CN101679508A - 基于靶向抗原至抗原呈递细胞上表达的dcir的疫苗 - Google Patents
基于靶向抗原至抗原呈递细胞上表达的dcir的疫苗 Download PDFInfo
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Abstract
本发明包括用于使用DCIR特异性抗体或其片段(抗原与其结合形成抗体-抗原复合物,其中该抗原通过与该抗体-抗原复合物接触的树突细胞加工和呈递)增加抗原呈递效力的组合物和方法。
Description
发明的技术领域
一般而言,本发明涉及疫苗接种领域,更具体地,本发明涉及与基于靶向抗原至抗原呈递细胞上表达的DCIR的疫苗。
相关申请的交叉引用
本申请要求2007年2月2日提交的美国临时申请系列号60/888,032的优先权,其内容以其整体引入作为参考。
联邦政府资助研究的声明
根据NIH给予的合同号为1U19AI0572340100003的美国政府资助作出本发明。在本发明中政府具有某些权利。
发明背景
不限制本发明的范围,描述与抗原呈递相关的本发明的背景。
基于靶向树突细胞(DC)的人疫苗是建立在小鼠模型中引人注目的研究上的新构思。这里,由针对某些DC受体的抗体运送至DC的小剂量的相对弱的抗原可以引起有效且广泛的免疫反应。为开发用于人的此类疫苗,需要对确切哪种DC受体应该用于该抗原靶向应用有更好的理解。这是因为在小鼠和人免疫系统之间不总是精确的一致,以及还因为不是所有可能的DC受体都已经仔细地进行了针对该疫苗应用的检验。
因此,已经启动了体外测试多种抗人DC受体标靶的研究,例如,在HLA I类和II类分子的情况下用与针对甘露糖受体活化T细胞的人mAb融合的黑色素瘤抗原pmell7靶向的DC(Ramakrishna,Treml等,2004)。此外,通过人源化的抗DC-SIGN mAb使模式抗原KLH靶向DC有效地诱导了抗原特异性的初次反应以及剂量节约的记忆T细胞反应(Tacken,de Vries等,2005)。除甘露糖受体和DC-SIGN之外,人DC表达已知与抗原捕获有关的其它受体。这些中许多是C型凝集素受体(CLR),包括LOX-1、DEC205、DC-ASGPR、Langerin、DCIR、BDCA-2、DECTIN-1和CLEC-6。这些CLR由不同的DC亚型不同地表达,并且它们的表达可以随DC成熟状态而变化(Figdor,van Kooyk等,2002;Geijtenbeek,van Vliet等,2004)。
DC亚型刺激不同的免疫反应,因此,通过差异表达的受体靶向抗原至这些亚型应该引起不同的免疫反应(Shortman和Liu 2002)。此外,在相同DC亚型上的不同受体可以指导抗原到单独的加工途径(Trombetta和Mellman 2005)。最后,这些受体中一些不是固有活化的(例如,DEC205(Bonifaz,Bonnyay等,2004)),而其它的可能是活化的(例如,LOX-1(Delneste,Magistrelli等,2002))或还没有被彻底研究。伴随抗原摄取的DC活化的重要性还未知。但是如果这是有益的,通过靶向性mAb的DC活化可能使靶向性疫苗的制剂简单化。
发明概述
在这些考虑的情况下,本发明的发明人已意识到对通过体外详细研究CD4+和CD8+T细胞初次及记忆反应确定对于需要的免疫结果最合适的人DC靶向性受体的系统比较的迫切需要。本申请描述特定的DC受体-树突细胞抑制性受体(DCIR)-特殊且出乎意料的特性,其显示它是对于靶向抗原至人DC以用于预防性和治疗性疫苗接种目的来说的理想的受体。
