CN1889977A - 含白介素18和皂苷佐剂系统的疫苗组合物 - Google Patents
含白介素18和皂苷佐剂系统的疫苗组合物 Download PDFInfo
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Abstract
本发明涉及一种用于治疗或预防感染性疾病、癌症、自身免疫病和相关病症的联合治疗。
Description
本发明涉及一种应用于感染性疾病、癌症、自身免疫病和相关疾病的治疗或预防的联合治疗。具体地说,该联合治疗包括给予TH-1细胞因子(具体地说为IL-18)和免疫原性组合物(具体地说为含抗原和皂苷佐剂的疫苗)。具体地说,本发明涉及IL-18或其生物活性片段或变体以及含肿瘤相关抗原和皂苷佐剂的免疫原性组合物治疗癌前病变或癌症的用途。本发明进一步涉及适于本发明用途的联合制剂和药盒。这些治疗方法和药用制剂对刺激适于预防和免疫治疗应用(特别是用于预防和/或治疗肿瘤)的免疫应答尤其有用。
发明背景
癌症是由于遗传改变而由单细胞发展成的一种疾病。尽管投入了众多的财力和人力资源,但癌症仍然是主要的死因之一。临床上检查出这些肿瘤通常是在疾病的较晚期,在通过手术可去除原发性肿瘤时,经常已经出现聚集在不同器官中的微量转移。尽管在了解致癌机制方面取得了显著进步,但在转移性癌症治疗和防止早期肿瘤向更恶性和转移性病变发展方面进展甚微。化疗经常不能完全去除这些细胞,那么这些细胞仍然是疾病复发源。
TH-1型细胞因子,如IFN-γ、TNFα、IL-2、IL-12、IL-18等,趋向于支持诱导针对所给予抗原的细胞介导的免疫应答。相反,高水平的Th2-型细胞因子(如IL-4、IL-5、IL-6和IL-10)趋向于支持诱导体液免疫应答。白介素(IL-18),也叫做干扰素-γ(IFNg)诱导因子,被称为是一种具有刺激患者自身免疫系统对抗疾病(例如癌症)的免疫调节作用的多效细胞因子。IL-18在免疫应答早期表达,对体液和细胞免疫应答都起作用,并将应答导向更好的TH-1型模式。IL-18由活化的抗原提呈细胞产生,据报道其具有几种生物活性,具体地说是促进幼稚CD4 T细胞分化为Th1细胞,刺激天然杀伤(NK)细胞、天然杀伤T(NKT)细胞,以及诱导活化T细胞增殖,主要是诱导细胞毒性T细胞(CD8+表型)分泌γ干扰素(IFN-γ)(Okamura H.et al.1998,Adv.Immunol.70:281-312)。IL-18还介导Fas-诱导的肿瘤死亡,促进产生IL-1a和GMCSF,并具有抗血管生成活性。
IL-18能够刺激先天免疫以及Th1和Th2二者介导的应答。在IL-12存在时,IL-18可作用于Th1细胞、非极化T细胞、NK细胞、B细胞和树突细胞,以产生IFNg。在没有IL-12辅助时,IL-18在T细胞、NK细胞、肥大细胞和嗜碱性粒细胞中潜在诱导IL-4和IL-13产生。
已经表明,IL-18通过产生IFN-γ诱导肿瘤退化,IFN-γ是内源性和细胞因子诱导性抗肿瘤免疫应答的关键组分。已用不同肿瘤动物模型证实了效力(Jonak Z et al.2002,J.Immunother.25,S20-S27;Akamatsu S;et al.2002,J.Immunother.25,S28-S34)。含IL-18和其它物质组合的组合物已有描述,特别是IL-18和化疗剂组合(US6,582,689)。还描述了IL-18起疫苗佐剂作用(WO 99/56775;WO03/031569)。
皂苷述于:Lacaille-Dubois,M and Wagner H.(1996.A review ofthe biological and pharmacological activities of saponins,Phytomedicine,第2卷,363-386页)。皂苷为类固醇或三萜糖苷,广泛分布于植物和海洋动物界。皂苷的特点是形成振荡起泡沫的胶体水溶液和沉淀胆固醇。当皂苷接近细胞膜时,其在膜中产生孔样结构,使膜爆裂。红细胞溶血是该现象的一个实例,该实例是某些而不是全部皂苷的特性。
已知皂苷为系统给予疫苗的佐剂。本领域已深入研究了各种皂苷的佐剂和溶血活性(Lacaille-Dubois and Wagner,出处同上)。例如,Quil A(来源于南美奎拉雅属皂树(Quillaja Saponaria Molina)的树皮)及其组分描述于US 5,057,540和“Saponins as vaccine adjuvants”,Kensil,C.R.,Crit Rev Ther Drug Carrier Syst,1996,12(1-2):1-55以及EP 0362 279 B1。含Quil A或其组分的颗粒结构称为免疫刺激复合物(ISCOM),已用于生产疫苗(Morein,B.,EP 0 109 942 B1)。这些结构据报道具有佐剂活性(EP 0 109 942 B1;WO 96/11711)。美国专利No.5,057,540和EP 0 362 279 B1描述了为有效系统佐剂的溶血性皂苷QS21和QS17(Quil A的HPLC纯化组分),并公开了其生产方法。在这些参考文献中还描述了QS7(Quil-A的一种非溶血性组分)起系统疫苗有效佐剂作用的用途。QS21的用途进一步描述于Kensil et al.(1991.J.Immunology,146卷,431-437)。还已知QS21和聚山梨醇酯或环糊精的组合(WO 99/10008)。含Quil A组分的颗粒佐剂系统如QS21和QS7描述于WO 96/33739和WO 96/11711。
已用于系统接种研究的其它皂苷包括来源于其它植物物种如满天星和肥皂草的皂苷(Bomford et al.,Vaccine,10(9):572-577,1992)。
还已知皂苷已用于粘膜应用疫苗的研究,其在诱导免疫应答方面取得了不同成果。先前已表明当鼻内给予抗原时Quil-A皂苷对诱导免疫应答无效(Gizurarson etal.1994.Vaccine Research 3,23-29)。同时,其它作者使用该佐剂取得了成功(Maharaj et al.,Can.J.Microbiol,1986,32(5):414-20;Chavali and Campbell,Immunobiology,174(3):347-59)。含Quil A皂苷的ISCOM已用于胃内和鼻内疫苗制剂,并表现出佐剂活性(Mcl Mowat et al.,1991,Immunology,72,317-322;MclMowat and Donacie,Immunology Today,12,383-385)。还描述了Quil A的无毒组分QS21为口服或鼻内佐剂(Sumino etal.,J.Virol.,1998,72(6):4931-9;WO 98/56415)。
本发明涉及令人惊奇的发现:联合给予TH-1细胞因子如IL-18和含抗原与皂苷佐剂(包括但不限于QS-21)的免疫原性组合物是极为有效的,提供了对感染性疾病、原发性和转移性肿瘤疾病(即癌症)、自身免疫病和相关病症的有效和良好耐受的预防或治疗,特别是有效抑制表达肿瘤相关抗原的人癌症细胞的生长。
发明陈述
因此,本发明提供在患者中激发针对抗原的增强免疫应答的方法,其包括给予患者安全有效量的i)免疫原性组合物,具体地说是疫苗,其包含抗原或其免疫原性衍生物和皂苷佐剂,和ii)IL-18多肽或其生物活性片段或变体。在另一个实施方案中,本发明提供减轻患者癌症严重性的方法,包括治疗既有肿瘤(原发性肿瘤和转移性肿瘤)或防止癌症复发,所述方法包括给予有需要患者安全有效量的i)IL-18多肽或其生物活性片段或变体,和ii)免疫原性组合物,具体地说是疫苗,其包含肿瘤相关抗原或其免疫原性衍生物和皂苷佐剂。
在一个实施方案中,IL-18多肽为鼠或人IL-18多肽或其生物活性片段或变体。在另一个实施方案中,抗原为肿瘤相关抗原。在再另一个实施方案中,皂苷为Quil A的无毒组分,例如QS-17或QS-21。在一个实施例中,皂苷为QS21。因此,在一个实施方案中,本发明涉及减轻患者癌症严重性的方法,包括治疗既有肿瘤(原发性肿瘤和转移性肿瘤)或防止癌症复发,具体地说是乳癌、肺癌(特别是非小细胞肺癌)、黑素瘤、结直肠癌、卵巢癌、前列腺癌、膀胱癌、头颈鳞状细胞癌、胃癌和其它GI(胃肠)癌,特别是食道癌,所述方法包括给予哺乳动物i)免疫原性组合物,具体地说是疫苗,其包含肿瘤相关抗原或其免疫原性衍生物和QS-21,和ii)IL-18多肽或其生物活性片段或变体。
本发明还涉及含以下各种组分作为活性成分的联合制剂:(1)IL-18多肽或其生物活性片段或变体,和(2)含抗原和皂苷佐剂的免疫原性组合物,活性成分同时、单独或序贯用于预防和/或治疗感染性疾病、癌症(包括原发性和转移性肿瘤)、自身免疫病和相关病症。在一个实施方案中,联合制剂中的免疫原性组合物包含其它的免疫刺激化学物质,其选自:胆固醇、3D-MPL、免疫刺激性寡核苷酸、氢氧化铝、磷酸铝、生育酚和水包油乳剂或者两种或多种所述佐剂的组合。例如,另外的佐剂可为免疫刺激性寡核苷酸。
在相关方面,本发明还提供药盒,其包含以下各种组分作为活性成分:(1)IL-18多肽或其生物活性片段或变体,和(2)含抗原或其免疫原性衍生物和皂苷佐剂的免疫原性组合物,活性成分同时、单独或序贯用于预防和/或治疗感染性疾病、癌症(包括原发性和转移性肿瘤)和自身免疫病。
本发明进一步涉及以下组分在药物生产中的用途:(1)IL-18多肽或其生物活性片段或变体,和(2)含抗原或其免疫原性衍生物和皂苷佐剂的免疫原性组合物,以通过给予患者安全有效量的两种组分,在所述患者中获得保护性免疫应答或减轻疾病严重性。
本发明进一步涉及制备所述免疫原性组合物的方法、所述组合物预防和/或治疗疾病(特别是癌症)的用途以及所述组合物在哺乳动物(包括人)中抑制肿瘤或癌细胞生长的用途。
发明详述
在一种形式的本发明中,免疫原性组合物中的皂苷佐剂为Quil A的无毒组分,例如QS-17或QS-21,如QS-21。抗原可为感染性生物来源的抗原,例如肿瘤相关抗原或其免疫原性衍生物或衍生物。在一个实施方案中,TH-1细胞因子是鼠或人IL-18或其生物活性片段。免疫原性组合物和IL-18可在诱导抗原特异性抗体时协同起作用,并可有效诱导或增强按惯例与TH-1型免疫系统相关的体液或/和细胞免疫应答。所述免疫应答增强指免疫应答总体增加,这可由体液和/或细胞介导的免疫应答确定,或由肿瘤大小和/或肿瘤载荷的减小确定。所述协同性指IL-18多肽或其免疫原性片段或变体在联合治疗中与本发明的免疫原性组合物一起给予时,能够诱导免疫应答,该免疫原性组合物的存在可增强IL-18多肽或其免疫原性片段或变体的效力。诱导免疫应答的结果可为预防、减轻疾病严重性(对于癌症,包括减轻既有的原发性或转移性肿瘤或防止癌症复发)和/或治疗。
因此,在一个实施方案中,本发明提供一种在哺乳动物中激发针对抗原的免疫应答的方法,其包括给予哺乳动物i)有效量的免疫原性组合物,其包含感染性生物来源的抗原或肿瘤相关抗原和QS-21,和ii)IL-18多肽或其生物活性片段或变体。在一个实施方案中,治疗的两种组分序贯给予。就是说使用所述免疫原性组合物加强通过给予IL-18激发的体液和/或细胞免疫应答。或者,在另一个实施方案中,使用本发明的免疫原性组合物在随后接受IL-18的个体中激发体液和/或细胞免疫应答。在再另一个实施方案中,所述治疗的两种组分同时给予,方法是在两个不同部位一起给予或混合在同一制剂中。技术人员会理解,两种免疫原性组合物和IL-18多肽或其免疫原性片段或变体可一次性给予或重复给予。
所规划的属于本发明范围的联合治疗与任一种组分单独使用相比至少等效,例如效力增加。特别是在癌症领域,联合治疗是有优势的,因为其组合了两种抗癌剂,每种都通过不同的作用机制以累加方式(例如协同地)起作用,产生增强的抗人肿瘤细胞的细胞毒性反应。
在一个相关实施方案中,本发明提供含以下组分作为活性成分的联合制剂(例如药用多瓶包装):(1)IL-18多肽或其生物活性片段或变体,和(2)含抗原和皂苷佐剂的免疫原性组合物,活性成分同时、单独或序贯用于预防和/或治疗感染性疾病和癌症。
