CN1457258A - 用il－18和il－18组合物治疗病毒性疾病的方法 - Google Patents
用il－18和il－18组合物治疗病毒性疾病的方法 Download PDFInfo
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Abstract
本发明主要涉及使用含有IL－18也称为干扰素－γ－诱导因子(IGIF)的组合物以及IL－18与其它制剂的组合物来预防和/或治疗由HIV、HSV、HPV、HAV、HBV和HCV引起的病毒性疾病。
Description
发明领域
本发明主要涉及使用IL-18也称为干扰素-γ-诱导因子(IGIF)以及IL-18与本发明其它制剂的组合物预防和/或治疗病毒性疾病。
发明背景
IL-8是最近才发现的新的细胞因子，活性IL-18含有157个氨基酸残基。它具有很强的生物活性，包括诱导T细胞和脾细胞生成γ-干扰素，增强NK细胞的杀伤活性，和促进幼稚的CD4+T细胞分化成Th1细胞。此外，人IL-18还增加GM-CSF的生成，并减少IL-10的生成。已经表明IL-18的干扰素-γ诱导能力比IL-12强，并且似乎具有不同受体并利用不同的信号转导途径。
CD4+T细胞是所有免疫应答的中枢调节元件，它们分为2个亚类，Th1和Th2。每一亚类是通过其分泌不同细胞因子的能力定义的。有趣的是，对分化最有效力的诱导物是细胞因子自身。从幼稚前体向Th2细胞的发育是由IL-4诱导的。在发现IL-18之前，IL-12被认为是主要的Th1诱导型细胞因子。IL-18也是Th1诱导型细胞因子，并且在刺激γ-干扰素生成方面，其效力比IL-12强。
Th1细胞分泌IL-2、γ-干扰素和TNF-β。标志性Th1细胞因子——γ-干扰素直接作用于巨噬细胞以增强它们杀微生物和吞噬细胞的活性。结果使得激活的巨噬细胞可有效地破坏细胞内病原体和肿瘤细胞。Th2细胞生成IL-4、IL-5、IL-6、IL-10和IL-13，它们作用于B细胞使之发育成抗体生成细胞。总体来说，Th1细胞主要引起细胞介导的免疫，而Th2引起体液免疫。
IL-18，其编码核苷酸序列，以及该纯化蛋白的特定物理化学性质是已知的。
在1996年1月17日出版的Kabushiki Kaisha Hayashibara SeibutsuKayaku Kenkyujo′s(″Hayashibara″)的US 5，912，324(对应于EP 0 692 536)公开了一种诱导免疫活性细胞生成γ-干扰素的鼠蛋白，该蛋白被进一步鉴定为具有特定的物理化学性质和确定的部分氨基酸序列。该文献还公开了具有157个氨基酸的序列的蛋白、其两个片段、编码该蛋白的DNA(471bp)、杂交瘤、蛋白纯化方法、以及检测该蛋白的方法。
在1996年5月22日出版的Hayashibara的US 6,214,584(对应于EP 0 712931)公开了157个氨基酸的人蛋白及其同系物、编码该蛋白的DNA、转化体、制备该蛋白的方法、抗该蛋白的单克隆抗体、杂交瘤、蛋白纯化方法、以及检测该蛋白的方法，和治疗和/或预防恶性肿瘤、病毒性疾病、细菌性传染病和免疫疾病的方法。
在1997年7月10日出版的Incyte Pharmaceuticals，Inc.′s的WO 97/24441中公开了对应于IL-18前体的一种193个氨基酸的蛋白及其编码DNA。
目前采用如抗病毒剂、免疫治疗和疫苗来治疗和/或预防病毒性疾病如HIV、HSV、HPV、HAV、HVB和HCV，但这些治疗并不总是有效的，因此需要有一种更有效的对这种病毒性疾病的治疗方法。
发明简述
一方面，本发明提供了一种治疗和预防病毒性疾病如HIV、HSV、HPV、HAV、HBV和HCV的方法，包括给予抑制病毒性疾病的量的多肽，其中所述多肽与SEQ ID NO：1或SEQ ID NO：2的全长氨基酸序列至少有70％的同一性，该多肽可以单独施用，也可以与抗病毒剂以及与疫苗组合使用，所用抗病毒剂如但不局限于foscamet、阿昔洛韦(acyclovir，ACV)、ACV-磷酸盐、brivudine(溴乙烯基脱氧尿苷止痛药，BVDU)、cidofovir(HPMPC，GS504)、环状HPMPC、famciclovir、更昔洛韦(ganciclovir，GCV)、GCV-磷酸盐、lobucavir(双羟甲基环丁基鸟嘌呤，BHCG)、penciclovir、三氮唑核苷(ribavirin)、爱得呋韦(adefovir)、拉米夫定(lamivudine，3TC)、爱博开呋(abacavir)、去氢双脱氧胸苷(stavudine)、瑞得呋啶(zidovudine)、tenovir，其它细胞因子如IL-2、IL-12、IFN，或免疫调节剂如但不限于三氮唑核苷(ribavirin)、胸腺素α、皮质类固醇、镇静剂、imiquimod，所述疫苗如但不局限于Havrix、Engerix。
附图说明
图1显示了人类IL-18的氨基酸序列(Sequence ID NO：1)。
图2显示了人类IL-18的氨基酸序列(Sequence ID NO：2)。
图3图示用不同量的鼠IL-18的缓冲盐水溶液腹膜内给药小鼠后，IFN-γ蛋白的诱导。
图4图示不同量的鼠IL-18的缓冲盐水溶液腹膜内给药小鼠后，IFN-γmRNA的诱导。
图5图示小鼠经鼠IL-18腹膜内给药后，用致命剂量的HSV-1(SC-16)处理，其在-2小时、一天和两天时相对于对照增加了存活。
图6图示施用IL-18导致流感引起的体重减少得到改善。