本发明包括用于制备和使用为引起针对抗原的有效且广泛的免疫反应的目的而特异性靶向(递送)该抗原至抗原呈递细胞的疫苗的组合物和方法。该目的主要是引起针对抗原衍生于其的活性剂(agent)(病原体或癌)的保护性或治疗性免疫反应。
更特别地,本发明包括组合物、方法以及用于设计和制备以受控的模块结构载有一个或多个抗原的靶特异性单一重组抗体(mAb)、活化蛋白或其它抗体的方法。可以使用本发明的模块式rAb载体例如(通过针对内在化的人树突细胞受体的一个原发重组抗体)靶向多个抗原和/或抗原与活化的细胞因子至树突细胞(DC)。此外,本发明还提供以受控且确定的方式首尾相连地连接两种不同的重组mAb的方法。
本发明包括用于通过分离和纯化DCIR特异性抗体或其片段增加表达DCIR的抗原呈递细胞的抗原呈递效力的组合物和方法,其中靶试剂(targetedagent)与所述DCIR特异性抗体或其片段结合形成抗体-抗原复合物,其中该活性剂通过已与该抗体-活性剂复合物接触的例如树突细胞加工并呈递。在一个实施方案中,抗原呈递细胞是树突细胞并且DCIR特异性抗体或其片段与Coherin/Dockerin(协调素/锚定素)对的一半结合。DCIR特异性抗体或其片段还可与Coherin/Dockerin对的一半结合而抗原与该Coherin/Dockerin对的互补性一半(complementary half)结合,形成复合物。非限制的实例活性剂包括一种或多种肽、蛋白质、脂质、碳水化合物、核酸及其组合。
活性剂可以是一种或多种细胞因子,所述细胞因子选自白细胞介素,转化生长因子(TGF),成纤维细胞生长因子(FGF),血小板衍生生长因子(PDGF),表皮生长因子(EGF),结缔组织活性肽(CTAP),成骨因子,以及这些生长因子的生物活性类似物、片段和衍生物,B/T细胞分化因子,B/T细胞生长因子,促有丝分裂细胞因子,趋化细胞因子,集落刺激因子,血管生成因子,IFN-α,IFN-β,IFN-γ,IL1,IL2,IL3,IL4,IL5,IL6,IL7,IL8,IL9,IL10,IL11,IL12,IL13,IL14,IL15,IL16,IL17,IL18等,瘦素(leptin),肌肉生长抑制素(myostatin),巨噬细胞刺激蛋白,血小板衍生生长因子,TNF-α,TNF-β,NGF,CD40L,CD137L/4-1BBL,人淋巴毒素-β,G-CSF,M-CSF,GM-CSF,PDGF,IL-1α,IL1-β,IP-10,PF4,GRO,9E3,促红细胞生成素,内皮抑素(endostatin),血管抑素(angiostatin),VEGF,包括β转化生长因子(例如TGF-β1、TGF-β2、TGF-β3)在内的转化生长因子(TGF)超基因家族;骨形态发生蛋白(例如BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9);肝素结合生长因子(成纤维细胞生长因子(FGF),表皮生长因子(EGF),血小板衍生生长因子(PDGF),胰岛素样生长因子(IGF));抑制素(例如抑制素A、抑制素B);生长分化因子(例如GDF-1);以及活化素(例如活化素A、活化素B、活化素AB)。在另一个实施方案中,活性剂包括抗原,该抗原为细菌蛋白、病毒蛋白、真菌蛋白、原生动物蛋白或癌蛋白。
本发明还包括用于增加树突细胞的抗原呈递效力的组合物和方法,包括结合DCIR特异性抗体或其片段,其中抗原与该DCIR特异性抗体或其片段结合形成抗体-抗原复合物,其中该抗原通过已与该抗体-抗原复合物接触的树突细胞加工并呈递。另一个实施方案是针对DCIR的抗体或其它特异性结合分子用于递送抗原至抗原呈递细胞以引起保护性或治疗性免疫反应的用途。对DCIR特异的抗原靶向性试剂用于经皮肤的疫苗接种的用途;DCIR特异的抗原靶向性试剂与共给药或连接的佐剂相结合用于疫苗接种或者能够作为重组抗原-抗体融合蛋白表达的特定抗原用于抗原靶向(疫苗接种)目的的用途。