所述联合制剂指药用制剂或药物(多瓶)包装或分配装置,其可含一种或多个含活性成分的单位剂型。包装例如可包含金属或塑料箔,例如泡罩包装。包装或分配装置可附有给予说明。当IL-18多肽或其生物活性片段或变体和免疫原性组合物欲作为两种单独的组合物给予时,可以例如多瓶包装的形式提供这些组合物。同时、单独或序贯给予的本发明活性成分不是表现为已知物质的单纯累积,而是具有令人惊奇的有价值特性的全新组合,IL-18多肽或其生物活性片段或变体的应用使得可以同时刺激免疫系统的先天部分和获得性部分,包括NK细胞活化以及T细胞介导的免疫应答和细胞因子产生,由此增加免疫原性组合物的效力。这产生了一种新的有效治疗。要理解地是,联合制剂,也称为配套试剂盒,是指联合制剂的组分不必一体化(例如以组合物)提供,以便可单独或序贯应用。因此,表述配套试剂盒是指就组分的物理分离而言不必真正混合。
联合制剂可用于治疗或预防癌症,具体地说是减轻癌症严重性或防止癌症复发。可由本文所述联合治疗获益的癌症包括其特征在于不受控的细胞生长和增殖、瘤前病变、原发性肿瘤和转移性肿瘤病变的任何疾病,其包括但不限于乳癌、肺癌(特别是非小细胞肺癌,NSCLC)、黑素瘤、结直肠癌、卵巢癌、前列腺癌、膀胱癌、头颈鳞状细胞癌、胃癌和其它GI(胃肠)癌(特别是食道癌)、白血病、淋巴瘤、骨髓瘤和浆细胞瘤。
代表性的抗原或其衍生物和片段(包括肽,即少于约50个氨基酸)包括MAGE(黑素瘤抗原编码基因)家族编码的被称为癌症(睾丸)抗原的抗原(Gaugler B.et al.J.Exp.Med.,1994,179:921;Weynants P.et al.Int.J.Cancer,1994,56:826;Patard J.J.et al.Int.J.Cancer,1995,64:60)。表达MAGE蛋白的癌症被称为MAGE相关肿瘤。MAGE基因属于一个紧密相关基因的家族,包括即位于染色体X上的MAGE1、MAGE 2、MAGE 3(黑素瘤抗原编码基因-3)、MAGE 4、MAGE 5、MAGE 6、MAGE 7、MAGE 8、MAGE 9、MAGE 10、MAGE 11、MAGE 12,其编码序列互相之间共有的同源性为64-85%(De Plaen E.et al.,Immunogenetics,1994,40,360-369)。有时这些基因被称为MAGEAl、MAGE A2、MAGE A3、MAGE A4、MAGE A5、MAGE A6、MAGE A7、MAGE A8、MAGE A9、MAGE A10、MAGE A11、MAGEA12(MAGE A家族)。两个其它蛋白组也是MAGE家族的一部分,尽管相关性更远。它们是MAGE B组和MAGE C组。MAGE B家族包括MAGE B1(也称为MAGE Xp1和DAM 10)、MAGE B2(也称为MAGE Xp2和DAM 6)、MAGE B3和MAGE B4,MAGE C家族目前包括MAGE C1和MAGE C2。一般而言,MAGE蛋白可定义为包含核心序列特征,其位于蛋白的C末端(例如对于MAGE A1来说,其为309个氨基酸的蛋白,核心特征对应于氨基酸195-279)。
因此,如下描述核心特征的共有模式:其中x代表任意氨基酸,小写字母残基是保守的(允许为保守变体),大写字母残基是完全保守的。
核心序列特征:
LixvL(2x)1(3x)g(2x)apEExiWexl(2x)m(3-4x)Gxe(3-4x)gxp(2x)IIt(3x)VqexYLxYxqVPxsxP(2x)yeFLWGprA(2x)Et(3x)kv
保守取代是众所周知的,一般在序列比对计算机程序中作为默认记分矩阵。这些程序包括PAM250(Dayhoft M.O.et al.,1978,“Amodel of evolutionary changes in proteins”,载于“Atlas of Proteinsequence and structure”5(3)M.O.Dayhoft(编辑),345-352),NationalBiomedical Research Foundation,Washington,以及Blosum 62(StevenHenikoft & Jorja G.Henikoft(1992),“Amino acid substitution matriciesfrom protein blocks”),Proc.Natl.Acad.Sci.USA 89(Biochemistry):10915-10919。
一般地说,以下组内的取代为保守取代,但组间的取代被认为是非保守的。所述组为:
i)天冬氨酸/天冬酰胺/谷氨酸/谷氨酰胺
ii)丝氨酸/苏氨酸
iii)赖氨酸/精氨酸
iv)苯丙氨酸/酪氨酸/色氨酸
v)亮氨酸/异亮氨酸/缬氨酸/甲硫氨酸
vi)甘氨酸/丙氨酸
一般地和在本发明范围内,MAGE蛋白的核心区与MAGE Al的氨基酸195-279的同一性约为50%。
MAGE-3在69%的黑素瘤中表达(Gaugler B.et al.J.Exp.Med.,1994,179:921),还可在44%的NSCLC(Yoshimatsu T.J SurgOncol.,1998,67,126-129)、75%的小细胞肺癌(SCLC)(Traversari C.et al.,GeneTher.1997,4:1029-1035)、48%的头颈鳞状细胞癌、34%的膀胱过渡型细胞癌、57%的食道癌、32%的结肠癌和24%的乳癌(Van Pel A.et al.,Immunol.Rev.,1995,145:229;Inoue H.et al.Int.J.Cancer,1995,63:523;Nishimura S et al.,Nihon Rinsho Meneki Gakkai Kaishi 1997,Apr,20(2):95-101)中检测出来。已在MAGE-3蛋白上鉴别出几种表位,其分别具有MHC I类分子HLA.A1或HLA.A2(Van der Bruggen P.etal.,Eur.J.Immunol.,1994,24,3038-3043)和HLA.B44(Herman,J.et al.,Immunogenetics,1996,43,377-383)等位基因的特异性结合基序。
尽管已在黑素瘤、肺和食道癌中检测出MAGE-3,但这些抗原在MAGE-相关肿瘤患者中的表达水平看起来有限,低于免疫识别的阈值(Weiser T.S.et al.,Ann.Thorac.Surg.2001,71:295-302)。
其它代表性的抗原或其衍生物或由其产生的片段包括例如公开于WO 99/40188的MAGE抗原、PRAME(WO 96/10577)、BAGE、RAGE、LAGE 1(WO 98/32855)、LAGE 2(也称为NY-ESO-1,WO98/14464)、XAGE(Liu et al,Cancer Res,2000,60:4752-4755;WO02/18584)、SAGE和HAGE(WO 99/53061)或GAGE(Robbins andKawakami,1996,Current Opinions in Immunology 8,628-636页;Vanden Eynde et al.,International Journal of Clinical & Laboratory Research(1997提交);Correale et al.(1997),Journal of the National CancerInstitute 89,293页。实际上,这些抗原在广泛类型的肿瘤中表达,例如黑素瘤、肺癌、肉瘤和膀胱癌。
在一个实施方案中,使用前列腺抗原,例如前列腺癌抗原或前列腺特异性分化抗原(PSA)、PAP、PSCA(PNAS 95(4)1735-17401998)、PSMA或称为前列腺蛋白酶(Prostase)的抗原。
在另一个实施方案中,前列腺抗原是P501S或其片段。P501S也叫做Prostein(Xu et al.,Cancer Res.61,2001,1563-1568),已知为WO 98/37814的SEQ ID NO.113,是一个553个氨基酸的蛋白。在以上引用的专利申请中公开了其含20或至少20、50或至少50或100或至少100个连续氨基酸的免疫原性片段和部分,本发明具体规划了其用途。可使用的片段公开于WO 98/50567(PS108抗原),其为前列腺癌相关蛋白(WO 99/67384的SEQ ID NO:9)。可使用的其它片段为全长P501S蛋白的氨基酸51-553、34-553或55-553。具体地说,可考虑使用构建物1、2和3(参见图2,SEQ ID NO.27-32),其可在酵母系统中表达,例如可在酵母系统中表达编码该多肽的DNA序列。
前列腺蛋白酶是前列腺特异性丝氨酸蛋白酶(胰蛋白酶样),254个氨基酸长,具有保守的丝氨酸蛋白酶催化三联体H-D-S和氨基末端前原肽序列,表明潜在的分泌功能(P.Nelson,Lu Gan,C.Ferguson,P.Moss,R.linas,L.Hood & K.Wand,“Molecular cloning andcharacterisation of prostase,an androgen-regulated serine protease withprostate restricted expression”载于Proc.Natl.Acad.Sci.USA(1999)96,3114-3119)。描述了推定的糖基化位点。预测的结构非常类似于其它已知的丝氨酸蛋白酶,表明成熟多肽折叠成单个结构域。成熟蛋白为224个氨基酸长,具有至少一个显示出被天然加工的A2表位。前列腺蛋白酶核苷酸序列和推定的多肽序列以及同源物公开于Ferguson,et al.(Proc.Natl.Acad.Sci.USA 1999,96,3114-3119)和国际专利申请WO 98/12302(还有对应的授予专利US 5,955,306)、WO 98/20117(还有对应的授予专利US 5,840,871和US 5,786,148)(前列腺特异性激肽释放酶)和WO 00/04149(P703P)。
由WO 98/37418和WO/0 04149可知其它的前列腺特异性抗原。另一个是STEAP(PNAS 96 14523 14528 7-12 1999)。
用于本发明范围的其它肿瘤相关抗原包括:Plu-1(J Biol.Chem274(22)15633-15645,1999)、HASH-1、HASH-2(Alders,M.et al.,Hum.Mol.Genet.1997,6,859-867)、Cripto(Salomon et al Bioessays 199,2161-70,美国专利5654140)、CASB616(WO 00/53216)、Criptin(US5,981,215)。另外,与癌症治疗中的疫苗特别相关的抗原还包括酪氨酸酶、端粒酶、P53、NY-Br1.1(WO 01/47959)和例如公开于WO00/43420的其片段、B726(WO 00/60076,SEQ ID NO 469和463;WO 01/79286,SEQ ID NO 474和475)、P510(WO 01/34802 SEQ ID NO537和538)和生存蛋白。
本发明还与乳癌抗原如Her-2/neu、乳腺球蛋白(mammaglobin)(美国专利5,668,267)、B305D(WO 00/61753 SEQ ID NO 299、304、305和315)或公开于WO 00/52165、WO 99/33869、WO 99/19479、WO98/45328的那些抗原联用。其中Her-2/neu抗原公开于美国专利5,801,005。Her-2/neu可包含完整胞外结构域(大约含氨基酸1-645)或其片段以及整个胞内结构域的至少免疫原性部分(大约C端的580个氨基酸)。具体地说,胞内部分可包含磷酸化结构域或其片段。这样的构建物公开于WO 00/44899。一种可使用的构建物被称为ECD-PhD,第二种被称为ECD δPhD(参见WO00/44899),也叫做dHer2。本文使用的Her-2/neu可来源于例如大鼠、小鼠或人。
某些肿瘤抗原是小肽抗原(即少于约50个氨基酸)。代表性的肽包括粘蛋白衍生肽,例如MUC-1(参见例如US 5,744,144、US5,827,666、WO 88/05054、US 4,963,484)。具体考虑的是MUC-1衍生肽,其包含MUC-1肽的至少一个重复单元,或至少两个该重复单元,其由SM3抗体识别(US 6,054,438)。其它的粘蛋白衍生肽包括来自MUC-5的肽。