图7图示施用IL-18导致由脉冲血氧计测定的肺部机能的改善。
图8表明了IL-18对HBV复制的效应。
图9(a)-9(d)用于图解说明IL-18诱导的IL-8 14-倍(图9(a))、新蝶呤7-倍(图9(b))、GM-CSF 100-倍(图9(c))和IFN-γ 8-倍(图9(d))。
图10(a)-10(c)用于图解说明IL-18诱导产生了IFN-γ(图10(a))、新蝶呤(图10(b))和IL-8(图10(c))。在本研究中，单独用IL-2处理作为对照。
图11表明了IL-12和IL-18对HBV复制的效应。
发明详述
本发明一般涉及预防和/或治疗病毒性疾病如HIV、HSV、HPV、HAV、HBV和HCv的方法，包括给予抑制病毒性疾病的量的IL-18和含有IL-18的组合物。
提供下述定义以帮助理解在本申请中频繁使用的一些术语和缩写。
本领域已知的“同一性”是指通过比较序列确定的2个或2个以上多肽序列或2个或2个以上多核苷酸序列之间的关系。在本领域内，“同一性”还表示多肽或多核苷酸序列之间序列相关的程度，根据具体情况可通过这些序列的匹配程度来确定。“同一性”和“相似性”可通过已知方法轻易地计算出，包括但不局限于下述文献中描述的方法：(Computational MolecularBiology，Lesk，A.M.，ed.，Oxford University Press，New York，1988；Biocomputing：Informatics and Genome Projects，Smith，D.W.，ed.，AcademicPress，New York，1993；Computer Analysis of Sequence Data，Part I，Griffin，A.M.，and Griffin，H.G，eds.，Humana Press，New Jersey，1994；SequenceAnalysis in Molecular Biology，von Heinje，G.，Academic Press，1987；andSequence Analysis Primer，Gribskov，M.and Devereux，J.，eds.，M StocktonPress，New York，1991；and Carillo，H.，and Lipman，D.，SIAM J.Applied Math.，48：1073(1988)。测定同一性的优选方法被设计成在所测试序列之间给出最大匹配。测定同一性和相似性的方法被编辑在公众可得到的计算机程序中。用于测定两个序列之间的同一性和相似性的优选的计算机程序方法包括但不限于GCC程序包(Devereux，J.，et al.，Nucleic Acids Research 12(1)：387(1984))，BLASTP，BLASTN，and FASTA(Atschul，S.F.et al.，J. Molec.Biol.215：403-410(1990).The BLAST X program is publicly available from NCBI andother sources(BLAST Manual，Altschul，S.，et al.，NCBI NLM NIH Bethesda，MD 20894；Altschul，S.，et al.，J.Mol.Biol.215：403-410(1990)。也可使用众所周知的Smith Waterman运算法则来测定同一性。
“分离的”表示“通过人工”将天然状态改变。如果“分离的”组合物或物质在自然界中存在，则它们被改变或者从其最初的环境中移出或兼而有之，例如，如本文所用的此术语所表示的那样，天然存在于活生物体中的多核苷酸或多肽是未“分离的”，但是从天然状态的共存材料中分离出的相同多核苷酸或多肽是“分离”的。
“多肽”是指包含彼此通过肽键或修饰的肽键连接的2个或2个以上氨基酸的肽或蛋白，即，肽等排物。“多肽”既包括通常称为的肽、寡肽或寡聚物的短链多肽，也包括通常称为蛋白的长链多肽。多肽可含有不同于20-基因编码氨基酸的氨基酸。“多肽”包括通过天然方法例如翻译后加工或通过本领域众所周知的化学修饰技术修饰的氨基酸序列。基于教科书和更详细的专题论文以及很多研究文献中清楚地描述了这些修饰。可在多肽的任意位置进行修饰，包括在肽骨架、氨基酸侧链、以及氨基或羧基末端上修饰。应当理解，在给定多肽中几个位点上可存在相同或不同程度的相同类型修饰。给定多肽也可具有多种类型的修饰。多肽可以呈支链形式(这是遍在蛋白化的作用的结果)，也可以是具有或不具有支链的环状形式。环状、支链和具有支链的环状多肽可以是通过翻译后天然加工产生的，或者可通过合成方法制得。修饰包括乙酰化、酰化、ADP-核糖基化、酰胺化、与黄素共价连接、与血红素部分共价连接、与核苷酸或核苷酸衍生物共价连接、与脂质或脂质衍生物共价连接、与磷酯酰肌醇共价连接、交联、环化、形成二硫键、去甲基化、形成共价交联、形成胱氨酸、形成焦谷氨酸、甲酰化、γ-羧基化、糖基化、形成GPI锚、羟基化、碘化、甲基化、肉豆寇酰基化、氧化、蛋白水解加工、磷酸化、异戊二烯化、外消旋化、硒代酰化、磺化、通过转运-RNA介导向蛋白中加入氨基酸例如精氨酰化和遍在蛋白化(参见，例如蛋白-结构和分子特征，第二版，T.E.Creighton，W.H.Freeman和Company，纽约，1993；世界，F.，翻译后蛋白的修饰：前景和观点，pgs.1-12，蛋白翻译后的共价修饰，B.C.Johnson，Ed.，学术出版社，纽约，1983；Semeret al.，“蛋白修饰和非蛋白辅因子的检验”，Meth Enzymol(1990)182：626-646and Rattan et al.，“蛋白合成：翻译后修饰和老化”，Ann NY Acad Sci(1992)663：48-62)。