另一个实施方案包括通过以下用于增加树突细胞的效力的方法:分离患者的树突细胞;使所述树突细胞暴露于活化量的抗DCIR抗体或其片段和抗原,形成负载抗原的活化树突细胞;和将所述负载抗原的活化树突细胞再引入所述患者中。抗原可以是细菌蛋白、病毒蛋白、真菌蛋白、原生动物蛋白或癌蛋白。本发明还包括从哺乳动物细胞分泌的抗DCIR免疫球蛋白或其部分以及与该免疫球蛋白结合的抗原。该免疫球蛋白与cohesin/dockerin结构域的一半结合,或者它还可包括与同模块式rAb载体形成复合物的抗原结合的cohesin-dockerin结合对的互补性一半,或与抗原构成融合蛋白的cohesin-dockerin结合对的互补性一半。抗原特异性结构域可以是全长抗体、抗体可变区结构域、Fab片段、Fab′片段、F(ab)2片段、Fv片段、Fabc片段和/或具有部分Fc结构域的Fab片段。抗DCIR免疫球蛋白还可以与毒素结合,其中该毒素选自放射性同位素、金属、酶、肉毒杆菌毒素、破伤风、蓖麻毒素、霍乱、白喉、黄曲霉毒素、产气荚膜梭菌(perfringen)毒素、真菌毒素、志贺菌毒素、葡萄球菌肠毒素B、T2、seguitoxin、蛤蚌毒素、相思豆毒素、cyanoginosin、α毒素、河豚毒素、aconotoxin、蛇毒和蜘蛛毒。抗原可以是与免疫球蛋白构成的融合蛋白或者化学共价结合或不是。
另一个实施方案是具有DCIR特异性抗体或其片段的疫苗,其中抗原与该DCIR特异性抗体或其片段结合形成抗体-抗原复合物,其中该抗原通过已与该抗体-抗原复合物接触的树突细胞加工并呈递。
本发明的新型抗体还能显示新的组织分布信息。由于它们的特异亲合力,发现本发明的抗DCIR抗体结合猴DCIR,并且体内[hu-小鼠]使用抗DCIR-Flu ml靶向扩增Flu ml特异性的CD8细胞以及离体人皮肤细胞的体外靶向是有效的。此外,发现,DCIR的碳水化合物配体复合物能被用作抗DCIR活性剂的替代品用于抗原递送。因此,本发明的另一个实施方案是T细胞抗原,其包括与聚糖的至少一部分结合的抗原性T细胞表位肽,该聚糖包括与DCIR特异性结合的Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-3(Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-6)Manβ1-4GlcNAcβ1-4GlcNAcβ-Spl2)。聚糖(及其衍生物)也能单独或组合使用以阻断DCIR结合。
附图的简要说明
为了更完整地理解本发明的特征和优点,现在参考发明详述以及附图,在附图中:
图1A至1F显示许多,但不是全部,与对照相比引起MCP-1特异性产生的杂交瘤上清液,即**mAb 4C7、9E8、19E3、1G3、10A5、29G10、3C2、3G2、24A5、30F3、12E2、5F9、2F11、24E7、31A6、6A11、29E9、2H8、30D9、6C8、35F1、3F12被选择用于进一步表征;
图2显示通过ELISA的mAb与结合到板上的DCIR的高亲合力相互作用;
图3显示用于FACS的高亲合抗体的结合;
图4显示DCIR也在从人皮肤直接分离出的三种人DC亚型中表达;
图5显示人扁桃腺中生发中心周围的一群细胞的DCIR特异性染色;
图6显示交联-F1u M1蛋白和DCIR的mAb的实例;
图7显示Coh.Flu M1与抗DCIR_2C9mAb的交联;