或者,所述抗原可为白介素,例如IL13和IL14。或者,所述抗原可为自身肽激素,例如完整长度的促性腺激素释放激素(GnRH,WO95/20600),其为10个氨基酸长度的短肽,用于治疗多种癌症或用于免疫去势。其它的肿瘤特异性抗原包括但不限于肿瘤特异性神经节苷脂,例如GM2和GM3。
抗原还可以来自人致病原,例如人免疫缺陷病毒HIV-1(例如tat、nef、逆转录酶、gag、gp120和gp160)、人单纯疱疹病毒如gD或其衍生物或立即早期蛋白如HSV1或HSV2的ICP27、巨细胞病毒((esp Human)(例如gB或其衍生物))、轮状病毒(包括活-减毒病毒)、EB病毒(例如gp350或其衍生物)、水痘-带状疱疹病毒(例如gpI、II和IE63),或来自肝炎病毒,例如乙肝病毒(例如乙型肝炎表面抗原或其衍生物)、甲肝病毒、丙肝病毒和戊肝病毒,或来自其它病毒病原体,例如副粘病毒:呼吸道合胞病毒(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...)、黄病毒(例如黄热病毒、登革病毒、蜱传脑炎病毒、日本脑炎病毒)或流感病毒(在鸡蛋或MDCK细胞中培养的全活病毒或失活病毒、裂解流感病毒,或全流感病毒组(如R.Gluck,Vaccine,1992,10,915-920所述)或其纯化或重组蛋白,例如HA、NP、NA或M蛋白,或其组合),或来自细菌病原体,例如奈瑟氏球菌(Neisseria spp),包括淋病奈瑟氏球菌(N.gonorrhea)和脑膜炎奈瑟氏球菌(N.meningitidis)(例如荚膜多糖及其缀合物、转铁结合蛋白、乳铁结合蛋白、PiIC、粘附素);酿脓链球菌(S.pyogenes)(例如M蛋白或其片段、C5A蛋白酶、脂磷壁酸质)、无乳链球菌(S.agalactiae)、变异链球菌(S.mutans);杜氏嗜血菌(H.ducreyi);莫拉氏菌(Moraxella spp),包括粘膜炎莫拉氏菌(M catarrhalis),也称为粘膜炎布兰汉氏球菌(Branhamella catarrhalis)(例如高和低分子量的粘附素和侵袭素);博德特氏菌(Bordetella spp),包括百日咳博德特氏菌(B.pertussis)(例如百日咳杆菌粘附素(Pertactin)、百日咳毒素或其衍生物、丝状血凝素、腺苷酸环化酶、菌毛)、副百日咳博德特氏菌(B,parapertussis)和支气管炎博德特氏菌(B.bronchiseptica);分枝杆菌(Mycobacterium spp),包括结核分枝杆菌(M.tuberculosis)(例如ESAT6、Antigen 85A、-B或-C)、牛分枝杆菌(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(Legionella spp),包括侵肺军团菌(L.pneumophila);埃希氏菌(Escherichia spp),包括肠毒性大肠杆菌(例如定居因子、不耐热毒素或其衍生物、热稳定性毒素或其衍生物)、肠出血性大肠杆菌、肠致病性大肠杆菌(例如志贺毒素样毒素或其衍生物);弧菌(Vibrio spp),包括霍乱弧菌(V.cholera)(例如霍乱毒素或其衍生物);志贺氏菌(Shigella spp),包括索氏志贺氏菌(S.sonnei)痢疾志贺氏菌(S.dysenteriae)、弗氏志贺氏菌(S.flexnerii);耶尔森氏菌(Yersinia spp),包括小肠结肠炎耶尔森氏菌(Y.enterocolitica)(例如Yop蛋白)、鼠疫耶尔森氏菌(Y.pestis)、假结核耶尔森氏菌(Y.pseudotuberculosis);弯曲杆菌(Campylobacter spp),包括空肠弯曲杆菌(C.jejuni)(例如毒素、粘附素和侵袭素)和大肠弯曲杆菌(C.coli);沙门氏菌(Salmonella spp),包括伤寒沙门氏菌(S.typhi)、副伤寒沙门氏菌(S.paratyphi)、猪霍乱沙门氏菌(S.choleraesuis)、肠沙门氏菌(S.enteritidis);利斯特氏菌(Listeria spp),包括单核细胞增生利斯特氏菌(L.monocytogenes);螺杆菌(Helicobacter spp),包括幽门螺杆菌(H.pylori)(例如脲酶、过氧化氢酶、空泡毒素);假单胞菌(Pseudomonasspp),包括铜绿假单胞菌(P.aerugmosa);葡萄球菌(Staphylococcusspp),包括金黄色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis);肠球菌(Enterococcus spp),包括粪肠球菌(E.faecalis)、屎肠球菌(E.faecium);梭菌(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)(例如肉毒杆菌毒素及其衍生物)、艰难梭菌(C.difficile)(例如梭状芽孢杆菌毒素A或B及其衍生物);芽孢杆菌(Bacillus spp),包括炭疽芽孢杆菌(B.anthracis)(例如肉毒杆菌毒素及其衍生物);棒杆菌(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(Borrelia spp),包括布氏疏螺旋体(B.burgdorferi)(例如OspA、OspC、DbpA、DbpB)、嘎氏疏螺旋体(B.garinii)(例如OspA,OspC,DbpA,DbpB)、阿氏疏螺旋体(B.afzelii)(例如OspA、OspC、DbpA、DbpB)、(B.andersonii)(例如OspA、OspC、DbpA、DbpB)、赫氏蜱疏螺旋体(B.hermsii);埃里希氏体(Ehrlichia spp),包括马埃里希氏体(E.equi)和人粒细胞埃里希氏体病病原体;立克次氏体(Rickettsia spp),包括立氏立克次氏体(R.rickettsii);衣原体(Chlamydia spp),包括砂眼衣原体(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.psiffaci);钩端螺旋体(Leptospira spp),包括问号钩端螺旋体(L.interrogans);密螺旋体(Treponema spp),包括彻白密螺旋体(T.pallidum)(例如稀有外膜蛋白)、齿垢密螺旋体(T.denticola)、猪痢疾密螺旋体(T.hyodysenteriae);或来自寄生物,例如疟原虫(Plasmodium spp),包括恶性疟原虫(P.falciparum);弓形虫(Toxoplasma spp),包括刚地弓形虫(T.gondii)(例如SAG2、SAG3、Tg34);阿米巴(Entamoeba spp),包括溶组织内阿米巴(E.histolytica);巴贝虫(Babesia spp),包括田鼠巴贝虫(B.microti);锥虫(Trypanosoma spp),包括枯氏锥虫(T.cruzi);贾第鞭毛虫(Giardia spp),包括蓝氏贾第鞭毛虫(G.lamblia);利什曼虫(Leshmania spp),包括硕大利什曼虫(L.major);肺囊虫(Pneumocystisspp),包括卡氏肺囊虫(P.carinii);毛滴虫(Trichomonas spp),包括阴道滴虫(T.vaginalis);血吸虫(Schisostoma spp),包括曼氏血吸虫(S.mansoni);或来自酵母,例如假丝酵母(Candida spp),包括白假丝酵母(C.albicans);隐球菌(Cryptococcus spp),包括新生隐球菌(C.neoformans)。
其它结核分枝杆菌(M.tuberculosis)抗原例如为TbRa12、Tb H9、Tb Ra35、Tb38-1、Erd 14、DPV、MTI、MSL、mTTC2和hTCC1(WO99/51748)。结核分枝杆菌(M.tuberculosis)的蛋白还包括融合蛋白及其变体,其中至少两个或至少三个结核分枝杆菌多肽融合成较大蛋白。融合蛋白的实例包括Ra12-TbH9-Ra35、Erd14-DPV-MTI、DPV-MTI-MSL、Erd14-DPV-MTI-MSL-mTCC2、Erd14-DPV-MTI-MSL、DPV-MTI-MSL-mTCC2、TbH9-DPV-MTI(WO 99/51748)。
衣原体抗原包括例如高分子量蛋白(HWMP)(WO 99/17741)、ORF3(EP 366 412)和推测膜蛋白(Pmp)。疫苗制剂的其它衣原体抗原可选自描述于WO 99/28475的抗原组。
细菌抗原可得自链球菌(Streptococcus spp),包括肺炎链球菌(S.pneumoniae)(例如荚膜多糖及其缀合物、PsaA、PspA、链球菌溶血素、胆碱结合蛋白)和蛋白抗原肺炎球菌溶血素(Biochem Biophys Acta,1989,67,1007;Rubins et al.,Microbial Pathogenesis,25,337-342),以及其突变脱毒衍生物(WO 90/06951;WO 99/03884)。其它细菌抗原得自嗜血杆菌(Haemophilus spp),包括B型流感嗜血杆菌(H.influenzaetype B)(例如PRP及其缀合物)、不定型流感嗜血杆菌(non typeable H.influenzae),例如OMP26、高分子量粘附素、P5、P6、D蛋白和脂蛋白D,以及丝束蛋白和丝束蛋白衍生肽(US 5,843,464)或其多拷贝变体或融合蛋白。
乙型肝炎表面抗原衍生物是本领域众所周知的,其中包括描述于欧洲专利申请EP-A-414 374、EP-A-0304 578和EP 198-474的陈述为PreS1、PreS2、S抗原的那些抗原。在一个实施方案中,HBV抗原为HBV聚合酶(Ji Hoon Jeong et al,1996,BBRC 223,264-271;Lee H.J.et al,Biotechnol.Lett.15,821-826)。还规划了HIV衍生抗原,例如HIV-1抗原gp120,尤其是在CHO细胞中表达时。
本发明的免疫组合物可包含得自人乳头瘤病毒的抗原(HPV 6a、6b、11、16、18、31、33、35、39、45、51、52、56、58、59和68),特别是那些被认为引起生殖器疣的HPV血清型(HPV 6或HPV 11等)和引起子宫颈癌的HpV病毒(HPV16、HPV18等)。合适的HPV抗原是E1、E2、E4、E5、E6、E7、L1和L2。作为生殖器疣预防或治疗形式的实例,融合蛋白含L1颗粒或衣壳体,融合蛋白所包含的一种或多种抗原选自:HPV 6和HPV 11蛋白E6、E7、L1和L2。融合蛋白的实例是:WO 96/26277公开的L2E7和WO 99/10375公开的蛋白D(1/3)-E7。HPV子宫颈感染或子宫颈癌的预防或治疗性疫苗组合物可包含HPV 16或18抗原。例如,一起提供L1或L2抗原单体或L1或L2抗原作为病毒样颗粒(VLP),或在VLP或衣壳体结构中仅提供单独的L1蛋白。这样的抗原、病毒样颗粒和衣壳体本身是已知的。参见例如WO94/00152、WO94/20137、WO94/05792和WO93/02184。
另外,可包含单独的或作为融合蛋白的早期蛋白,例如E7、E2或E5;其它实施方案包括含L1E7融合蛋白的VLP(WO96/11272)。HPV 16抗原可包含早期蛋白E6或E7,其与D蛋白载体融合,形成D蛋白-HPV 16的E6或E7融合体,或其组合;或E6或E7和L2的组合(WO96/26277)。
或者,HPV 16或18早期蛋白E6和E7可以单个分子提供,例如D蛋白-E6/E7融合体。其它融合体可选地包含HPV 18的E6和E7蛋白的任一种或两种,例如为D蛋白-E6或D蛋白-E7融合蛋白形式或D蛋白E6/E7融合蛋白形式。融合蛋白可包含其它HPV毒株的抗原,例如毒株HPV 31或33的抗原。
还考虑了得自引起疟疾的寄生物的抗原。例如恶性疟原虫(Plasmodia falciparum)抗原包括RTS,S和TRAP。RTS是杂种蛋白,包含恶性疟原虫(P.falciparum)环孢(CS)蛋白的大致全部C末端部分,其通过乙型肝炎表面抗原preS2部分的4个氨基酸连接至乙型肝炎病毒的表面(S)抗原。其完整结构公开于WO93/10152。当在酵母中表达时,生产的RTS为脂蛋白颗粒,当其与HBV的S抗原共表达时,其产生称为RTS,S的混杂颗粒。TRAP抗原描述于WO90/01496。本发明的一个实施方案是融合蛋白,其中抗原制剂包含RTS,S和TRAP抗原的组合。可能为融合蛋白组分候选物的其它疟原虫抗原为恶性疟原虫(P.falciparum)MSP1、AMA1、MSP3、EBA、GLURP、RAP1、RAP2、钳合蛋白、PfEMP1、Pf332、LSA1、LSA3、STARP、SALSA、PfEXP1、Pfs25、Pfs28、PFS27/25、Pfs16、Pfs48/45、Pfs230及其在疟原虫(Plasmodium spp)中的类似物。