“变体”是指与参考多核苷酸或多肽不同、但是仍然保留其基本特性的多核苷酸或多肽。典型的多核苷酸变体在核苷酸序列方面与其他的参照多核苷酸不同。变体中核苷酸序列的改变可能改变或不改变由参考多核苷酸编码的多肽的氨基酸序列。如下所述，核苷酸改变可在由参考序列编码的多肽中导致氨基酸取代、插入、缺失、融合和截短。多肽的典型变体的氨基酸序列与另一参考多肽不同。这些差异通常是有限的，使得参考多肽与变体的序列总体上很类似，并且在许多区域是相同的。变体和参考多肽在氨基酸序列方面可能由于一个或多个取代、插入、缺失(以任意组合)而不同。取代或插入的氨基酸残基可能是或不是由遗传密码编码的。多核苷酸或多肽的变体有可能是天然产生的，例如等位变体，或者可以是自然界未知的变体。多核苷酸和多肽的非天然变体可通过诱变技术或通过直接合成而制得。
用于多肽序列比较的优选参数包括：
1)算法：Needleman和Wunsch，J.Mol Biol.，48：443-453(1970)
比较模型：Hentikoff和Hentikoff，Proc.Natl.Acad.Sci.USA，89：10915-10919(1992)中的BLOSSUM62。
缺口罚分：12
缺口长度罚分：4
一个包含这些参数的有效程序是公众可以从遗传计算机组(GeneticsComputer Group，Madison WI)获得的“缺口”程序。上述参数是用于比较肽的缺省参数(末端缺口没有任何罚分)。
本发明的肽序列可以与SEQ ID NO：1或SEQ ID NO：2所示参考序列相同，即100％相同，或者其相对于参考序列可包括一定整数数目的氨基酸变更，从而使同一性低于100％。这种变更选自：至少一个氨基酸缺失、取代、包括保守取代和非保守取代、或插入，其中所述变更可在参考多肽序列的氨基或羧基末端发生，或者在这两个末端之间的任意位置发生，单独散布于参考序列的氨基酸上，或以一个或多个相连组散布于参考序列内。具有给定的同一性百分数的氨基酸变更的数目是这样确定的：将SEQ ID NO：1或SEQ ID NO：2中的氨基酸总数乘以各自的同一性百分比(除以100)，然后分别从SEQ ID NO：1或SEQ ID NO：2的氨基酸总数减去上面得到的乘积，或者：
na≤xa-(Xa·y)，
其中na是氨基酸变更的数目，xa是SEQ ID NO：1或SEQ ID NO：2中的氨基酸总数，y是例如0.70(对于70％)、0.80(对于80％)、0.85(对于85％)等，在从xa中减去之前，将xa和y的任一非整数乘积下舍入最接近的整数。
“融合蛋白”是指由2个通常无关的融合基因或其片断编码的蛋白。在一个实例中，EP-A-0 464公开了包含不同比例的免疫球蛋白恒定区与另一人类蛋白或其部分的融合蛋白。在许多情况下，在治疗和诊断中应用免疫球蛋白Fc区作为融合蛋白的一部分，有利于改善药动学特征[参见例如EP0232262A]。另一方面，对于某些应用，在融合蛋白表达、检测和纯化之后可能需要能够删除该Fc部分。
IL-18多肽
IL-18多肽已经在EP0692536A2、EP0712931A2、EP0767178A1和WO972441中公开了。所述多肽包括分离的多肽，其包含分别与SEQ IDNO：1(人IL-18)和SEQ ID NO：2(鼠IL-18)的全长氨基酸序列有至少70％的同一性、优选有至少80％的同一性、更优选有90％的同一性、还更优选有至少95％的同一性、最优选有至少97-99％的同一性的氨基酸序列。这种多肽包括分别包含SEQ ID NO：1和SEQ ID NO：2所示氨基酸的多肽。
本发明的多肽是诱导干扰素-γ的多肽，它们在诱导细胞介导的免疫中起主要作用，包括诱导T细胞和脾细胞生成γ-干扰素，增强NK细胞的杀伤活性，和促进幼稚CD4+T细胞分化成Th1细胞。这些特性在下文称为“IL-18活性”或“IL-18多肽活性”或“IL-18的生物活性”。这些活性还包括所述IL-18多肽的抗原和免疫原活性，尤其是SEQ ID NO：1和SEQ ID NO：2多肽的抗原和免疫原活性。本发明多肽优选表现出IL-18的至少一种生物活性。
本发明的多肽可以是“成熟”蛋白形式，或者可以是较大蛋白例如融合蛋白的一部分。包含下述额外的氨基酸序列通常是有利的：即含有分泌或前导序列、前序列、有助于纯化的序列例如多个组胺酸残基、或用于在重组制备期间起稳定作用的其它序列的氨基酸序列。
本发明还可包括上述多肽的变体、即由于保守氨基酸取代(氨基酸残基被具有类似特性的另一氨基酸残基取代)而与参考多肽不同的多肽。典型的这种取代是在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；或芳香残基Phe和Tyr之间取代。其中取代、缺失或插入(以任意组合)几个、5-10个、1-5个、1-3个、1-2个、或1个氨基酸的变体是特别优选的。
本发明的多肽可通过任一适当方法制备。这些多肽包括分离的天然多肽、通过重组制得的多肽、通过合成制得的多肽、或通过联合采用这些方法制得的多肽。制备这些多肽的方法在本领域内是公知的。
本发明的重组多肽可通过本领域众所周知的方法由包含表达系统的基因工程宿主细胞制得。因此，另一方面，本发明涉及包含编码本发明多肽的一或多个多核苷酸的表达系统，具有所述表达系统的基因工程宿主细胞，和通过重组技术制备本发明多肽的方法。也可采用无细胞翻译系统、使用源自本发明DNA构建物的RNAs来制备本发明蛋白。