图8显示与抗DCIR mAb交联的Flu M1比没有与mAb连接的Flu M1蛋白质更有效地诱导Flu M1特异性CD8+T细胞的扩增;
图9显示与抗DCIR mAb交联的Flu M1通过LC比Int-DC更有效地诱导FluM1特异性CD8+T细胞的扩增;
图10显示编码嵌合小鼠-人rAb的H+L链载体,该嵌合小鼠-人rAb相当于许多不同的抗DCIR mAb共转染入293细胞中,通过抗人FC ELISA测定分泌入培养物上清液的rAb;
图11显示与抗DCIR.Doc rAb连接的Coh.Flu M1特异性地与GM/IL-15人DC结合;
图12显示与抗DC-SIGN/L.Doc或抗DCIR.Doc rAb连接的Coh.Flu M1结合并内在化入GM-CSF/IL-4人DC;
图13显示抗DCIR.Doc:Coh.Flu复合物比其它[抗DC受体rAb.Doc:Coh.FluM1]复合物更有效地扩增Flu M1特异性CD8+T细胞;
图14显示给药1天的抗DCIR.Doc:Coh.Flu复合物比其它[抗DC受体rAb.Doc:Coh.Flu M1]复合物更有效地扩增Flu M1特异性CD8+T细胞;
图15显示以与rAb H链的C末端的融合体表达的多种抗原对rAb.抗原的分泌有固有的影响;
图16显示抗DCIR.Flu HA5rAb取决于可变区的性质以不同的效率分泌;
图17显示抗DCIR mAb增强HIV抗原特异性CD8+细胞的启动;
图18显示抗DCIR mAb增强HIV抗原特异性CD8+细胞的启动;
图19显示在人上皮层中DCIR分布的免疫组织化学分析;
图20A-20D显示DCIR抗原的单克隆抗体对DCIR的特异性亲合力;
图21显示抗DCIR mAb与恒河猴(Rhesus macaque)DCIR的交叉反应性;
图22是显示DCIR胞外结构域与特定聚糖结构的结合的图表;
图23A至23C显示DCIR是对于所有血液DC亚型的普遍标靶;以及
图24显示表明用DCIR-FluM1疫苗接种允许产生FluM1特异的记忆CD8+T细胞免疫性。
发明详述
当以下详细讨论本发明的多种实施方案的制备及使用时,应该理解本发明提供了许多可以在多种特定情况下具体实施的可应用的发明构思。本文讨论的特定实施方案仅仅是说明制备和使用本发明的特定方法,而不限定本发明的范围。
为便于理解本发明,许多术语定义如下。本文定义的术语具有与本发明相关的领域中的普通技术人员通常理解的含义。术语诸如″一个″、″一种″、″该″等不意欲仅仅指单数实体,而是包括其中特定实例可以用于例证的总的类别。本文术语用于描述本发明的特定实施方案,但是它们的用法并不限制本发明,除非在权利要求中概述的。
树突细胞(DC)是在调控抗原特异性免疫中起关键作用的抗原呈递细胞(Mellman和Steinman 2001),(Banchereau,Briere等,2000),(Cella,Sallusto等,1997)。DC捕获抗原,把它们加工成肽,并将它们呈递给T细胞。因此将抗原直接递送到DC是改良疫苗的焦点领域。一个这样的实施例是使用离体抗原负载然后再给予患者的自体DC开发基于DC的疫苗(Banchereau,Schuler-Thurner等,2001),(Steinman和Dhodapkar 2001)。另一个改良疫苗效力的策略是将与针对内在化DC特异性受体的抗体结合的抗原特异性靶向DC。通过关键的小鼠研究突出了对于疫苗接种靶向DC的可能性。在体内,用与卵清蛋白(OVA)偶联的抗LOX-1mAb靶向通过向MHC I类途径的外源性抗原交叉呈递诱导保护性CD8+T细胞反应(Delneste,Magistrelli等2002)。