本文使用的术语“免疫原性组合物”在其广义上用于指当给予患者时确实影响所述患者的免疫应答的组合物。免疫原性组合物提供给患者增强的系统或局部免疫应答,其或者为细胞免疫应答,例如CTL,或者为体液免疫应答,例如激发抗体。具体地说,本发明的免疫原性组合物可指一种制剂,其含有效量的抗原多肽/蛋白(例如肿瘤相关抗原)及其免疫原性衍生物(例如其片段或编码多核苷酸)和药学可接受的载体。所述安全有效量是指蛋白剂量,如必要的话其可与佐剂相关联,当该剂量给予人时,产生可检测的免疫应答,例如体液应答(抗体)或细胞应答,或该剂量能够免疫调节免疫系统,而无通常的疫苗接种者中的明显的副作用。该量根据所使用的具体免疫原和其如何提供而有所变化。一般来说,预期每剂含1-5000μg蛋白,例如1-1000μg蛋白,例如1-500μg,例如1-100μg,例如1-50μg。具体疫苗的最佳量可通过标准研究确定,包括观察受试者的合适免疫应答。在初始接种后,受试者可接受一次或数次足够间隔的加强免疫。疫苗制剂一般描述于Vaccine Design(“The subunit and adjuvantapproach”(eds.Powell M.F.&Newman M.J).(1995)Plenum Press NewYork)。在脂质体中包囊化描述于Fullerton的美国专利4,235,877。
免疫原性抗原多肽指在免疫实验(例如ELISA或T细胞刺激实验)中可检测地与表达所述多肽的患者的抗血清和/或T细胞反应的多肽。可使用技术人员众所周知的技术进行免疫活性的筛选。例如,可使用例如描述于Harlow and Lane,Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory,1988的方法进行该筛选。在一个说明性实施例中,可将多肽固定在固体支持体上,并与患者血清接触,以使血清中的抗体和固定化多肽结合。然后可去除未结合血清,并使用例如125I-标记的A蛋白检测结合抗体。
本发明提供的多肽抗原经SDS PAGE检测例如至少为80%纯,例如至少90%纯。多肽抗原经SDS PAGE检测可呈现为单一条带。
本发明还包括免疫原性衍生物,例如抗原的免疫原性片段或部分,例如肿瘤相关抗原或肿瘤特异性抗原的片段或部分。本文使用的“免疫原性片段”是自身与识别多肽的B细胞和/或T细胞表面抗原受体免疫反应(即特异性结合)的片段。一般可使用众所周知的技术,例如概述于Paul,Fundamental Immunology,第3版,243-247(RavenPress,1993)和其中提及的参考文献中的技术,鉴别免疫原性部分。这样的技术包括筛选与抗原特异性抗体、抗血清和/或T细胞系或克隆反应的能力。
如果本文使用的抗血清和抗体特异性结合抗原(即它们在ELISA或其它免疫实验中与蛋白反应,但不与不相关蛋白可检测地反应),则它们是“抗原特异性的”。这样的抗血清和抗体可如本文所述和使用众所周知的技术制备。
在一个实施方案中,多肽的免疫原性部分是以基本不低于全长多肽的反应性(例如在ELISA和/或T细胞反应性实验中的反应性)的水平与抗血清和/或T细胞反应的部分。免疫原性部分的免疫活性水平可为全长多肽免疫原性的至少约50%、至少约70%或约90%以上。在某些情况下,鉴别出的免疫原性部分的免疫活性水平高于对应的全长多肽,例如超过约100%或150%或更高的免疫活性。在某些其它实施方案中,示例性免疫原性部分可包括N端前导序列和/或跨膜结构域缺失的肽。相对于成熟蛋白,其它示例性免疫原性部分少量N端或C端缺失(例如约1-50个氨基酸、约1-30个氨基酸、约5-15个氨基酸)。
在另一个实施方案中,本发明的示例性免疫原性组合物,例如疫苗组合物,包含编码如上所述的一种或多种多肽的多核苷酸,使得多肽原位产生。多核苷酸可在各种已知传递系统的任一种中给予。实际上,众多的基因传递技术在本领域都是广为人知的,例如描述于Rolland,Crit.Rev.Therap.Drug Carrier Systems 15:143-198,1998和其中提及的参考文献中的技术。当然,合适的多核苷酸表达系统包含在患者中表达所必需的调节子DNA调节序列(例如合适的启动子和终止信号)。或者,细菌传递系统可包括给予在其细胞表面上表达免疫原性部分或分泌该表位的细菌(例如卡介苗)。
在本发明的一个实施方案中,给予/传递的多核苷酸为“裸”DNA,如Ulmer et al.,Science 259:1745-1749,1993所述和Cohen,Science 259:1691-1692,1993综述。通过将DNA包被在有效转运入细胞中的生物可降解珠上,可增加裸DNA的摄取。在一个实施方案中,皮内传递组合物。具体地说,利用基因枪(特别是颗粒轰击)给予技术传递组合物,该技术如Haynes et al,J Biotechnology 44:37-42(1996)所述,包括将载体包被在珠(例如金)上,然后在高压下给入表皮中。
在一个说明性实施例中,用例如Powderject Pharmaceuticals PLC(Oxford,UK)and Powderject Vaccines Inc.(Madison,WI)生产的装置可实现气体驱动的颗粒加速,其一些实例描述于美国专利No.5,846,796、6,010,478、5,865,796、5,584,807和EP专利No.0500799。该方法提供了一种无针传递途径,其中极微小颗粒(例如多核苷酸)的干粉制剂在通过手提装置产生的氦气流中加至高速,将颗粒推进入目标靶组织中,通常是皮肤。颗粒可为0.4-4.0μm、0.6-2.0μm直径的金珠,DNA缀合物包被在其上,然后封装入放置“基因枪”的弹筒或弹盒中。
在一个相关实施方案中,可用于本发明组合物的气体驱动无针注射的其它装置和方法包括Bioject,Inc.(Portland,OR)提供的方法,其一些实例描述于美国专利No.4,790,824、5,064,413、5,312,335、5,383,851、5,399,163、5,520,639和5,993,412。
因此,在某些实施方案中,使用众多已知的病毒型系统中的任一种,将编码本文所述的免疫原性多肽的多核苷酸导入适于表达的哺乳动物宿主细胞中。在一个说明性实施方案中,逆转录病毒提供了一种方便有效的基因传递系统平台。可将选择的编码本发明多肽的核苷酸序列插入到载体中,并使用本领域已知的技术包装入逆转录病毒颗粒中。然后可分离重组病毒,并传递入受试者中。已经描述了许多示例性的逆转录病毒系统(例如美国专利No.5,219,740;Miller and Rosman(1989)BioTechniques 7:980-990;Miller,A.D.(1990)Human Gene Therapy 1:5-14;Scarpa et al.(1991)Virology 180:849-852;Burns et al.(1993)Proc.Natl.Acad.Sci.USA 90:8033-8037;和Boris-Lawrie and Temin(1993)Cur.Opin.Genet.Develop.3:102-109)。
另外,还描述了很多示例性的腺病毒型系统。与整合入宿主基因组的逆转录病毒不同,腺病毒驻留在染色体外,因此使与插入诱变相关的风险最小化(Haj-Ahmad and Graham(1986)J.Virol.57:267-274;Bett et al.(1993)J.Virol.67:5911-5921;Mittereder etal.(1994)Human Gene Therapy 5:717-729;Seth et al.(1994)J.Virol.68:933-940;Barr et al.(1994)Gene Therapy 1:51-58;Berkner,K.L.(1988)BioTechniques 6:616-629;和Rich et al.(1993)Human Gene Therapy 4:461-476)。因为人有时受到普通的人腺病毒血清型如AdHu5感染,所以相当大比例的人群对腺病毒具有中和抗体反应,其可能影响针对重组疫苗型系统中的外源抗原的免疫应答。非人灵长类腺病毒载体如黑猩猩腺病毒68(AdC68,Fitzgerald et al.(2003)J.Immunol 170(3):1416-22)可提供一种替代的腺病毒系统,其没有先前存在的中和抗体反应的劣势。
还开发了各种用于多核苷酸传递的腺相关病毒(AAV)载体系统。可使用本领域众所周知的技术容易地构建AAV载体。参见例如美国专利No.5,173,414和5,139,941、国际公开申请WO 92/01070和WO 93/03769、Lebkowski et al.(1988)Molec.Cell.Biol.8:3988-3996;Vincent et al.(1990)Vaccines 90(Cold Spring Harbor LaboratoryPress);Carter,B.J.(1992)Current Opinion in Biotechnology 3:533-539;Muzyczka,N.(1992)Current Topics in Microbiol.and Immunol.158:97-129;Kotin,R.M.(1994)Human Gene Therapy 5:793-801;Shelling and Smith(1994)Gene Therapy l:165-169;和Zhou et al.(1994)J.Exp.Med.179:1867-1875。
用于通过基因转移传递本发明多肽编码核酸分子的其它病毒载体包括来源于痘病毒家族的载体,例如痘苗病毒和禽痘病毒。作为实例,可如下构建表达新分子的痘苗病毒重组体。首先将多肽编码DNA插入到合适的载体中,以使其邻近于痘苗启动子,并位于痘苗DNA序列侧翼,例如编码胸苷激酶(TK)的序列。然后使用该载体转染细胞,该细胞同时用痘苗感染。同源重组用于将痘苗启动子和目的多肽编码基因插入到病毒基因组中。可通过在5-溴脱氧尿嘧啶存在下培养细胞,并挑选抗5-溴脱氧尿嘧啶的病毒斑,选择产生的TK-重组体。
痘苗型感染/转染系统可方便地用于在生物体宿主细胞中提供可诱导的瞬时表达或共表达的一种或多种本文所述多肽。在该特定系统中,首先用编码噬菌体T7 RNA聚合酶的痘苗病毒重组体体外感染细胞。该聚合酶展示出灵敏的特异性,即其仅转录携带T7启动子的模板。在感染后,在T7启动子引导下用一种或多种目的多核苷酸转染细胞。在胞浆中表达的痘苗病毒重组体聚合酶将转染的DNA转录成RNA,然后由宿主翻译系统将RNA翻译成多肽。该方法提供了高水平的、瞬时的、胞浆生产的大量RNA及其翻译产物。参见例如ElroyStein and Moss,Proc.Natl.Acad.Sci.USA(1990)87:6743-6747;Fuerst et al.Proc.Natl.Acad.Sci.USA(1986)83:8122-8126。
或者,还可以使用禽痘病毒如鸟痘病毒和金丝雀痘病毒传递目的编码序列。已知当表达哺乳动物病原体免疫原的重组禽痘病毒给予非禽物种时,产生保护性免疫。在人和其它哺乳动物物种中使用禽痘病毒载体是特别适合的,因为禽痘病毒属成员仅可在易感的禽物种中有效复制,因此在哺乳动物细胞中不是感染性的。生产重组禽痘病毒的方法是本领域已知的,如上文关于痘苗病毒生产的描述使用基因重组。参见例如WO 91/12882、WO 89/03429和WO92/03545。
还可使用众多α病毒载体中的任一种传递本发明的多核苷酸组合物,例如描述于美国专利No.5,843,723、6,015,686、6,008,035和6,015,694的那些载体。还可以使用某些基于委内瑞拉马脑炎(VEE)的载体,示例性实例可见于美国专利No.5,505,947和5,643,576。
