残留物用硅胶层析(120g RediSep柱,0%至30%梯度的乙酸乙酯/己烷洗脱50分钟,85mL/min)纯化,从而得到为白色固体的产物37(10.2g,72%的产率)。
实施例35
(R)-2-氧代-2-苯基乙基-3-癸酰氧基十四烷酸酯(39)
在0℃下,向37(4.80g,13.2mmol)和吡啶(2.10g,26.5mmol)的DCM(100mL)溶液添加癸酰氯(38,2.8g,4.8mmol)。将该混合物搅拌14小时并使该混合物的温度升高至室温。将该混合物用NaHCO3饱和溶液(100mL)和盐水(100mL)洗涤并用Na2SO4干燥。将干燥剂通过过滤去除并使用旋转蒸发仪去除溶剂。将残留物用硅胶层析(120g RediSep柱,0%到40%梯度的乙酸乙酯/己烷洗脱50分钟,85mL/min)纯化,从而得到为无色液体的产物39(6.68g,97%)。
实施例36
(R)-3-(癸酰氧基)十四酸(40)
将酯39(10.15g,20.77mmol)溶解于乙酸(100mL)。加入锌(15.5g,237mmol)并将该混合物回流加热至4小时。真空去除乙酸并将残留物与甲苯共沸至干燥。将残留物用硅胶层析(120g RediSep柱,0%至60%梯度的乙酸乙酯/己烷洗脱50分钟,85mL/min)纯化,从而得到为无色液体的产物40(7.2g,89%)。1H NMR(300MHz,CDCl3)δ5.23-5.19(m,1H),2.62-2.55(m,2H),2.34-2.25(m,2H),1.65-1.58(m,2H),1.28-1.20(m,32H),0.85(m,6H)。
实施例37
(R)-甲基3-羟基十四烷酸酯(39)
将甲基3-氧代十四烷酸酯(41,5.27g,20.6mmol)的甲醇(30mL)浆体在300mL高压反应器玻璃套管中由N2喷射10分钟。添加二氯-R-2,2’-双(二苯基膦基)-1,1’-二萘基钌(142mg,1.1mmol)并将该混合物置于Parr 5500系列紧凑反应器中。将反应器用H2(60psi)填充并排放三次。随后反应器填充有最后部分的H2(60psi),并搅拌(600rpm)且加热至50℃并持续20小时。随后将反应器冷却至室温并将该混合物真空浓缩。将所得的残留物用硅胶层析纯化,用0%至50%梯度的乙酸乙酯/己烷洗脱,从而提供为灰白色固体的42(3.97g,74%)。1H NMR(CDCl3)δ4.00-3.98(m,1H),3.71(s,3H),2.82(d,J=6.5Hz,1H),2.62-2.30(m,2H),1.54-1.39(m,3H),1.27(br s,17H),(m,20H),0.86(t,J=7.0Hz,3H)。
实施例38
(R)-3-羟基十四酸(36)
将一水氢氧化锂(1.98g,47.2mmol)加入至(R)-甲基3-羟基十四烷酸酯(42,8.17g,31.5mmol)的THF(66mL)和水(66mL)的溶液并在室温下搅拌2小时。随后将该混合物用二乙醚(1L)稀释并用盐酸溶液(1N)将pH值调节至约为3。随后将溶液用二乙醚(200mL)萃取,并将有机部分合并且用Na2SO4干燥。将Na2SO4通过过滤去除并将滤液真空浓缩,从而提供为灰白色固体的(R)-3-羟基十四酸(36,7.59g,98%)。1H NMR(CDCl3)δ3.99-3.94(m,1H),2.45-2.39(m,2H),1.47(br s,3H),1.29(br s,17H),0.89(t,J=7.0Hz,3H)。
实施例39
(R)-2-氧代-2-苯基乙基-3-十四酰氧基十四烷酸酯(46)
将十四酰氯(45,8.83g,35.8mmol)添加至(R)-2-氧代-2-苯基乙基3-羟基十四烷酸酯(37,根据实施例34制备,10.8g,29.8mmol)的吡啶(40mL)溶液。将反应混合物在室温下搅拌14小时。随后将该混合物真空浓缩,并通过将残留物溶解在甲苯(100mL)中并真空浓缩来去除残留的吡啶。将所得的残留物用硅胶层析纯化,0%至20%梯度的乙酸乙酯/己烷洗脱,从而提供为无色油状的46(16.31g,83%)。1H NMR(CDCl3)δ7.90(m,2H),7.64-7.57(m,1H),7.50-7.45(m,2H),5.33(s,2H),5.31-5.27(m,1H),2.80-2.70(m,2H),2.33-2.26(t,J=4.5Hz,2H),1.65-1.58(m,2H),1.31-1.21(m,40H),0.85(t,J=10.0Hz,6H)。