此外,与抗DEC205mAb结合的OVA和CD40L成熟刺激物组合在体内增强通过DC的MHC I类限制性呈递并引起效应器记忆CD8+T细胞持久的生成(Bonifaz,Bonnyay等2004)。这两个研究均显示显著的剂量节约(即以非常低的抗原剂量产生强的免疫反应)并提示比通常用其它种类OVA免疫更广泛的反应。最近通过DEC205使HIVgag抗原靶向DC的工作把这些构思扩展到临床相关抗原并证实使抗原靶向DC的宗旨-来自单一疫苗接种的显著的剂量节约的保护性反应,以及在CD8和CD4两区室中抗原特异性T细胞的扩增(Trumpfheller,Finke等2006)。
本发明提供以受控的、多变量的方式将多个抗原或蛋白质(独立地从原发mAb工程化、表达和纯化)与单一原发重组mAb复合。目前,有工程化位点特异的生物素酰化位点以提供将不同的蛋白质(工程化的各个独立地与链霉抗生物素连接)加入该唯一原发mAb的方法。然而,本发明提供将单独工程化的蛋白质的多组合以固定的等摩尔比值和位置加入原发mAb。
如本文所用,术语″模块式rAb载体″用于描述重组抗体系统,该系统被工程化以提供不同的抗原、活化蛋白质或其它抗体以受控的模块式方式加入单一重组单克隆抗体(mAb)。rAb可以是使用标准杂交瘤技术、重组抗体展示、人源化单克隆抗体等制备的单克隆抗体。模块式rAb载体可用于,例如,(通过一种针对例如人树突细胞受体的内在化受体的原发重组抗体)靶向多个抗原和/或抗原与活化的细胞因子至树突细胞(DC)。模块式rAb载体还可以用于以受控且确定的方式首尾相连地连接两种不同的重组mAb。
″模块式rAb载体″的抗原结合部分可以是一种或多种可变结构域、一种或多种可变结构域与第一恒定结构域,Fab片段、Fab′片段、F(ab)2片段和Fv片段,以及Fabc片段和/或具有部分Fc结构域的Fab片段,同源的模块式结合部分添加到氨基酸序列和/或与其结合。模块式rAb载体中使用的抗体可以是任何同种型或类别、亚类或者来自任何来源(动物和/或重组体)。
在一个非限制性实施例中,模块式rAb载体被工程化为具有一种或多种模块式cohesin-dockerin蛋白质结构域,用于制备在工程化的重组mAb情况下的特异且明确的蛋白质复合物。mAb是包括一种或多种来自mAb的抗原结合结构域的模块式cohesin-dockerin蛋白质结构域羧基的融合蛋白的一部分。cohesin-dockerin蛋白质结构域甚至可以在翻译后,例如使用化学交联剂和/或二硫键连接。
本文使用的术语″抗原″指的是可以在该抗原的接受者中启动体液和/或细胞免疫反应的分子。抗原可以用于本发明的两种不同情况中:作为抗体或rAb的其它抗原识别结构域的标靶或者作为分子,该分子通过模块式rAb载体的dockerin/cohesin-分子补体的一部分的rAb运送到和/或进入细胞或标靶。抗原通常是引起疾病的活性剂,对于该疾病,疫苗接种可能是有益的治疗。当抗原被呈递在MHC上时,该肽通常是约8到约25个氨基酸。抗原包括任何类型的生物分子,包括,例如,简单的中间代谢物、糖、脂质和激素以及大分子诸如复合碳水化合物、磷脂、核酸和蛋白质。抗原的常见种类包括但不限于病毒抗原,细菌抗原,真菌抗原,原生动物及其他寄生虫抗原,肿瘤抗原,自身免疫性疾病、过敏症和移植排斥中涉及的抗原,及其他各种抗原。
模块式rAb载体能够运载许多活化剂,例如抗生素、抗感染药、抗病毒药、抗肿瘤药、解热药、镇痛药、抗炎药、骨质疏松症的治疗剂、酶、细胞因子、抗凝血药、多糖、胶原、细胞及两种或更多前述活化剂的组合。使用本发明递送的抗生素的实例无限制地包括四环素、氨基糖苷类、青霉素、头孢菌素、磺胺类药物、氯霉素琥珀酸钠、红霉素、万古霉素、林可霉素、克林霉素、制霉菌素、两性霉素B、金刚烷胺、碘苷、对氨基水杨酸、异烟肼、利福平、放线菌素D、光辉霉素、道诺霉素、阿霉素、博来霉素、长春碱、长春新碱、甲基苄肼、咪唑甲酰胺等等。