以预防或治疗有效量给予含抗原性肽编码核苷酸序列的载体。要给予的量可在每剂1pg至16mg核苷酸的范围内,对于颗粒介导的传递在每剂1pg至10μg核苷酸范围内,对于其它途径在每剂10μg至16mg核苷酸的范围内。确切的量可根据要免疫患者的体重和给予途径而显著变化。
适于将裸多核苷酸或载体导入患者中的技术还包括合适载体的局部应用。核酸可通过例如鼻内、口、阴道内或直肠内给予局部给予至皮肤或粘膜表面。裸多核苷酸或载体可与药学可接受的赋形剂一起提供,例如磷酸缓冲盐水(PBS)。可通过使用单独的或纳入DNA制剂中的促进剂如丁哌卡因进一步促进DNA摄取。其它直接给予受者核酸的方法包括超声波、电刺激、电穿孔和描述于US 5,697,901的微接种。
可利用几种已知转染技术增强核酸构建物的摄取,例如包括使用转染剂的技术。这些转染剂的实例包括阳离子剂(例如磷酸钙)和DEAE葡聚糖和脂转染剂,例如Lipofectam和Transfectam。要给予的核酸的剂量可改变。
在再另一个实施方案中,本发明的免疫原性组合物包括抗体或血清或抗体结构域,例如Fab和F(ab′)2片段。抗体可为单克隆抗体或其片段。有效剂量通常为100μg至500mg/kg患者体重,例如为1mg至50mg/kg患者体重。因此,本发明的方法包括被动免疫治疗或被动免疫预防。
本发明的免疫原性组合物和IL-18多肽可通过各种途径传递,例如肌内、皮下、腹膜内或静脉内。
本发明的IL-18多肽或其生物活性片段诱导主要为Th1型的免疫应答。高水平的Th1型细胞因子(例如IFN-γ、TNFα、IL-2、IL-12、IL-18等)倾向于支持诱导针对所给予抗原的细胞介导的免疫应答。相反,高水平的Th2-型细胞因子(例如IL-4、IL-5、IL-6和IL-10)倾向于支持诱导体液免疫应答。关于细胞因子家族的综述,参见Mosmannand Coffman,Ann.Rev.Immunol.7:145-173,1989。所述“IL-18”或“IL-18多肽”指公开于EP0692536、EP0712931、EP0767178和WO97/2441的IL-18多肽。IL-18多肽衍生物或变体包括分离的多肽,其含有的氨基酸序列与图1所示的SEQ ID NO:6(人IL-18)或SEQ IDNO:7(鼠IL-18)的氨基酸序列的同一性,分别为全长SEQ ID NO:6和SEQ ID NO:7的至少70%、至少80%、至少90%、至少95%、至少97-99%。这样的多肽包括分别含SEQ ID NO:6和SEQ ID NO:7的氨基酸的多肽。IL-18多肽可为SEQ ID NO:6和SEQ ID NO:7所列出的氨基酸序列。还规划了IL-18片段,即能够表现出IL-18的生物(抗原性或免疫原性)活性(如诱导IFN-γ)的IL-18片段。可使用IL-18生物活性片段,可使用IL-18免疫原性片段。
IL-18多肽可为成熟蛋白形式,或者可为较大蛋白如融合蛋白的一部分。还规划了IL-18变体,即通过由一个具有类似特性的残基取代另一个残基的保守氨基酸取代而改变的多肽。通常,所述取代发生在Ala、Val、Leu和Ile之间;在Ser和Thr之间;在酸性残基Asp和Glu之间;在Asn和Gln之间;在碱性残基Lys和Arg之间;或芳香族残基Phe和Tyr之间。例如,其中几个、5-10、1-5、1-3、1-2或1个氨基酸以任意组合被取代、缺失或添加的变体。还规划了IL-18生物活性片段。所述“生物活性片段”指基本保留了和全长IL-18相同的生物活性的IL-18片段。所述生物活性指任一种以下特性:增强了天然杀伤(NK)细胞活性和Th1细胞应答(活化NK、NKT细胞、诱导活化的T细胞增殖)、抗血管生成活性;增强活化的NK、NKT细胞和T细胞上的Fas配体的表达;增加IFNg、GM-CSF和其它细胞因子如Th1-型细胞因子的生产;能够刺激先天免疫性以及Th1-和Th2-介导的应答。
具体地说,IL-18的生物活性片段是根据KG-1检测系统的体外检测,保留了增加IFNg生产的能力的片段。表达人IL-18受体的人髓样单核细胞系(KG-1)对IL-18治疗有反应,即增加IFNg的生产(分泌)(通过ELISA检测)和活化NfkB(Matsuko Taniguchi et al.J.Immunological Methods,1998,217,97-102)。
可以任何合适的方式制备本发明的IL-18多肽。其包括分离的天然多肽、重组或合成产生的所述多肽等。该制备方法是本领域周知的。
有利地,本发明的免疫原性组合物可包含药学可接受的赋形剂或载体。载体分子可含几种形式,包括载体生物,例如活细菌载体或细菌载体菌株,水、盐水或免疫刺激化学物质。载体可为水、盐水或其它缓冲性生理溶液。载体分子还可包括多孔聚合颗粒,例如微珠或纳米颗粒,以及金属盐颗粒,例如氢氧化铝、磷酸铝或磷酸钙或磷酸镁、磷酸铁、碳酸钙、碳酸镁、硫酸钙、氢氧化镁,或双盐,例如磷酸铵-铁、磷酸钾-铁、磷酸钙-铁、碳酸钙-镁或任一种这些盐的混合物。
在给予本文提供的联合制剂时,患者将承受包括Th1-型和Th2-型应答的免疫应答。
可通过各种途径传递本发明的免疫原性组合物和IL-18多肽或其生物活性片段或变体,例如肌内、皮下、腹膜内或静脉内。
以预防或治疗有效量给予含抗原性肽编码核苷酸序列的载体。要给予的量一般在每剂1pg至16mg核苷酸的范围内,对于颗粒介导的传递在每剂1pg至10μg核苷酸范围内,对于其它途径在每剂10μg至16mg核苷酸的范围内。确切的量可根据要免疫患者的体重和给予途径而显著变化。
适于将裸多核苷酸和载体导入患者中的技术还包括合适载体的局部应用。核酸可通过例如鼻内、口、阴道内或直肠内给予局部给予至皮肤或粘膜表面。裸多核苷酸或载体可与药学可接受的赋形剂一起提供,例如磷酸缓冲盐水(PBS)。可通过使用单独的或纳入DNA制剂中的促进剂如丁哌卡因促进DNA摄取。其它直接给予受者核酸的方法包括超声波、电刺激、电穿孔和描述于US 5,697,901的微接种。
可通过几种已知的转染技术增强核酸构建物的摄取,例如包括使用转染剂的技术。这些转染剂的实例包括阳离子剂(例如磷酸钙)和DEAE葡聚糖和脂转染剂,例如Lipofectam和Transfectam。要给予的核酸的剂量可改变。
本发明的IL-18多肽或其生物活性片段诱导主要为Th1型的免疫应答。高水平的Th1型细胞因子(例如IFN-γ、TNFo、IL-2、IL-12、IL-18等)倾向于支持诱导针对所给予抗原的细胞介导的免疫应答。相反,高水平的Th2-型细胞因子(例如IL-4、IL-5、IL-6和IL-10)倾向于支持诱导体液免疫应答。关于细胞因子家族的综述,参见Mosmannand Coffman,Ann.Rev.Immunol.7:145-173,1989。这些细胞因子的水平可使用标准检测容易地评价。所述“IL-18”指公开于EP0692536、EP0712931、EP0767178和WO97/2441的IL-18多肽。IL-18多肽包括分离的多肽,其含有的氨基酸序列与图1所示的SEQ ID NO:1(人IL-18)或SEQ ID NO:2(鼠IL-18)的氨基酸序列的同一性,分别为全长SEQ ID NO:1和SEQ ID NO:2的至少70%、至少80%、至少90%、至少95%或至少97-99%。这样的多肽包括分别含SEQ ID NO:1和SEQ ID NO:2的氨基酸的多肽。IL-18多肽可具有SEQ ID NO:1和SEQ ID NO:2所列出的氨基酸序列。还规划了IL-18片段,即能够表现出IL-18的生物(抗原性或免疫原性)活性(如诱导IFN-γ)的IL-18片段。
IL-18多肽可为成熟蛋白形式,或者可为较大蛋白如融合蛋白的一部分。还规划了IL-18变体,即通过由一个具有类似特性的残基取代另一个残基的保守氨基酸取代而改变的多肽。典型的所述取代在Ala、Val、Leu和Ile之间;在Ser和Thr之间;在酸性残基Asp和Glu之间;在Asn和Gln之间;在碱性残基Lys和Arg之间;或芳香族残基Phe和Tyr之间。例如,其中几个、5-10、1-5、1-3、1-2或1个氨基酸以任意组合被取代、缺失或添加的变体。
可以任何合适的方式制备本发明的IL-18多肽。其包括分离的天然多肽、重组或合成产生的所述多肽等。该制备方法是本领域周知的。
在给予本文提供的联合制剂时,患者将发生包括Th1-型和Th2-型应答的免疫应答。
在本发明的实施方案中,免疫原性组合物还包含另一种佐剂,例如诱导主要为Th1型的免疫应答的佐剂。TH-1诱导佐剂可选自以下佐剂:脂多糖衍生的佐剂如肠细菌脂多糖(LPS)、3D-MPL、胆固醇和CpG寡核苷酸或两种或多种所述佐剂的混合物。主要激发Th1型应答的佐剂可包括例如单磷酰脂质A(例如3-脱氧-酰化单磷酰脂质A)和铝盐的组合。MPL佐剂可得自Corixa Corporation(Seattle,WA;参见例如美国专利No.4,436,727、4,877,611、4,866,034和4,912,094)。
在一个实施方案中,本发明的免疫原型组合物还含有免疫刺激性CpG寡核苷酸。
含CpG的寡核苷酸(其中CpG二核苷酸未甲基化)也诱导Th1为主的应答。这样的寡核苷酸是众所周知的,描述于例如WO 96/02555、WO 99/33488和美国专利No.6,008,200和5,856,462。例如,Sato et al.,Science 273:352,1996也描述了免疫刺激性DNA序列。
本领域已知CpG在系统和粘膜途径给予时都是佐剂(WO96/02555、EP 468520,Davis et al.,J.Immunol,1998,160(2):870-876;McCluskie and Davis,J.Immunol.,1998,161(9):4463-6)。CpG是DNA中存在的胞嘧啶-鸟苷二核苷酸基序的缩写。在历史上,观察到BCG DNA组分可发挥抗肿瘤作用。在进一步的研究中,来源于BCG基因序列的合成寡核苷酸显示出能够诱导免疫刺激作用(体外和体内均可)。这些研究的作者断定:某些回文序列,包括中央CG基序,具有这种活性。CG基序在免疫刺激中的核心作用后来由Krieg,Nature 374,546页,1995的出版物阐明。详细分析表明,CG基序肯定在某些序列当中,这些序列常见于细菌DNA,但在脊椎动物DNA中罕见。免疫刺激序列通常为:嘌呤、嘌呤、C、G、嘧啶、嘧啶;其中双核苷酸CG基序未甲基化,但已知其它未甲基化CpG序列是免疫刺激性的,可用于本发明。
在某些6个核苷酸的组合中存在回文序列。这些基序或者为一个基序的重复,或者为不同基序的组合,其中有几个可存在于相同的寡核苷酸。存在一个或多个含寡核苷酸的这些免疫刺激序列可活化各种免疫组成部分,包括天然杀伤细胞(其产生IFNγ,并具有溶细胞活性)和巨噬细胞(Wooldrige et al Vol 89(no.8),1977)。尽管其它含未甲基化CpG的序列不具有该共有序列,但已被表明其是免疫刺激性的。
用于本发明的寡核苷酸可包含两个或多个双核苷酸CpG基序,其由至少3个、至少6个或更多个核苷酸分隔。本发明的寡核苷酸可为脱氧核苷酸。在一个实施方案中,寡核苷酸中的核苷酸之间是二硫代磷酸酯键或硫代磷酸酯键,尽管磷酸二酯键和其它核苷酸间键在本发明范围内,包括具有混合的核苷酸间键的寡核苷酸。生产硫代磷酸寡核苷酸或二硫代磷酸酯的方法描述于US 5,666,153、US5,278,302和WO95/26204。
寡核苷酸的实例具有以下序列。该序列可包含硫代磷酸酯修饰的核苷酸间键。
OLIGO 1(SEQ ID NO:3):TCC ATG ACG TTC CTG ACG TT(CpG 1826)
OLIGO 2(SEQ ID NO:4):TCT CCC AGC GTG CGC CAT(CpG1758)
OLIGO 3(SEQ ID NO:5):ACC GAT GAC GTC GCC GGT GACGGC ACC ACG
OLIGO 4(SEQ ID NO:6):TCG TCG TTT TGT CGT TTT GTCGTT(CpG 2006也称为CpG 7909)
OLIGO 5(SEQ ID NO:7):TCC ATG ACG TTC CTG ATG CT(CpG 1668)
替代性的CpG寡核苷酸可包含其中具有无义缺失或添加的以上序列。
本发明使用的CpG寡核苷酸可利用本领域已知的任何方法(例如EP 468520)合成。方便地,可使用自动化合成仪合成该寡核苷酸。