实施例40
(R)-3-(十四酰氧基)十四酸(47)
将锌粉(24.42g,373.3mmol)添加至46(16.28g,28.42mmol)的乙酸(150mL)溶液。随后将该混合物加热至回流(115℃)并持续3小时。随后将该混合物真空浓缩,并通过将残留物溶解在甲苯(100mL)且真空浓缩来去除残留的吡啶。将所得的残留物用硅胶层析纯化,0%至30%梯度的乙酸乙酯/己烷洗脱,从而提供为无色油状的(R)-苄基3-(十四酰氧基)十四酸(47,11.14g,86%的产率)。1H NMR(CDCl3)δ5.29-5.18(m,1H),2.62-2.55(m,2H),2.34-2.25(m,2H),1.65-1.58(m, 3H),1.28-1.20(m,40H),0.85(m,6H)。
实施例41
叔丁基二甲基甲硅烷基-2-叠氮基-4-O-苄基-2-脱氧-β-D-吡喃葡萄糖苷(47)
将化合物4(根据实施例3制备,1.32g,3.36mmol)溶解于BH3(1M)的THF(18.1mL,18.1mmol)溶液。在0℃下将该混合物搅拌5分钟之后,滴加三氟化二丁基硼(1M,溶于DCM,3.62mL,3.62mmol),并在0℃下反应混合物再搅拌1小时。随后,加入三乙胺(0.5mL)和甲醇(约0.5mL)直至溶解的H2气逸出。将溶剂真空蒸发,并将残留物与甲醇(3×50mL)共蒸发。将残留物用硅胶柱层析(己烷/乙酸乙酯,8:1(v/v))纯化,从而得到为无色油状的14(0.67g,49%)。Rf=0.40(己烷/乙酸乙酯,3:1(v/v))。1H NMR(500MHz,CDCl3)δ7.32-7.31(m,5H),4.81(d,J=11.4Hz,1H),4.70(d,J=11.4Hz,1H),4.55(d,J=7.5Hz,1H),3.84(m,1H),3.70(dd,1H,J=12.0,1.5Hz,1H),3.49-3.43(m,2H),3.33(br s,1H),3.22-3.17(m,1H),0.92(s,9H),0.14(s,6H)。
实施例42
Th1-型体内免疫反应的诱导
本实施例表明具有如下结构(IX)的本发明示例性化合物的Th1-型体内免疫刺激活性:
化合物IX在包含被称为ID83的结核杆菌抗原多肽的疫苗中使用。采用标准免疫学方法和试剂(Current Protocols in Immunology,Coligan等人(Eds.)2006 John Wiley&Sons,NY)。在三周的时间间隔内,用ID83抗原的水溶液将小鼠(每组四只C57BL/6动物)免疫三次(对于每次免疫,每只动物8μg),将ID83抗原(对于每次免疫,每只动物8μg)配制在稳定的乳剂载体中,或者将ID83抗原(对于每次免疫,每只动物8μg)配制在包含(i)GLA-SE(对于每次免疫,每只动物10μg)或(ii)化合物IX(对于每次免疫,每只动物8μg)的稳定乳剂中。
在每次注射一周后,将小鼠取血以评价抗原特异性抗体(IgG1和IgG2c)反应。在最后免疫之后三周,将小鼠处死并取脾脏以分析T细胞依赖性IFN-γ细胞因子对体内抗原刺激的应答,其根据公开方法通过酶联免疫斑点法进行测定(同上)。IFN-γ细胞因子反应已与抗结核杆菌感染的TH1保护性表型相关联。
图1表示相比于在GLA-SE、SE或水中配制的ID83,通过使用与10μg化合物IX的稳定乳剂(SE)配制的ID83抗原和ID83组分抗原(Rv2608、Rv1813和Rv3620)在第三次免疫后的三周时,在小鼠中诱导的抗-ID83IFN-γ细胞因子产生的酶联免疫斑点数据。示出每组中脾细胞的每百万IFN-γ分泌细胞的平均值和SEM。如在本文实施例中所使用,“GLA-SE”指在共有的第20080131466号美国专利公开中所描述的化合物的稳定乳剂,其中R1、R3、R5和R6为C11直链烃基;且R2和R4为C13直链烃基。