合适宿主细胞的代表性实例包括细菌细胞，例如链球菌(streptococcci)、葡萄球菌(staphylococci)、大肠杆菌(E.coli)、链霉菌(Streptomyces)和枯草芽孢杆菌(Bacillus subtilis)细胞；真菌细胞，例如酵母细胞和曲霉属(Aspergillus)细胞；昆虫细胞，例如果蝇S2(Drosophila S2)和草地夜蛾Sf9(Spodoptera Sf9)细胞；动物细胞，例如CHO、COS、HeLa、C127、3T3、BHK、HEK 293和鸭黑素瘤细胞；和植物细胞。
可使用多种表达系统，例如染色体系统、附加体系统和病毒衍生系统，例如源自细菌质粒的载体，源自噬菌体的载体，源自转座子的载体，源自酵母附加体的载体，源自插入元件的载体，源自酵母染色体元件的载体，源自病毒例如杆状病毒、乳多空病毒如SV40、痘苗病毒、腺病毒、禽痘病毒、假狂犬病病毒、和逆转录病毒的载体，以及源自它们的组合的载体，例如源自质粒和噬菌体遗传元件的载体如粘粒和噬菌粒。表达系统可包含调控以及引起表达的控制区域。通常可使用能在宿主内维持、繁殖或表达多核苷酸以生成多肽的任何系统或载体。可通过多种众所周知的常规技术，例如在Sambrook等人所著的《分子克隆实验室手册》(第二版，冷泉港实验室，冷泉港，纽约，1989)中描述的技术，将适当核苷酸序列插入表达系统中。可将适当分泌信号掺入到所需的多肽中，以使得翻译的蛋白分泌到内质网腔、周质空间或细胞外环境中。这些信号可以是多肽的内源性信号，或者可以是异源信号。
可通过众所周知的方法从重组细胞培养物中回收和纯化本发明多肽，包括硫酸铵或乙醇沉淀、酸提取、阴离子或阳离子交换层析、磷酸纤维素层析、疏水作用层析、高效液相层析、羟基磷灰石层析和凝集素层析。更优选使用亲和层析来进行纯化。当多肽在分离和纯化过程中发生变性时可以采用公知的重折叠蛋白技术使之恢复活性。
已经评估了IL-18在动物模型中预防/治疗某些病毒性疾病的治疗潜力，并证实了其保护效应。给予正常小鼠、无胸腺小鼠或SCID小鼠IL-18后提高了在HSV-l感染中的存活率，这种保护至少一部分是由IFNγ介导的(Fujioka等，1999，J.Virology，73：2401)。另外，最近的数据表明IFNγ对于潜伏期之后再活化的HSV的快速抑制起了非常重要的作用(Cantin等，1999，J.Virology，73：5196；Cantin等，1999，J.Virology，73：3418)，这暗示了在抑制由于再活化导致的复发疾病中IL-18的治疗潜力。通过IL-18的处理减少了痘苗病毒诱导的痘疱形成，该结果与IFNγ受体敲除小鼠中痘苗病毒复制的加强相一致。在疱疹病毒和痘苗病毒感染的模型中，IL-18可以是预防性给药，和/或在感染后的早期给药。
本发明的多肽可以单独使用或与抗病毒剂、其它细胞因子、IFN、抗生素或抗病毒疫苗组合使用来治疗和/或预防各种病毒性疾病。
HIV
在HIV感染的例子中，本发明的多肽可以单独使用或与其它制剂组合使用，例如蛋白酶抑制剂(PI)，核苷类似物逆转录酶抑制剂(NRTI)，非核苷逆转录酶抑制剂(NNRTI)，HIV受体或共受体抑制剂，融合抑制剂，反义寡核苷酸抑制剂，葡糖苷酶抑制剂、其它细胞因子，IFN，抗生素或免疫调节剂。PI的例子包括但不局限于amprenavir、crixivan、DMP-323、DMP-450、英地那韦(indinavir)、KNI-272、1asinavir、lopinavir、viracept、PDl78390、利托那韦(ritonavir)、RPI 312、沙奎那韦(saquinavir)、SC-5215l、SDZ PRI 053、tipranavir、U-103017和A-77003。NRTI的例子包括但不局限于爱博开呋(abacavir)、阿特福韦(adefovir)、alovudine、AZdU、CS-92、DAPD、地达诺森(didanosine)、dOTC、coviracil、拉米呋啶(lamivudine)、lobucavir、iodenosine、司塔夫定(stavudine)、tenofovir、塞西太并(zalcitabine)和瑞得呋啶(zidovudine)。NNRTI的例子包括但不局限于atevirdine mesylate、calanolideA、capravirine、地拉夫定(delavirdine)、衣非韦伦(efavirenz)、emivirine、GW420867X、HBY 097、loviride、耐呋洛平(nevirapine)、PETT-5、tivirapine和trovirdine。受体、共受体、融合抑制剂的例子包括但不局限于AMD 3100、TAK 779、T-20和T-1249。这些例子和其它以各种机制对抗HIV的抗病毒剂的例子可以在周期性归纳的International Antiviral News中找到，例如2000年1月第8卷第一期中的实施例。细胞因子和免疫调节剂的例子包括但不局限于IL-2、类固醇和镇静剂。本发明也可以给药于被感染的个体，以单一治疗的形式增强个体的天然免疫应答，使个体能控制或清除感染。
HSV