使用本发明递送的抗炎药的实例无限制地包括NSAIDS、阿司匹林、甾族化合物、地塞米松、氢化可的松、泼尼松龙、双氯芬酸钠等等。
使用本发明递送的治疗骨质疏松症的治疗剂和作用于骨和骨骼的其它因子的实例无限制地包括钙,阿仑膦酸盐,骨GLa肽,甲状旁腺激素及其活性片段,组蛋白H4相关骨形成和增殖肽及其突变体、衍生物和类似物。
使用本发明递送的酶和酶辅因子的实例无限制地包括胰酶(pancrease)、L-天冬酰胺酶、透明质酸酶、胰凝乳蛋白酶、胰蛋白酶、tPA、链激酶、尿激酶、胰酶制剂、胶原酶、胰蛋白酶原、胰凝乳蛋白酶原、血纤维蛋白溶酶原、链激酶、腺苷酸环化酶、过氧化物歧化酶(SOD)等等。
使用本发明递送的细胞因子的实例无限制地包括白细胞介素,转化生长因子(TGF),成纤维细胞生长因子(FGF),血小板衍生生长因子(PDGF),表皮生长因子(EGF),结缔组织活化肽(CTAP),成骨因子及这些生长因子的生物活性类似物、片段和衍生物。细胞因子可以是B/T细胞分化因子、B/T细胞生长因子、促有丝分裂细胞因子、趋化细胞因子、集落刺激因子、血管生成因子、IFN-α、IFN-β、IFN-γ、IL1、IL2、IL3、IL4、IL5、IL6、IL7、IL8、IL9、IL10、IL11、IL12、IL13、IL14、IL15、IL16、IL17、IL18等、瘦素、肌肉生长抑制素、巨噬细胞刺激蛋白、血小板衍生生长因子、TNF-α、TNF-β、NGF、CD40L、CD137L/4-1BBL、人淋巴毒素-β、G-CSF、M-CSF、GM-CSF、PDGF、IL-1α、IL1-β、IP-10、PF4、GRO、9E3、促红细胞生成素、内皮抑素、血管抑素、VEGF或其任何片段或组合。其它细胞因子包括转化生长因子(TGF)超基因家族成员,包括β转化生长因子(例如TGF-β1、TGF-β2、TGF-β3);骨形态发生蛋白质(例如,BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9);肝素结合生长因子(例如成纤维细胞生长因子(FGF)、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、胰岛素样生长因子(IGF));抑制素(例如,抑制素A、抑制素B);生长分化因子(例如,GDF-1);以及活化素(例如,活化素A、活化素B、活化素AB)。
使用本发明递送的生长因子的实例无限制地包括可以从天然或自然的来源诸如从哺乳动物细胞分离的,或可以合成地制备诸如通过重组DNA技术或通过多种化学方法制备的生长因子。此外,可以使用这些因子的类似物、片段或衍生物,只要它们显示天然分子的至少一些生物活性。例如,可以通过表达位点特异性突变或其它遗传工程技术改变的基因来制备类似物。
使用本发明递送的抗凝血药的实例无限制地包括华法林、肝素、水蛭素等等。使用本发明递送的作用于免疫系统的因子的实例无限制地包括控制炎症和恶性赘生物的因子以及攻击感染性微生物的因子,诸如趋化肽和缓激肽。