用于本发明的寡核苷酸可为脱氧核苷酸。在一个实施方案中,寡核苷酸中的核苷酸间键为二硫代磷酸酯键或硫代磷酸酯键,尽管磷酸二酯属于本发明范围。规划了含不同核苷酸间键的寡核苷酸,例如混合的硫代磷酸酯磷酸二酯。可使用使寡核苷酸稳定的其它核苷酸间键。
CpG当配制成疫苗时,一般在和游离抗原一起的游离溶液中给予(WO 96/02555;McCluskie and Davis,出处同上),或共价缀合至抗原给予(PCT说明书WO 98/16247),或与载体如氢氧化铝配制给予((乙肝表面抗原)Davis et al.出处同上;Brazolot-Millan et al.,Proc.Natl.Acad.Sci.,USA,1998,95(26),15553-8)。
一种增强的制剂可包括含CpG的寡核苷酸和皂苷衍生物的组合,特别是如WO00/09159和WO00/62800所公开的CpG和QS21的组合。这样的制剂还可含有水包油乳浊液和生育酚。因此,在再另一个实施方案中,本发明的免疫原性组合物包含CpG寡核苷酸和皂苷(例如QS21)的组合,可选地配制成水包油乳剂。可选地,制剂还可包含3D-MPL佐剂。可如WO 96/33739所述,以其基本无反应原性的组合物提供QS-21,其中QS21用胆固醇抑制。
在另一个实施方案中,本发明的免疫原性组合物另外包含肠细菌脂多糖衍生的佐剂,例如单磷酰脂质A,如3-脱氧-酰化单磷酰脂质A。
很久以来就知道肠细菌脂多糖(LPS)是免疫系统的有效刺激物,尽管其毒性作用削弱了其佐剂用途。Ribi et al(1986,Immunology andInmunopharmacology of bacterial endotoxins,Plenum Publ.Corp.,NY,407-419页)描述了LPS的无毒衍生物单磷酰脂质A(MPL),其通过去除核心糖基和还原末端葡糖胺的磷酸产生,其具有以下结构:
进一步脱毒形式的MPL叫做3-O-脱酰化单磷酰脂质A(3D-MPL),其通过去除二糖骨架3-位的酰基链产生。其可通过GB2122204B讲述的方法纯化和制备,该参考文献还公开了二磷酰脂质A及其3-O-脱酰化变体的制备。3D-MPL可为小颗粒直径小于0.2μm的乳浊液形式,其生产方法公开于WO94/21292。在WO98/43670A2中公开了含单磷酰脂质A和表面活性剂的水性制剂。
可由细菌来源纯化和加工配制成本发明佐剂组合物的细菌脂多糖衍生的佐剂,或者可合成该佐剂。例如,Ribi et al 1986(出处同上)描述了纯化的单磷酰脂质A,GB 2220211和US 4912094描述了来源于沙门氏菌(Salmonella sp.)的3-O-脱酰化单磷酰脂质A或3-O-脱酰化二磷酰脂质A。其它纯化和合成的脂多糖也有描述(WO 98/01139;US 6,005,099和EP 0 729 473 B1;Hilgers et al.,1986,Int.Arch.Allergy.lmmunol.,79(4):392-6;Hilgers et al.,1987,Immunology,60(1):141-6;以及EP 0 549 074 B1)。细菌脂多糖佐剂可包括描述于US 6,005,099和EP 0 729 473 B1的3D-MPL和β(1-6)葡糖胺二糖。
因此,可用于本发明的LPS衍生物是那些结构上类似于LPS或MPL或3D-MPL的免疫刺激物。在本发明的另一方面,LPS衍生物可为酰化单糖,其为以上MPL结构的附属部分。
二糖佐剂的实例是下式的纯化或合成的脂质A:
其中R2可为H或PO3H2;R3可为具有下式的酰基链或β-羟基肉豆寇酰或3-酰氧基酰基残基:
其中
其中X和Y的值为0至约20。
在EP 0 761 231 B中描述了3D-MPL和来源于奎拉雅属皂树树皮的皂苷佐剂的组合。WO 95/17210公开了基于鲨烯、α-生育酚和聚氧乙烯脱水山梨糖醇单油酸酯(TWEEN80)的佐剂乳浊液系统,其与免疫刺激物QS21一起配制,任选与3D-MPL一起配制。
因此,在另一个实施方案中,本发明的免疫原性组合物包含(1)抗原或其免疫原性片段,和(2)皂苷(例如QS21,例如为其用胆固醇抑制的形式)和一种或多种例如选自以下的佐剂的组合:CpG免疫刺激性寡核苷酸、3D-MPL和水包油乳剂。
在一个实施方案中,免疫原性组合物包括单磷酰脂质A和皂苷佐剂的组合,例如WO94/00153所述的3D-MPL佐剂和QS21的组合,或如WO96/33739所述的较小反应原性的组合物,其中QS21用胆固醇抑制。其它制剂除了QS21以外,还可包含水包油乳剂和生育酚。WO95/17210描述了另一种制剂,其使用QS21、3D-MPL佐剂和生育酚在水胞油乳剂中的组合。因此,本发明的免疫原性组合物包含抗原(例如肿瘤相关抗原)、皂苷佐剂(例如QS21)以及3D-MPL佐剂,除了包含QS21以外,还可选地含有水包油乳剂和生育酚。例如,用胆固醇抑制QS-21。
另一种制剂包括含CpG的寡核苷酸和皂苷衍生物的组合,例如在WO00/09159和WO00/62800中公开的CpG和QS21的组合。该制剂还可含有水包油乳剂和生育酚。因此,在再另一个实施方案中,本发明的免疫原性组合物包含皂苷(例如QS21)和CpG寡核苷酸的组合,其可选地配制在水包油乳剂中。该制剂可选地还可含有3D-MPL佐剂。QS-21可在如WO96/33739所述的较小反应原性的组合物中提供,其中QS21用胆固醇抑制。
或者,在本发明免疫原性组合物中的皂苷佐剂可联用由壳聚糖或其它聚阳离子聚合物组成的疫苗载体、聚交酯和聚交酯-共-乙交酯颗粒、聚-N-乙酰葡糖胺型聚合基质、由多糖或化学修饰的多糖组成的颗粒、脂质体和脂质型颗粒、由甘油单酯组成的颗粒等。还可在胆固醇存在下配制皂苷,以形成例如脂质体或ISCOM的颗粒结构。而且,可将皂苷和聚氧乙烯醚或酯一起配制成无颗粒溶液或悬浮液,或配制成例如少层微泡(paucilamelar)脂质体或ISCOM的颗粒结构。皂苷还可与赋形剂如Carbopol配制,以增加粘度,或者可与粉末赋形剂如乳糖一起配制成干粉形式。
疫苗和免疫原性组合物可以单位剂量或多剂量容器提供,例如密封安瓿或小瓶。这样的容器可进行密封,以保持制剂的无菌性,直至使用。一般而言,制剂可作为在油性或水性溶媒中的悬浮液、溶液或乳浊液储存。或者,可将疫苗或免疫原性组合物在冻干条件下储存,在临使用前仅需加入无菌液体载体。
在免疫原性组合物和疫苗中可使用各种传递载体中的任一种,以利于产生靶向肿瘤细胞的抗原特异性免疫应答。按照本发明的一个实施方案,本文描述的免疫原性组合物通过抗原提呈细胞(APC)传递至宿主,抗原提呈细胞例如为树突细胞、巨噬细胞、B细胞、单核细胞和其它可制成有效APC的细胞。APC细胞可以(但不是必须的)进行遗传修饰,以增加提呈抗原的能力、改善T细胞应答的活化和/或维持、自身具有抗肿瘤作用和/或与受者免疫相容(即匹配的HLA单倍型)。APC一般可分离自各种生物流体和器官中的任一种,包括肿瘤和肿瘤周围的组织,并可为自体、异体、同源或异源细胞。
本发明的的某些实施方案使用树突细胞或其祖作为抗原提呈细胞。树突细胞是高度有效的APC(Banchereau J.& Steinman R.M.,Nature,1998,392:245-251),并已表明其作为生理佐剂有效激发预防性或治疗性抗肿瘤免疫(参见Timmerman J.M.and Levy R.,Ann.Rev.Med,1999,50:507-529)。一般来说,树突细胞可根据其典型形状(原位星型,体外可见具有明显的胞突(树突))、高效摄取、加工和提呈抗原的能力及其活化原初T细胞应答的能力来鉴别。当然,树突细胞可制成表达通常在体内或先体外后体内的树突细胞上不常见的特异性细胞表面受体或配体,本发明规划了这样的修饰的树突细胞。作为树突细胞的替代物,可在疫苗中使用载荷分泌性囊泡抗原的树突细胞(称为外体)(参见Zitvogel L.et al.,Nature Med.,1998,4:594-600)。因此,本发明提供一种免疫刺激性制剂,例如疫苗,其含有有效量的树突细胞或抗原提呈细胞以及药学有效载体,这些细胞通过体外载荷本文所述的多肽进行修饰,或体外遗传修饰,以表达本文所述多肽。
树突细胞和祖细胞可得自外周血、骨髓、肿瘤浸润细胞、肿瘤周围组织浸润细胞、淋巴结、脾、皮肤、脐带血或任何其它合适的组织或体液。例如,可通过向由外周血收集的单核细胞培养物中加入组合的细胞因子如GM-CSF、IL-4、IL-13和/或TNFα,先体外后体内分化树突细胞。或者,可通过向培养基中加入GM-CSF、IL-3、TNFα、CD40配体、脂多糖LPS、flt3配体和/或其它诱导树突细胞分化、成熟和增殖的化合物,将由外周血、脐带血或骨髓收集的CD34阳性细胞分化为树突细胞。树突细胞通常被分类为“不成熟”和“成熟”细胞,其提供了一种在两种充分表征的表型之间进行区分的简单方法。但是,该命名法不应被解释为排除了分化的所有可能中间阶段。不成熟树突细胞的特征在于具有高抗原摄取和加工能力的APC,其与Fcγ受体和甘露糖受体的高表达相关联。成熟表型通常表征为这些标记物的较低表达,但负责T细胞活化的细胞表面分子(例如MHC I类和II类分子、粘附分子(例如CD54和CD11)以及共刺激分子(例如CD40、CD80、CD86和4-1BB))高表达。
APC一般可用编码肿瘤蛋白(例如MAGE-3、Her2/neu或其衍生物)的多核苷酸转染,使得肿瘤多肽或其免疫原性部分表达在细胞表面上。这样的转染可先体外后体内发生,然后,含该转染细胞的组合物或疫苗可如本文所述用于治疗目的。或者,可将靶向树突细胞或其它抗原提呈细胞的基因传递载体给予患者,使得转染在体内发生。例如,一般可使用本领域已知的任何方法,例如描述于WO97/24447的方法或Mahvi D.M.et al.,Immunology and Cell Biology,1997,75:456-460描述的基因枪方法,进行树突细胞的体内和先体外后体内转染。通过将树突细胞或祖细胞与肿瘤多肽、DNA(裸DNA或在质粒载体中)或RNA温育;或将树突细胞或祖细胞与表达抗原的重组细菌或病毒(例如痘苗病毒、鸟痘病毒、腺病毒或慢病毒载体)温育,可实现树突细胞的抗原载荷。
其它合适的传递系统包括微球体,其中抗原物质掺入到或缀合至生物可降解聚合物/微球体,使得抗原物质可与合适的药用载体混合,并用作疫苗。术语“微球体”一般用于描述大致为球形并且直径在10nm至2mm范围内的胶体颗粒。已发现由广泛范围的天然和合成聚合物制备的微球体可有各种各样的生物医学用途。对于体内半寿期短、需要多次治疗来提供效力的蛋白,或由于其相对较高的分子量而在生物流体中不稳定或不能被胃肠道完全吸收的蛋白,该传递系统特别有优势。已经描述了几种为蛋白释放基质的聚合物。合适的聚合物包括明胶、胶原、藻酸盐、葡聚糖。传递系统可包括生物可降解聚(DL-乳酸)(PLA)、聚(丙交酯-共-乙交酯)(PLG)、聚(乙醇酸)(PGA)、聚(ε-己内酯)(PCL)和共聚物聚(DL-乳酸-共-乙醇酸)(PLGA)。其它系统可包括异源水凝胶,例如含基于亲水性聚(乙二醇)(PEG)和疏水性聚(丁烯对苯二甲酸酯)(PBT)或聚(乙二醇)-对苯二甲酸酯/聚(丁烯对苯二甲酸酯)(PEGT/PBT)的重复嵌段的聚(醚酯)多嵌段共聚物(Sohier et al.Eur.J.Pharm and Biopharm,2003,55,221-228)。例如PLGA、PLA和PEGT/PBT的系统可提供1-3个月的持续释放。
根据有关患者的大小和种族、给予的核酸疫苗和/或蛋白组合物的量、给予途径、使用的任一种佐剂化合物的效力和剂量以及其它对熟练医师显而易见的因素,治疗方案可显著变化。
参照以下的非限制性实施例进一步阐述本发明:
实施例I
使用QS21型免疫原性组合物的疫苗制剂
I.1.-在水包油乳浊液中含QS21和3脱氧-酰化单磷酰脂质A(3D-MPL)的免疫原性制剂(AS02制剂):
该佐剂系统AS02先前已描述于WO95/17210。
3D-MPL:是来源于革兰氏阴性菌明尼苏达沙门氏菌(Salmonellaminnesota)的脂多糖(LPS)的免疫刺激物。MPL已脱酰化,在脂质A部分没有磷酸基团。该化学处理极大地降低了毒性,同时保留了免疫刺激特性(Ribi,1986)。Ribi Immunochemistry为SB-Biologicals生产和提供MPL。