单纯疱疹病毒(HSV)是能主要感染粘膜表面或皮肤的疱疹病毒科的一员。在感觉神经元和自主神经结中潜伏。在某些刺激如压力、感冒、UV辐射或免疫抑制情况下，病毒可以在初始感染位置或任何通过神经结神经支配的位点复活。目前已有抗病毒剂并能高效抑制α-疱疹病毒的复制，然而，虽然它们使复原时间略有缩短，但对于病毒潜伏状态的建立的疗效有限的。最近的数据表明，IFN-γ对于潜伏期之后再活化的HSV的快速抑制起了非常重要的作用(Cantin等，Joumal of Virology，73：3418-3423，5196-5200)，暗示了IL-18治疗在抑制由于再活化导致的疾病复发中的潜力。
单纯疱疹性脑炎(HSE)是一种严重的散发病，占到病毒性脑炎病例的10-20％。它是单纯疱疹病毒(HSV)感染的最严重形式，导致病灶、病变坏死，从而在许多例子中导致了严重的神经后遗症(Whitley和Roizman，1998，Clin.Inf.Dis.，26：541-547)。HSV-1和2伴有中枢神经系统(CNS)的感染。抗病毒治疗可以使与HSE有关的死亡减少约30％，但是幸存者可能仍然留下了严重的神经损伤(Skoldenberg，1996，Sc.J.Inf.Dis.，100：8-13；Kimberlin等，1998，J.Neurovirology，4：474-485)。
本发明的多肽可以单独使用或与抗病毒剂如病毒聚合酶抑制剂(例子如阿昔洛韦、valacylcovir、penciclovir、famciclovir、更昔洛韦、vangancilcovir、foscamet、codofovir和其它核苷酸或核苷)组合使用。多肽也能与细胞因子例如IFN、IL-2、IL-12等、以及其它免疫调节剂组合使用。本发明也可以作为单独性治疗来给药被感染的个体，从而增强个体的天然免疫应答，使个体能控制或清除感染。
HPV
对于预防和/或治疗HPV感染有着迫切(unmet)的需求。到今天已经鉴定了约100种HPV型。感染可能是无症状的，可能产生疣或导致各种良性或恶性生殖肿瘤包括宫颈癌(回顾于Koutsky，Am.J.Med.，102：3-8，1997)。虽然不能获得精确的数字，但据估计美国性生活活跃的成人中，有1％有肉眼可见的生殖器疣，而且至少有15％的人已经由分子证据确认感染了HPV，其结果是每年有65,000例的宫预癌和生殖器癌发生。目前还没有抗病毒药物，HPV病的治疗是通过化学或物理切除、细胞毒制剂或免疫治疗(Miller、R.L.等，Int J Immunopharmacology，21：1-14，1999)。虽然目前大多数的疗法最终可以清除大部分患者体内的疣，但它们并不能阻止病毒的传播或疾病的进展(Beumer和Ferenczy，Am.J.Med.，102：28-37，1997)。有异常奶头(pap)涂片和高风险HPV血清型的妇女可被鉴别为，通过治疗，具有诱导持久免疫和防止宫颈癌发生的前景。
本发明的多肽可以与抗病毒剂，如cidofovir(HPMPC，GS504)、BVDU、BVRU，以及其它核苷和核苷酸组合使用。本发明也能与其它免疫调节因子如干扰素或干扰素诱导物(imiquimod，Aldara，IL-12)组合使用。本发明也能与目前正在开发的(预防性或治疗性)重组疫苗组合使用。本发明还可以作为单独性治疗来给药被感染的个体，从而增强个体的天然免疫应答，使个体控制或清除感染。
最近的数据表明，IL-18在与疱疹病毒相关的肿瘤发生中潜在的保护作用。IL-18，也称之为干扰素-γ，在EBV急性感染细胞中起正调节作用，在由EBV诱导的移植后淋巴增生性疾病中起负调节作用(Setsuda等，1999，American Journal ofPathology，155：257-265)。这些数据表明，这些媒介物参与宿主对抗EBV致癌特性的防御作用。本发明可以与诸如针对HSV列出的那些试剂组合使用。本发明也能作为单独性治疗来给药被感染的个体，从而增强个体的天然免疫应答，使个体控制或清除感染。
HAV
甲型肝炎病毒(HAV)属于小RNA病毒科。甲型肝炎是人与人之间高度接触传染的，它可以经由粪-口途径传播，包括通过污染的食物、食物器皿、污染的水、食用来自于污染的水中的有壳水生动物以及其它从人到人的直接途径。HAV在肝脏中复制和分泌于胆汁中。感染是急性的，通常有症状，包括从轻微和暂时性的症状到严重和长期性的症状，有发烧、呕吐、腹泻、黄疸和肝大。治疗通常是支持性的，仅在特别严重的病例中进行肝移植。预防可以是在暴露于病毒之前通过灭活病毒(Havrix)进行主动免疫或在暴露于病毒之后用集聚的免疫球蛋白进行被动免疫。
本发明的多肽可以与目前的疫苗组合使用以增强免疫力或获得治疗效果(一旦患者已经被感染)。本发明也可以作为单独性治疗来给药被感染的个体，从而增强个体的天然免疫应答，使个体控制或清除感染。
HBV
乙型肝炎病毒(HBV)是DNA病毒，属于嗜肝DNA病毒科的一员。HBV是经由血液或体液通过类似HIV传染的途径在人-人之间传播的。HBV主要在肝脏中复制，该病毒被释放进血流中，之后可以在身体分泌物包括精液和唾液中发现。在暴露于病毒和有临床症状之间有60-180天的潜伏期，临床症状包括无症状感染到黄疸性肝炎，偶有肝衰竭。在急性阶段过后，大部分患者清除了病毒并产生免疫力。某些患者发展成慢性感染，并因此可能导致严重的肝脏疾病、纤维样变性和肝细胞癌。
许多试剂可以用来治疗HBV，但绝大多数仅仅对于部分慢性HBV感染有效。现有已获准销售和正处在实验阶段的制剂包括抗病毒剂(拉米夫定[3TC]、famciclovir、lobucavir、Adefovir，和许多其它核苷和核苷酸制剂)，免疫调节因子(干扰素α、β、γ，皮质类固醇，Levamisole，胸腺素α，IL-2，三氮唑核苷)和治疗性疫苗或超免疫球蛋白。