所有的动物均与ConA、有效细胞活化素和分裂素相等地反应。ID83+化合物IX接种诱导出强效的ID83抗原特异性细胞因子反应, 而在ID83+水或ID83+SE对照组中观察到很少或不存在这种反应。在用ID83组分抗原(Rv2608、Rv1813和Rv3620)再激发后,从用ID83+化合物IX或ID83+GLA-SE免疫的小鼠中纯化的脾细胞中提取出相似水平的IFN-γ分泌细胞。
总之,具有结核杆菌疫苗抗原候选物ID83的稳定油性制剂中的化合物IX显著地诱导了与保护性TH1表型相关的细胞型(T细胞)的抗原特异性免疫反应。
实施例43
Th1-型和Th2-型体内免疫反应的诱导
该实施例说明在包含被称为ID83的结核杆菌抗原的疫苗中的化合物IX的体内Th1-型和Th2-型免疫刺激剂活性。采用标准免疫学方法和试剂(Current Protocols inImmunology,Coligan等人(Eds.)2006John Wiley&Sons,NY)。
使用ID83抗原(对于每次免疫,每只动物8μg)在三周间隔内将小鼠免疫三次(每组四只C57BL/6动物),该抗原单独使用或配制在包含化合物IX(对于每次免疫,每只动物10μg)的稳定乳剂中。在每次免疫后一周,通过对动物取血来采集血清,并根据公开方法(同上)所使用的ELISA来检测对ID83的特异性IgG1和IgG2c抗体的血清水平。IgG1或IgG2c抗体同种型的任何一种的优势分别与TH2或TH1反应有关。已经表明TH1反应对于防止结核杆菌感染是必要的。
如图2A-2F所示,使用ID83水溶液的接种显著诱导了抗原特异性的IgG1抗体。与此相反,ID83+SE、ID83+化合物IX-SE或ID83+GLA-SE接种诱导了更高的IgG2c抗体滴定量,并且将表型转变为混合的IgG1:IgG2c抗原特异性抗体反应。
实施例44
人类细胞中的TLR4-依赖性免疫刺激的诱导
本实施例表明人类细胞中化合物IX的免疫刺激活性。使用具有表达载体的HEK293细胞(InvivoGen)在体内检测化合物IX,该表达载体 编码1)TLR4、MD-2和CD14或2)TLR2和TLR6以确定化合物活性及对TLR4的依赖性,并排除TLR2的激活。用NF-kB报道载体pNifty-2将这些HEK 293细胞株进一步稳定地转染以便当TLR信号通路激活时碱性磷酸酶分泌至生长培养基。将转染的细胞株放置在96孔板中,每孔5×104个细胞,并且刺激16-24小时且在包含化合物IX和其它佐剂的连续稀释的介质中培养。使用测试(InvivoGen)检测在培养基中的分泌碱性磷酸酶活性。将PBS负对照以上的NF-kB的增加部分作为检测数据。通过该分析,化合物IX在低至0.1μg/ml的浓度下表现出NF-kB的两倍以上的增加(图3)。这些实验的结果清楚地表明对于化合物IX的TLR4激动剂活性与TLR2的诱导没有关联。化合物IX是基于所报道的MD2和TLR4的原子结构性考虑而设计的。因此,其结合且引出与商用获准的TLR4激动剂相似的性质,该事实是意外且预料不到的结果。更特别地,当浓度增加时,化合物IX的性质有利地快速达到平衡,之前人们预期细胞因子水平增高至副作用可以影响其自身的点。因此,预期本发明的化合物IX和其它示例性化合物能够在宽范围的浓度下安全地使用,其在患者临床结果的重现性的情况下以及对于成年人和儿童的剂量的安全范围内是非常亟需的。对此,化合物IX的更低的细胞因子活性是令人意外且满意的结果,其将更加有利于在临床制剂中安全的使用。
实施例45
人类血细胞中免疫刺激细胞因子的诱导
在该实施例中,用化合物IX刺激人的全部血细胞,并采用ELISA分析来检测免疫刺激细胞因子的诱导。在96孔板中,由磷酸盐缓冲盐水连续稀释(1:5)化合物IX和其它佐剂,总共7次稀释。将100μl从两个不同的供体中新抽取的人血混合并用100μl的佐剂稀释液进行孵育。在孵育20小时后,将板离心并收集上清液(约70μl),去除血红细胞,并在-20℃下保存,然后使用标准生物化学过程进行MIP-1-α和TNF-αELISA。这些实验结果进一步证实化合物IX在初代人血细胞中具有免疫刺激活性(图4A-4D)。另外,这些初代供体结果与在人细胞株中所见的结果相似,且相对于对于该化合物的可能剂量范围和安全谱,扩展了这些重要发现。