QS21:是由南美奎拉雅属皂树的树皮提取的天然皂苷分子。开发出一种分离树皮粗提物中的各种皂苷的纯化技术,该技术允许分离特定皂苷QS21,其是一种三萜糖苷,和亲代组分相比,其显示出更强的佐剂活性和更低的毒性。已经表明,QS21活化针对几种亚单位抗原的MHC I类限制性CTL,并刺激抗原特异性淋巴细胞增殖(Kensil,1992)。Aquila(正式地为Cambridge Biotech Corporation)为SB-Biologicals生产和提供QS21。
油/水乳是浊液由有机相(由两种油(生育酚和鲨烯)制备)和含Tween80作为乳化剂的水相组成。乳浊液含5%鲨烯、5%生育酚、0.4%Tween80,平均颗粒大小为180nm,称为SB62(参见WO 95/17210)。
乳浊液SB62(2倍浓缩液)的制备:
将Tween 80溶解在磷酸缓冲盐水(PBS)中,以获得2%的PBS溶液。为提供100ml的2倍浓缩乳浊液,将5g DLα生育酚和5ml鲨烯涡旋至充分混合。加入90ml PBS/Tween溶液,并充分混合。然后,将产生的乳浊液通过注射器,最后用M110S微流体化设备微流体化。产生的油滴大小约为180nm。
制剂:如下制备在油/水乳浊液中含3D-MPL和QS21的典型制剂:将20μg-25μgC-LytA P2-P501S稀释在10倍浓缩的PBS pH6.8和水中,然后连续加入SB62(50μl)、MPL(20μg)、QS21(20μg),可选地含CpG寡核苷酸(100μg)和1μg/ml硫柳汞作为防腐剂。每种组分的量可根据需要变化。所有的温育都在搅拌下于室温进行。
I.2.-在脂质体制剂中含QS21和CpG的免疫原性制剂(AS15佐剂):
该佐剂系统AS15先前已描述于WO00/62800。
AS15是两种佐剂系统AS01B和AS07A的新组合。AS01B由含3D-MPL和QS21的脂质体组成,AS07A由CpG 7909(也称为CpG2006)的磷酸缓冲盐水溶液组成。
QS-21如上所述。
CpG:CpG ODN 7909是一种24个碱基长的合成单链硫代磷酸酯寡脱氧核苷酸(ODN)。其碱基序列为5′-T
CGT
CGTTTTG-T
CGTTTTGT
CGTT-3′,已为刺激人免疫系统进行了优化。已知CpGDNA或含CpG基序的合成ODN活化树突细胞、单核细胞和巨噬细胞,以使其分泌TH1-样细胞因子,并诱导TH1 T细胞应答,包括产生细胞毒性T细胞,刺激NK细胞分泌IFNg,并增加其溶细胞活性,它们还活化B细胞,以使其增殖(Krieg A et al.1995 Nature 374:546,Chu R et al.1997 J.Exp.Med.186:1623)。CpG 7909对任何已知的人基因组序列都不是反义的。CpG 7909是以Coley Pharmaceutical Group,Inc.,MA,US的名义开发和生产的一种专有佐剂。
含CpG的制剂:
在注射日进行配制。1只小鼠的注射体积是50或100μl。如下制备在脂质体中含CpG、3D-MPL和QS21的典型制剂:将20μg-25μg的抗原稀释在等渗的水和PBS pH7.4中。5分钟后,将以1/5的QS21/胆固醇重量比率与脂质体混合的QS21(0.5μg)(称为DQ)加入到制剂中。30分钟后,加入10μgCpG(ODN 2006),30分钟后加入1μg/ml硫柳汞作为防腐剂。所有的温育都在搅拌下于室温进行。
实施例II
mIL18和用AS02作为佐剂的HPV16D蛋白-E7疫苗的组合在TC1治疗模型E7-Tg小鼠和非E7-Tg小鼠中的作用
II.1实验设计
在第0日,使每组5只共7组的雌性E7Tg(C.Ledent et al.PNAS(USA)1990,87;6176-6180)或非Tg C57BI/6(Iffa Credo)小鼠接受200μl的106TC1细胞(SC)的肿瘤攻击。
表达HPV16E7蛋白的转基因小鼠:
转基因小鼠品系由M.Parmentier和C.Ledent在IRIBHN(ULB)生产(参考文献:PNAS(USA)1990,87;6176-6180)。由于转基因小鼠从出生就携带E7 HPV16基因,所以认为该小鼠对该基因“耐受”:E7来自HPV 16,在此情况下认为其是“自身抗原”。转基因的表达受甲状腺球蛋白启动子驱动。因为甲状腺球蛋白仅在甲状腺中组成型表达,所以E7在甲状腺中表达。由于该表达使甲状腺细胞增殖,小鼠出现甲状腺肿和小结,在6个月至1年后小鼠可发展成侵袭性癌症。
肿瘤细胞系TC1:
用HPV 16E6和E7永生化C57BL/6小鼠的原初肺上皮细胞,然后用活化的ras癌基因转化,产生表达E6和E7的致瘤细胞系(LinKY et al.1996)。使用小鼠HPV 16E7单克隆抗体(Triton Corp.Alameda,CA)通过FACS分析固定化和通透性TC1细胞,由此检验E7的表达。
疫苗:在第7天和第14天,肌内(IM)给予疫苗,该疫苗含如WO99/10375所述制备的5μg PD1/3E7(PDE7,批号02/025),以含QS-21的AS02B佐剂(人剂量的1/5(MPL 20μg/QS21 20μg/SB62 50μl)作为佐剂。
鼠IL18-mIL-18(batch SB-528775批号MJG-28800-176,1mg/ml),在3周内每日皮下(S.C.)给予100μl(在第7天开始)。
II.2体内肿瘤生长:
将在培养基中体外生长的TC1细胞胰蛋白酶化,用无血清培养基清洗两次,在小鼠的右胁腹皮下(S.C.)注射。
为评价既有肿瘤的治疗,以1×106细胞/小鼠的剂量注射TC1细胞。在肿瘤细胞注射后的第1周和第2周,用如WO99/10375所述制备的5μg 100μl protD 1/3E7His肌内(IM)接种小鼠,该5μg100μlprotD 1/3E7His以含QS21的AS02佐剂作为佐剂,或与单独的PBS一起。每组使用5只小鼠。
小鼠组别
-组1:PBS
-组2:PDE7 AS02B
-组3:PDE7 AS02B+100μg mIL-18
-组4:PDE7 AS02B+1μg mIL-18
-组5:PDE7 AS02B+0.1μg mIL-18
-组6:1μg mIL18
-组7:0.1μg mll18
在5周内(直至第35天)一周两次监测小鼠的体内肿瘤生长。在第35天分析血清学(免疫球蛋白总量和同种型)。平均肿瘤块/组(表示为mm2/每组5只小鼠)示于图2(对照非Tg小鼠)和图3(E7Tg小鼠)。图2A显示了用1μg IL-18所获得的结果,图2B显示了用100μg IL-18所获得的结果。图3A显示了用1μg IL-18所获得的结果,图3B显示了用100μg IL-18所获得的结果。
以下的表1概述了接种时组合或不组合IL-18重复注射的情况下完全抑制其肿瘤的小鼠的百分率,还清楚显示了疫苗和高剂量IL18组合的好处。
表1
小鼠组别 | %完全退化的对照 | %完全退化的E7Tg |
小鼠 | 小鼠 | |
PBS | 0 | 0 |
PDE7+AS02B | 20 | 0 |
PDE7+AS02B 0.1μg IL-18 | 20 | 0 |
PDE7+AS02B 1μg IL-18 | 0 | 0 |
PDE7+AS02B 100μg IL-18 | 100 | 100 |
0.1μg mlL18 | 0 | 0 |
1μg mlL18 | 0 | 0 |
100μg mlL18(来自先前的实验) | 20 | 0 |
II.3结论
该实验获得的数据表明:
-将IL-18与用含QS21的AS02B作为佐剂的E7疫苗组合,对对照非转基因小鼠以及E7Tg小鼠的肿瘤抑制都具有明显的益处。
-在攻击后保持无肿瘤的唯一小鼠组别是同时接受了疫苗和IL-18的小组。
-组合的益处也是剂量依赖性的。
II.4血清学-免疫学结果
如下所述,使用PD1/3E7-16(02/025)作为包被抗原,通过ELISA检测抗体应答和同种型谱(对于合并的血清而言)。
以和取器官相同的时间取各种血清,并提交进行间接ELISA。使用2μg/ml纯化的E7蛋白作为包被抗原。于37℃在PBS、0.1%tween20、1%BSA中饱和1小时后,在饱和缓冲液中连续稀释血清(以1/100开始),并于37℃温育90分钟。在用PBS、Tween 20 0.1%清洗后,使用生物素化山羊抗小鼠Ig(1/5000)或山羊抗小鼠Ig亚型(合计为IgG、IgG1、IgG2a、IgG2b)抗血清(1/5000)作为第二抗体,于37℃温育90分钟后,加入偶联过氧化物酶的链霉抗生物素蛋白,使用TMB(四-甲基-联苯胺/过氧化物)作为底物。10分钟后,用H2SO4 0.5M终止反应,并检测O.D.450。图4显示了用对照非Tg小鼠获得的结果,而图5显示了用E7Tg小鼠获得的结果。
II.5结论
在接受单独的IL-18的对照小鼠中,如所预期地一样未检测到E7-特异性抗体。无论哪组,都未观察到总Ig有大的差别。加入IL-18倾向于改善TH1同种型谱,尤其是在以高剂量和疫苗组合时。
在E7Tg小鼠中,看起来IL-18剂量和针对E7的抗体水平之间存在负相关。加入IL-18对同种型谱无大影响。
II.6总体结论
●IL-18自身以剂量依赖方式作用于TC1肿瘤生长;
●联合注射对对照小鼠和E7Tg小鼠的TC1肿瘤生长都有明显益处,尤其是在高剂量mIL-18(100μg)和E7+AS02B接种组合时;
●IL-18稍微影响接种诱导的抗体应答(对照小鼠的TH1同种型谱较好,E7Tg小鼠的滴度较好)。
实施例III
mIL18与以AS15作为佐剂的Her2/neu疫苗组合对TC1 Her2治疗模型的作用
III.1.实验设计
疫苗
Her-2/neu疫苗是ECD-PhD,含完整的胞外结构域(含氨基酸1-645)和含磷酸化结构域的胞内结构域的免疫原性部分。该疫苗构建物公开于WO00/44899,称为dHER2。
通过将抗原稀释在水、蔗糖和NaH2PO4/K2HPO4的混合物中,使dHER2蛋白和CpG共同冻干。5分钟后,加入CpG ODN 7909,获得含625μg/ml Her2neu、1250μg/ml CpG、3.15%蔗糖和5mM PO4pH7的最终原液,然后冻干。最终原液按照3天的周期冻干。对于即时配制,将含CpG和抗原的冻干饼重悬浮在625μl含100μg/mlMPL和DQ的AS01B稀释液中。
用50μl含25μg Her2/neu、50μg CpG和5μg MPL和DQ的液体注射小鼠。
表达HER-2/neu的肿瘤模型
在这些实验中使用的肿瘤模型:用编码HER-2/neu的重组逆转录病毒通过逆转录病毒转导TC1细胞(Dr T.C.Wu John′s HopkinsUniversity Baltimore提供)产生TC1HER2。
分离、扩增各个克隆,通过流式细胞仪证实HER2/neu的稳定性和MHC I类表达。
小鼠组别:
在第0天使每组5只共4组的雌性CB6F1小鼠接受2×106TC1Her2c18细胞的皮下(SC)攻击,接着用以下任一组接种:
-组1:PBS
-组2:由第7日至第27日每日皮下(SC)注射100μg mIL18(鼠)
-组3:在第7日和第14日肌内(IM)注射25μg dHER2蛋白的AS15溶液
-组4:疫苗和mIL-18的组合。
II.2.体内肿瘤生长和死亡率:
结果示于图6和表2。
表2:在TC1HER2肿瘤攻击后27天保持无肿瘤的小鼠的百分率
PBS | 0% |
Mill 8 | 20%(死亡率:2/5) |
dHER2/AS15 | 0% |
dHER2/AS15mIL18 | 60%(2/5出现小肿瘤) |
II.3结论
与单独用疫苗组合物或IL-18的接种策略相比,基于使用配制在佐剂(AS15)中的重组纯化的HER-2/neu蛋白(dHER2)并联合重复注射鼠重组IL-18的疫苗策略确实对表达HER2/neu抗原的既有肿瘤产生改善结果。先前已经表明,基于使用配制在AS15佐剂中的重组dHER蛋白的接种非常有效地保护小鼠抗表达HER2/neu抗原的这些肿瘤细胞的攻击。该保护作用是HER2/neu抗原特异性的,并与诱导长期免疫记忆相关。在为既有肿瘤的更严格的该治疗模型,已经表明接种基本无效,对生长的肿瘤仅有有限的作用(在这些条件下没有小鼠完全排斥肿瘤)。但是,令人惊奇的是,当两种治疗相伴给予时,观察到协同作用,60%的小鼠保持完全无肿瘤,而40%的小鼠仅出现小肿瘤。总之,如表2所示,联用mIL-18和疫苗有明显益处。这可能表示,疫苗诱导HER2/neu特异性T细胞应答和重复注射IL-18活化免疫系统实现肿瘤退化都是至关紧要的。
实施例IV
mIL18与用??作为佐剂的MAGE-3疫苗组合对TC1 Mage3治疗模型的作用