本发明的多肽可以与任何一种现有治疗或其它类似制剂组合使用。本发明还可以作为单独性治疗来给药被感染的个体，从而增强个体的天然免疫应答，使个体控制或清除感染。
HCV
丙型肝炎病毒(HCV)是单链RNA病毒，属于Hepacivirus或黄病毒科(Flavivirus)的一员。HCV出现在血液和身体分泌物中，经由与HIV和HBV相同的途径在人-人之间传播。HCV主要在肝脏中复制，虽然也发现病毒存在于其它类型的细胞如淋巴和树状细胞中。急性感染常常是无症状的，或是特征在于一种常常伴有更常见的病毒感染的轻度过程。在少量例子中，急性感染可能导致爆发性肝炎和死亡。大多数感染导致一种慢性的、常常是无症状的感染，该感染可能持续数十年，偶尔有肝酶的增多或肝硬变。某些病例会发展成严重的肝脏疾病包括肝衰和肝细胞癌。
一般通过干扰素-α、共有干扰素、或干扰素与三氮唑核苷的组合物来治疗HCV。真正的抗病毒化合物现正处于早期临床试验中，包括病毒聚合酶的抑制剂、反义多核苷酸、或核酶。
本发明可以与任何一种现有治疗或其它类似制剂组合使用。本发明还可以作为单独性治疗来给药已被感染的个体，从而增强个体的天然免疫应答，使个体能控制或清除感染。
相信在慢性HCV感染期间给予IL-18可以降低病毒水平，它是通过诱导非-细胞溶解的抗病毒细胞因子如IFNγ或TNFα的作用、或通过增强T-细胞对病毒抗原的反应来提高和维持保护性免疫力。
本发明也提供了含有有效治疗量的IL-18的药用组合物，任选还含有其它制剂如上文所述的制剂。还可以使用可药用载体或赋形剂。所用的可药用载体可以是例如固体或液体。固体载体的实例包括但不局限于乳糖、石膏粉、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸等。液体载体的实例包括但不局限于盐水、缓冲盐水、葡萄糖、水、甘油、乙醇浆、花生油、橄榄油、和它们的混合物。同样，载体或稀释剂可包括本领域内众所周知的缓释材料，例如单独的甘油单硬脂酸酯或甘油二硬脂酸酯或它们与蜡、乙基纤维素、羟丙基甲基纤维素、异丁烯酸甲酯等的混合物。
本发明还涉及包含填充有一种或多种上述本发明组合物组分的一个或多个容器的药物包装或药盒。多肽可单独使用，或者与其它化合物例如治疗化合物联合使用。
本发明组合物可适应于给药途径，例如适于系统性给药或口服给药。优选的系统性给药形式包括注射，主要是静脉注射。可使用其它注射途径，如皮下、肌内注射、或腹膜内注射。此外，如果可将本发明配制成肠溶或胶囊制剂，口服给药也是可能的。其它系统性给药手段包括使用渗透剂例如胆盐或夫西地酸或其它去污剂透粘膜给药和透皮给药。这些组合物还可以以膏剂、糊剂、凝胶剂等剂型局部给药和/或定位给药。
IL-18所需的剂量取决于助剂的选择，必要时，还取决于给药途径、制剂性质、患者的状态、以及临床医师的判断。IL-18的适当剂量是1纳克/Kg-1毫克/kg患者体重。然而，根据所用化合物的种类和不同给药途径的不同效力，所需剂量可有很大变化。例如，透皮给药将比静脉内注射给药需要更高的剂量。通过本领域内众所周知的用于最优化的经验性常规手段可调节这些剂量水平中的变化。
本发明组合物的给药方案取决于剂量、对助剂的选择、给药途径、制剂性质、患者的状态、以及临床医师的判断。合适的给药方案是每日一次，每周一次或每月一次。但是根据所用其它制剂的种类和不同给药途径的不同效力，本发明组合物的给药方案可有很大变化。例如，透皮给药将比静脉内注射给药需要更高的剂量。通过本领域内众所周知的用于最优化的经验性常规手段可调节本发明组合物给药方案中的变化。
本说明书中引用的所有出版物，包括但不局限于专利和专利申请都引入本发明以作参考，就象每一出版物都是具体和独自指明引入全文以作参考。
据信，通过上文中描述，本领域技术人员可最充分地应用本发明。因此，下述实施例仅是为了举例说明，并不是以任意方式对本发明的限制。
实施例
实施例1：用鼠IL-18治疗小鼠诱导了IFNγ和GM-CSF。
根据未感染小鼠的细胞因子信息传递的动力学和蛋白的诱导来评估鼠IL-18的活性。用10或100ug鼠IL-18对雌性Balb/C小鼠进行腹膜内(IP)处理，在处理后的0、2.5、4或6小时时收集样品。通过ELISA来评估处理2.5小时后收集的血清(n＝3)和单个脾组织的匀浆物(2ng/m1)中的TNF-α、IFN-γ和GM-CSF水平，与其活性对应。检测到了最小限度诱导的TNF-α(100pg/ml)，同时发现没有诱导GM-CSF。与此形成对照，通过定量实时PCR反应观察到了GM-CSF、IFN-γ和TNF的mRNA诱导。在注射后2.5-6个小时，IFNγmRNA的诱导达到了载体的20倍(图3)，GM-CSF的诱导为载体对照值的约6-10倍(没有显示)。这样就证实了鼠IL-18诱导细胞因子的活性。
图3表明了用溶于缓冲盐水的不同量的鼠IL-18通过IP途径给药后小鼠中IFN-γ蛋白的诱导。利用ELISA试剂盒参照操作指导(R&D Systems)检测了血清和脾组织匀浆中的蛋白水平。
图4表明了用溶于缓冲盐水的不同量的鼠IL-18通过IP途径给药后小鼠中IFN-γmRNA的诱导。从脾中提取出总RNA，使用实时PCR分析每份样品的cDNA(使用Superscript，Life Technologies制备)中的持家基因GAPDH和IFN-γ(方法描述于R.J.Cohrs等，J.Virology，2000，24：11464-11471)。
实施例2：鼠I1-18保护小鼠免于致命的HSV-1攻击