本说明书中引用和/或申请数据表中列出的所有上述美国专利、美国专利申请公布、美国专利申请、外国专利、外国专利申请和非专利出版物都通过引用以其整体形式并入本文。
通过上述应当理解,尽管为了说明的目的在本文中描述了本发明的具体实施方案,但可以进行各种变化,而不背离本发明的主旨和范围。因此,本发明仅受所附的权利要求书的限制。
Claims (34)
2.疫苗组合物,其包含与抗原或编码抗原的重组表达载体结合的权利要求1所述的化合物。
3.如权利要求2所述的疫苗组合物,其中所述重组表达载体为病毒载体。
4.如权利要求3所述的疫苗组合物,其中所述病毒载体选自腺相关的病毒载体、疱疹病毒载体、慢病毒载体、痘病毒载体以及逆转录病毒载体。
5.如权利要求3所述的疫苗组合物,其中所述病毒载体是腺病毒载体。
6.如权利要求2所述的疫苗组合物,其中所述抗原衍生自至少一种选自下组的感染性病原体:细菌、病毒和真菌。
7.权利要求1所述的化合物在制备用于引发或增强个体中抗原特异性免疫反应的疫苗中的用途。
8.药物组合物,其包含权利要求1所述的化合物以及药物可接受的载体或赋形剂。
9.如权利要求8所述的药物组合物,其不含抗原。
10.权利要求8所述的药物组合物在制备用于刺激个体中非特异性免疫反应的药物中的用途。
11.疫苗组合物,其包含权利要求1所述的化合物。
12.如权利要求11所述的疫苗组合物,其不含抗原。
13.权利要求1所述的化合物在制备用于刺激个体中免疫反应的药物组合物或疫苗组合物中的用途。
14.如权利要求13所述的用途,其中所述组合物为药物组合物且不含抗原。
15.如权利要求13所述的用途,其中所述组合物为疫苗组合物且包含抗原或编码抗原的重组表达载体。
16.权利要求1所述的化合物在制备用于引发或增强罹患癌症的个体中免疫反应的药物组合物或疫苗组合物中的用途。
17.如权利要求16所述的用途,其中所述组合物为药物组合物且不含抗原。
18.如权利要求16所述的用途,其中所述组合物为疫苗组合物且包含抗原或编码抗原的重组表达载体。
19.权利要求1所述的化合物在制备用于引发或增强罹患自身免疫病的个体中免疫反应的药物组合物或疫苗组合物中的用途。
20.如权利要求19所述的用途,其中所述组合物为药物组合物且不含抗原。
21.如权利要求19所述的用途,其中所述组合物为疫苗组合物且包含抗原或编码抗原的重组表达载体。
22.权利要求1所述的化合物在制备用于引发或增强罹患变态反应的个体中免疫反应的药物组合物或疫苗组合物中的用途。
23.如权利要求22所述的用途,其中所述组合物为药物组合物且不含抗原。
24.如权利要求22所述的用途,其中所述组合物为疫苗组合物且包含抗原或编码抗原的重组表达载体。
25.权利要求1所述的化合物在制备用于引发或增强罹患传染病的个体中免疫反应的药物组合物或疫苗组合物中的用途。
26.如权利要求25所述的用途,其中所述组合物为药物组合物且不含抗原。
27.如权利要求25所述的用途,其中所述组合物为疫苗组合物且包含抗原或编码抗原的重组表达载体。
28.权利要求1所述的化合物在制备用于治疗受试者中感染、季节性鼻炎、癌症、自身免疫病、过敏症或哮喘的药物组合物或疫苗组合物中的用途。
29.如权利要求28所述的用途,其中所述组合物为药物组合物且不含抗原。
30.如权利要求28所述的用途,其中所述组合物为疫苗组合物且包含抗原或编码抗原的重组表达载体。
31.权利要求1所述的化合物在制备用于引发或增强个体中至少一种选自TH1型T淋巴细胞反应、TH2型T淋巴细胞反应、细胞毒性T淋巴细胞(CTL)反应、抗体反应、细胞因子反应、淋巴因子反应、趋化因子反应和炎症反应的免疫反应的药物组合物中的用途。
33.权利要求32的用途,其中所述组合物进一步包含至少一种辅佐剂。
34.权利要求33的用途,其中所述辅佐剂为QS21。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18470309P | 2009-06-05 | 2009-06-05 | |
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