III.1.实验设计
疫苗
通过编码Mage3的DNA质粒(PcDNA3 Mage3)的经典转染遗传修饰TC1亲代细胞,由此产生表达Mage3肿瘤抗原的肿瘤模型(TC1Mage3)。该肿瘤模型通过用编码Mage3的PcDNA3转染亲代TC1细胞(由John′s Hopkins University,Baltimore的T.C.Wu提供)产生。按照试剂盒供应商(Gibco BRL Life Technologies,目录号18324-012)的建议,使用Lipofectamin进行转染。
这些细胞是致瘤性的,用2×106TC1Mage3细胞攻击的小鼠100%出现肿瘤。
在第0天使每组5只共4组的雌性CB6F1小鼠接受2×106TC1Mage3细胞的皮下(SC)攻击,接着用以下任一组接种:
-组1:PBS
-组2:由第7日至第27日每日皮下(SC)注射100μg mIL18(鼠)
-组3:在第7日和第14日肌内(IM)注射10μg Mage3蛋白的AS15溶液
-组4:联用疫苗和mIL-18。
评价Mage3的AS15溶液接种、IL-18注射和联合治疗诱导肿瘤退化的能力。还检测了接种或/和IL18治疗对免疫参数的影响(淋巴细胞增殖、细胞因子产生......)。
Claims (32)
1.一种增强哺乳动物中针对抗原的免疫应答的方法,其包括给予哺乳动物安全有效量的1)IL-18多肽或其生物活性片段或变体,和2)含抗原或其免疫原性衍生物和皂苷佐剂的免疫原性组合物。
2.权利要求2的方法,其中所述抗原或其免疫原性衍生物来自选自以下的生物:人免疫缺陷病毒HIV-1、人单纯疱疹病毒、巨细胞病毒、轮状病毒、EB病毒、水痘-带状疱疹病毒;来自肝炎病毒,例如乙肝病毒、甲肝病毒、丙肝病毒和戊肝病毒;来自呼吸道合胞病毒、副流感病毒、麻疹病毒、腮腺炎病毒、人乳头瘤病毒、黄病毒或流感病毒;来自奈瑟氏球菌(Neisseria spp);莫拉氏菌(Moraxellaspp);博德特氏菌(Bordetella spp);分枝杆菌(Mycobacterium spp),包括结核分枝杆菌(M.tuberculosis);埃希氏菌(Escherichia spp),包括肠毒性大肠杆菌;沙门氏菌(Salmonella spp);利斯特氏菌(Listeriaspp);螺杆菌(Helicobacter spp);葡萄球菌(Staphylococcus spp),包括金黄色葡萄球菌(S.aureus)、表皮葡萄球菌(S.epidermidis);疏螺旋体(Borrelia spp);衣原体(Chlamydia spp),包括砂眼衣原体(C.trachomatis)、肺炎衣原体(C.pneumoniae);疟原虫(Plasmodium spp),包括恶性疟原虫(P.falciparum);弓形虫(Toxoplasma spp);假丝酵母(Candida spp)。
3.一种减轻患者癌症严重性的方法,包括给予有需要的患者安全有效量的i)IL-18多肽或其生物活性片段或变体,和ii)含肿瘤相关抗原或其免疫原性衍生物和皂苷佐剂的免疫原性组合物。
4.权利要求3的方法,其中所述肿瘤相关抗原或其免疫原性衍生物选自:MAGE家族抗原、PRAME、BAGE、LAGE1、LAGE2、SAGE、HAGE、XAGE、PSA、PAP、PSCA、Prostein、P501S、HASH2、Cripto、B726、NY-BR1.1、P510、MUC-1、前列腺蛋白酶、STEAP、酪氨酸酶、端粒酶、生存蛋白、CASB616、P53或her 2 neu。
5.权利要求1-4任一项的方法,其中所述IL-18多肽或其生物活性片段或变体和免疫原性组合物同时、单独或以任何顺序序贯给予。
6.权利要求5的方法,其中所述TH-1细胞因子和免疫原性组合物以联合药物制剂的形式同时给予。
7.权利要求1-6任一项的方法,其中所述IL-18多肽或其生物活性片段或变体为人或鼠源。
8.权利要求7的方法,其中IL-18是SEQ ID NO.6或SEQ ID NO.7的多肽或其生物活性片段或衍生物。
9.权利要求1-8任一项的方法,其中所述皂苷佐剂是QS-21或QS-17。
10.一种含以下各种组分作为活性成分的联合制剂:(1)IL-18多肽或其生物活性片段或变体,和(2)含抗原和皂苷佐剂的免疫原性组合物,所述活性成分同时、单独或序贯用于预防和/或治疗感染性疾病、癌症、自身免疫病和相关病症。
11.权利要求10的联合制剂,其中组分(1)和(2)混合在组合物中。
12.权利要求10或11的联合制剂,其中所述免疫原性组合物含肿瘤相关抗原或其免疫原性衍生物,其具有抗癌症的预防或治疗活性。
13.权利要求12的联合制剂,其中所述肿瘤相关抗原或其免疫原性衍生物选自:MAGE家族抗原、PRAME、BAGE、LAGE1、LAGE2、SAGE、HAGE、XAGE、PSA、PAP、PSCA、Prostein、P501S、HASH2、Cripto、B726、NY-BR1.1、P510、MUC-1、前列腺蛋白酶、STEAP、酪氨酸酶、端粒酶、生存蛋白、CASB616、P53或her 2 neu。
14.权利要求10-13任一项的联合制剂,其中所述IL-18多肽或其生物活性片段或变体为人或鼠源。
15.权利要求14的联合制剂,其中IL-18是SEQ ID NO.6或SEQID NO.7的多肽或其生物活性片段或衍生物。
16.权利要求10-15任一项的联合制剂,其中所述皂苷佐剂为QS-21或QS-17。
17.权利要求10-16任一项中要求保护的联合制剂,其中所述免疫原性组合物另外含选自以下的免疫刺激化学物质:3D-MPL、胆固醇、含至少一种免疫刺激性CG二核苷酸的CpG寡核苷酸、氢氧化铝、磷酸铝、生育酚和水包油乳剂或两种或多种所述佐剂的组合。
18.权利要求17中要求保护的联合制剂,其中所述免疫原性组合物佐剂包含3D-MPL、QS21、胆固醇、水包油乳剂。
19.权利要求18中要求保护的联合制剂,其中所述水包油乳剂包含鲨烯、生育酚和聚氧乙烯脱水山梨糖醇单油酸酯(Tween 80)。
20.权利要求17中要求保护的联合制剂,其中所述免疫原性组合物包含QS21、胆固醇和含至少一种免疫刺激性CG二核苷酸的CpG寡核苷酸。
21.权利要求10-20任一项中要求保护的联合制剂,其中两种活性组分都是可注射溶液的形式。
22.一种含以下各组分作为活性成分的药盒:(1)IL-18多肽或其生物活性片段,和(2)含抗原或其免疫原性衍生物和皂苷佐剂的免疫原性组合物,所述活性成分同时、单独或序贯用于预防和/或治疗感染性疾病、癌症和自身免疫病。
23.权利要求22的药盒,其中所述免疫原性组合物包含肿瘤相关抗原或其免疫原性衍生物,其具有抗癌症的预防或治疗活性。
24.权利要求23的药盒,其中所述肿瘤相关抗原或其免疫原性衍生物选自:MAGE家族抗原、PRAME、BAGE、LAGE1、LAGE2、SAGE、HAGE、XAGE、PSA、PAP、PSCA、Prostein、P501S、HASH2、Cripto、B726、NY-BR1.1、P510、MUC-1、前列腺蛋白酶、STEAP、酪氨酸酶、端粒酶、生存蛋白、CASB616、P53或her 2 neu。
25.权利要求10-20任一项中要求保护的联合制剂,其用于药物。
26.权利要求1-9任一项中要求保护的方法,其包括使用权利要求10-20任一项的联合制剂。
27.IL-18多肽或其生物活性片段或变体在药物生产中的用途,所述药物用于预防和/或治疗患或易患感染性疾病、癌症、自身免疫病和相关疾病并已用含抗原或其免疫原性衍生物和皂苷佐剂的免疫原性组合物初免的患者。
28.含抗原或其免疫原性衍生物和皂苷佐剂的免疫原性组合物在药物生产中的用途,所述药物用于治疗患或易患感染性疾病、癌症、自身免疫病和相关疾病并已用IL-18多肽或其免疫原性片段或变体初免的患者。
29.权利要求27或28的用途,其中所述抗原为肿瘤相关抗原,所述癌症选自乳癌、肺癌、NSCLC、结肠癌、黑素瘤、卵巢癌、膀胱癌、头颈鳞状细胞癌、食道癌。
30.权利要求27-29任一项的用途,其中所述IL-18多肽或其生物活性片段或变体为人或鼠源。
31.权利要求30的用途,其中IL-18为SEQ ID NO.6或SEQ IDNO.7的多肽或其生物活性片段或衍生物。
32.权利要求27-31任一项的用途,其中所述皂苷佐剂为QS-21或QS-17。
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2006
- 2006-03-23 IL IL174544A patent/IL174544A0/en unknown
- 2006-03-27 IS IS8374A patent/IS8374A/is unknown
- 2006-04-07 CO CO06034535A patent/CO5700790A2/es not_active Application Discontinuation
- 2006-04-11 ZA ZA200602950A patent/ZA200602950B/xx unknown
- 2006-04-28 NO NO20061912A patent/NO20061912L/no not_active Application Discontinuation
- 2006-05-04 MA MA29002A patent/MA28149A1/fr unknown
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103025351A (zh) * | 2010-05-28 | 2013-04-03 | 辉瑞动物保健公司 | 包含胆固醇和作为唯一的佐剂-载剂分子的cpg的疫苗 |
CN103025351B (zh) * | 2010-05-28 | 2016-08-24 | 佐蒂斯比利时股份有限公司 | 包含胆固醇和作为唯一的佐剂-载剂分子的cpg的疫苗 |
CN109069619A (zh) * | 2015-12-17 | 2018-12-21 | 葛兰素史密丝克莱恩生物有限公司 | 佐剂用于预防和/或治疗自身免疫病的用途 |
CN110461355A (zh) * | 2016-10-31 | 2019-11-15 | 艾金株式会社 | 包含免疫调控剂和阳离子脂质体的免疫增强的组合物及其用途 |
CN110461355B (zh) * | 2016-10-31 | 2023-06-09 | 艾金株式会社 | 包含免疫调控剂和阳离子脂质体的免疫增强的组合物及其用途 |
WO2019101062A1 (zh) * | 2017-11-24 | 2019-05-31 | 长春百克生物科技股份公司 | 重组疫苗及其应用 |
CN113365657A (zh) * | 2018-12-18 | 2021-09-07 | 禾大国际股份公开有限公司 | 具有疫苗佐剂效应的丝状纳米颗粒 |
Also Published As
Publication number | Publication date |
---|---|
IL174544A0 (en) | 2006-08-01 |
RU2006111847A (ru) | 2007-11-20 |
BRPI0415304A (pt) | 2006-12-05 |
GB0323965D0 (en) | 2003-11-19 |
US20070212329A1 (en) | 2007-09-13 |
JP2007508272A (ja) | 2007-04-05 |
AU2004283457A1 (en) | 2005-05-06 |
NO20061912L (no) | 2006-06-02 |
KR20070054136A (ko) | 2007-05-28 |
MA28149A1 (fr) | 2006-09-01 |
CO5700790A2 (es) | 2006-11-30 |
EP1687025A1 (en) | 2006-08-09 |
ZA200602950B (en) | 2007-09-26 |
CA2541695A1 (en) | 2005-05-06 |
IS8374A (is) | 2006-03-27 |
WO2005039634A1 (en) | 2005-05-06 |
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