几项研究评估了在致命的全身性HSV感染模型中鼠IL-18的效果。在通过IP途径感染HSV-1(SC-16)的-2小时、24小时和48小时时通过IP途径给予鼠IL-18。在所有的研究中，仅用载体处理的动物没有存活者，以10ug/鼠的IL-18处理后有40％的存活率(图5)。在所有的研究中，IL-18处理导致死亡时间的滞后。在个别的研究中，两个每日100ug/鼠剂量的IL-18得到70％的存活率(没有显示)。
图5表明以IP途径给予鼠IL-18后-2小时、1天和2天时给予致命剂量的HSV-1(SC-16)后，相对于对照，增加了小鼠的存活数。
实施例3：IL-18改善流感诱导的致病性
在鼠流感肺炎模型中，用IL-18处理临床疾病能产生有益的效果。用一种亚致死量的适合于鼠的流感A/PR/8/34接种Balb/C小鼠鼻内。如实施例2所述给予IL-18导致流感诱导的体重降低改善了(图6)，用脉冲血氧计(图7)和全身体积描计术测定肺功能也得到改善(Buxco Electronics，没有给出)。
实施例4：IL-18给药后减少了HBV病毒的复制。
IL-18处理乙型肝炎病毒(HBV)转基因小鼠导致了病毒复制的剂量依赖性减少，表现为病毒DNA水平降低了(图8)。对HBV转基因小鼠(Guidotti等，1995，J.Virol，69：6158-6169)进行连续三次每日剂量(第0、1、2天)的皮下注射，注射的是四种不同剂量(100、10、1和0.1微克)重组鼠IL-18，在第3天时通过Southern印迹分析肝脏中的HBV DNA。所有的IL-18剂量水平都产生了效应，其中在最低剂量(0.1微克)时可见少许减少，而在较高剂量时减少得较多。
实施例5：在黑猩猩和人类外周血单核细胞(PBMC)中IL-18与IL-2协同诱导IFN的生成。
分离黑猩猩或人类的PBMC并用对照培养基、100ng/ml的人IL-18或IL-18(100ng/ml)与3ng/ml IL-2的组合物处理。孵育24、48、72或96小时后冷冻析出上清液，通过ELISA分析媒介物水平。图9和10中所示数据表明了人IL-18在黑猩猩PBMCs中产生了类似于在人PBMCs中的诱导细胞因子表达的动力学。而且IL-2和IL-18在诱导GM-CSF、IL-8、新蝶呤和IFN-γ(图9和10)时具有协同作用。这些发现在多个黑猩猩和人供体中得到了证实。
图9表明了人IL-18诱导的IL-8(14-倍)、新蝶呤(7-倍)、GM-CSF(100-倍)和IFN-γ(8-倍)。检测处理后96小时时采集的样品的最高蛋白水平，例外的是，IFN-γ是在24小时达到最高水平。用人IL-18和IL-2组合处理导致了显著高的诱导。
图10表明了上述发现在不同动物中的可重复性。在本研究中，单独用IL-2进行的处理作为对照。IFN-γ显示在图10(a)中，新蝶呤显示在图10(b)中，IL-8显示在图10(c)中。
实施例6：IL-18对HBV复制的抑制作用可用IL-12叠加或与之协同。
在与实施例4和图8相似的研究中，IL-18与IL-12组合处理乙型肝炎病毒(HBV)转基因小鼠，在减少病毒复制和病毒DNA转录方面比单独使用任一种细胞因子的效果要好。在第0天用IL-18(10微克)和IL-12(1微克)一起皮下处理HBV转基因小鼠一次后就能看到这种叠加效应或协同效应。当在第3天检查这些小鼠的肝脏时，通过检测病毒、对DNA进行Southem印迹(图11)表明HBV的复制显著减少了。而且，IL-18与IL-12的组合不仅减少了HBV DNA的产生而且显著地减少了病毒RNA的产生，正如对这些相同肝脏样品的Northern印迹的结果所示(图11)。
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Claims (10)
1.一种治疗哺乳动物中由流感病毒、HIV、HSV、HPV、HAV、HBV或HCV所致疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括与全长SEQ ID NO：1所示氨基酸序列至少有90％同一性的多肽。
2.一种治疗哺乳动物中由流感病毒、HIV、HSV、HPV、HAV、HBV或HCV所致疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括与SEQ ID NO：2所示全长氨基酸序列至少有90％同一性的多肽。
3.一种治疗哺乳动物中由流感病毒、HIV、HSV、HPV、HAV、HBV或HCV所致疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求1所述的多肽。
4.一种预防哺乳动物中由流感病毒HIV、HSV、HPV、HAV、HBV或HCV引起的疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求2所述的多肽。
5.一种治疗由病毒引起的疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求1或2所述的多肽和一种抗病毒剂。
6.一种治疗由病毒引起的疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求1或2所述的多肽和一种免疫调节性细胞因子。
7.一种治疗由病毒引起的疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求1或2所述的多肽和一种选自下组的制剂：三啖唑核苷(ribavirin)、干扰素α或β、IL-2、IL-12、GM、CSF、TNF、拉米呋啶(lamivudine)、rebetron(三氮唑核苷和干扰素α)、cidofovir、acylovir、valacylovir、penciclovir、famciclovir、更昔洛韦或valganeciclovir。
8.一种治疗由病毒引起的疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求1或2所述的多肽和一种来源于病毒蛋白或核苷酸序列的免疫原。
9.一种治疗由病毒引起的疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求1或2所述的多肽和一种病毒疫苗。
10.一种治疗由病毒引起的疾病的方法，该方法包括给予治疗有效量的组合物，其中所述组合物包括权利要求1或2所述的多肽和一种选自Havrix、Engerix B和Recombivax的疫苗。
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| CN104474534A (zh) * | 2014-12-22 | 2015-04-01 | 哈德逊（天津）生物技术有限责任公司 | 白介素-18抗病毒口腔喷剂 |
| CN111315395A (zh) * | 2017-09-06 | 2020-06-19 | 耶鲁大学 | 白细胞介素-18变体和使用方法 |
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| US20050079153A1 (en) * | 2002-08-14 | 2005-04-14 | Pfizer Inc. | Methods for enhancing immune functions in neonatal mammals by administration of IL-18 |
| EP1572228A4 (en) * | 2002-09-19 | 2009-03-04 | Centocor Inc | METHOD FOR INDUCING MATURATION OF DENDRITIC CELLS AND USES THEREOF |
| AU2004263274B2 (en) | 2003-07-21 | 2009-11-05 | Transgene S.A. | Novel multifunctional cytokines |
| DE602004031341D1 (de) * | 2003-07-21 | 2011-03-24 | Transgene Sa | Multifunktionelle cytokine |
| US20100061958A1 (en) * | 2006-09-14 | 2010-03-11 | The Trustees Of The University Of Pennsylvania | Modulation of Regulatory T Cells by Human IL-18 |
| ES2310129B1 (es) | 2007-06-01 | 2009-10-02 | Juan Carlos Garcia Saban | Nueva superficie de implantes metalicos a base de titanio destinados a ser insertado en tejido oseo. |
| ES2315194B1 (es) | 2007-09-10 | 2010-02-26 | Francisco J. GARCIA SABAN | Procedimiento para obtener una nueva superficie de un implante metalico a base de titanio destinado a ser insertado en tejido oseo. |
| EP4236990A1 (en) | 2020-11-02 | 2023-09-06 | Simcha Il-18, Inc. | Interleukin-18 variants and methods of use |
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| CN101039696B (zh) * | 2004-08-20 | 2011-08-17 | 史密丝克莱恩比彻姆公司 | 给药人il-18治疗创伤的方法 |
| CN104474534A (zh) * | 2014-12-22 | 2015-04-01 | 哈德逊（天津）生物技术有限责任公司 | 白介素-18抗病毒口腔喷剂 |
| CN111315395A (zh) * | 2017-09-06 | 2020-06-19 | 耶鲁大学 | 白细胞介素-18变体和使用方法 |
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| HUP0302233A2 (hu) | 2003-10-28 |
| NO20025722D0 (no) | 2002-11-28 |
| AU7516601A (en) | 2001-12-17 |
| ZA200209757B (en) | 2004-10-04 |
| JP2004514652A (ja) | 2004-05-20 |
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