病毒抗原的实例包括但不限于,例如,逆转录病毒抗原,诸如来自人免疫缺陷病毒(HIV)的逆转录病毒抗原,诸如gag、pol和env基因的基因产物,Nef蛋白,逆转录酶及其他HIV元件;肝炎病毒抗原,诸如乙型肝炎病毒的S、M和L蛋白,乙型肝炎病毒和其它肝炎例如甲、乙和丙型肝炎病毒的pre-S抗原,病毒元件诸如丙型肝炎病毒RNA;流感病毒抗原,诸如血球凝集素和神经氨酸酶及其他流感病毒元件;麻疹病毒抗原,诸如麻疹病毒融合蛋白及其他麻疹病毒元件;风疹病毒抗原,诸如蛋白E1和E2及其他风疹病毒元件;轮状病毒抗原,诸如VP7sc及其他轮状病毒元件;巨细胞病毒抗原,诸如包膜糖蛋白B及其他巨细胞病毒抗原元件;呼吸道合胞体病毒抗原,诸如RSV融合蛋白、M2蛋白及其他呼吸道合胞体病毒抗原元件;单纯性疱疹病毒抗原,诸如立即早期蛋白质、糖蛋白D及其他单纯性疱疹病毒抗原元件;水痘带状疱疹病毒抗原,诸如gpI、gpII及其他水痘带状疱疹病毒抗原元件;日本脑炎病毒抗原,诸如蛋白E、M-E、M-E-NS1、NS1、NS1-NS2A、80%E及其他日本脑炎病毒抗原元件;狂犬病病毒抗原,诸如狂犬病糖蛋白、狂犬病核蛋白及其他狂犬病病毒抗原元件。关于病毒抗原的其他实例,参见Fundamental Virology,第二版,编著Fields,B.N.和Knipe,D.M.(Raven Press,New York,1991)。
可以使用本发明的rAb-DC/DC-抗原疫苗递送的抗原标靶包括编码抗原诸如病毒抗原、细菌抗原、真菌抗原或寄生虫抗原的基因。病毒包括微小核糖核酸病毒、冠状病毒、披盖病毒、黄病毒、杆状病毒、副粘病毒、正粘病毒、布尼亚病毒、沙粒病毒、呼肠孤病毒、逆转录病毒、乳头瘤病毒、细小病毒、疱疹病毒、痘病毒、嗜肝DNA病毒和海绵状病毒。其它病毒标靶包括流感、单纯疱疹病毒1和2、麻疹、登革热、天花、脊髓灰质炎或HIV。病原体包括锥虫、绦虫、蛔虫、蠕虫、疟疾。肿瘤标记物诸如胚胎抗原或前列腺特异性抗原可以以这个方法靶向。其它实例包括:HIV env蛋白和乙型肝炎表面抗原。根据本发明用于疫苗接种目的的载体的给予可能要求载体结合的抗原是足够非免疫原性的以使得转基因能够长期表达,对此可期望强烈的免疫反应。在一些情况下,个体的疫苗接种可仅是不经常地需要,诸如每年或每两年一次,并提供对传染物的长期免疫保护。本发明用于载体中并最终作为抗原的生物体、过敏原及核酸和氨基酸序列的特定实例可以在美国专利6,541,011中找到,该专利的相关部分引入本文作为参考,尤其是可以用于本发明的匹配生物体和特定序列的表格。
用于本文公开的rAb疫苗的细菌抗原包括但不限于,例如,细菌抗原,诸如百日咳毒素、丝状血球凝集素、百目咳杆菌粘附素、FIM2、FIM3、腺苷酸环化酶及其他百日咳细菌抗原元件;白喉细菌抗原,诸如白喉毒素或类毒素及其他白喉细菌抗原元件;破伤风细菌抗原,诸如破伤风毒素或类毒素及其他破伤风细菌抗原元件;链球菌细菌抗原,诸如M蛋白及其他链球菌细菌抗原元件;革兰氏阴性杆菌细菌抗原,诸如脂多糖及其他革兰氏阴性细菌抗原元件;结核分枝杆菌细菌抗原,诸如霉菌酸、热休克蛋白65(HSP65)、30kDa主要分泌性蛋白、抗原85A及其他分枝杆菌抗原元件;幽门螺杆菌细菌抗原元件;肺炎球菌细菌抗原,诸如肺炎球菌溶血素、肺炎球菌荚膜多糖及其他肺炎球菌细菌抗原元件;流感嗜血杆菌细菌抗原,诸如荚膜多糖及其他流感嗜血杆菌细菌抗原元件;炭疽细菌抗原,诸如炭疽保护性抗原及其他炭疽细菌抗原元件;立克次氏体细菌抗原,诸如rompA及其他立克次氏体细菌抗原元件。本文描述的细菌抗原还包括任何其它细菌、分枝杆菌、支原体、立克次体或衣原体抗原。部分或完整的病原体还可以是:流感嗜血杆菌;镰状疟原虫;脑膜炎奈瑟氏球菌;肺炎链球菌;淋病奈瑟氏菌;伤寒沙门氏菌血清型;志贺氏菌;霍乱弧菌;登革热;脑炎;日本脑炎;莱姆病;鼠疫耶尔森氏菌;西尼罗河病毒;黄热病;兔热病;肝炎(病毒性;细菌性);RSV(呼吸道合胞病毒);HPIV 1和HPIV 3;腺病毒;天花;过敏物和癌症物质。
用于本发明的组合物和方法的真菌抗原包括但不限于,例如,念珠菌属真菌抗原元件;组织胞浆菌属真菌抗原,诸如热休克蛋白60(HSP60)及其他组织胞浆菌属真菌抗原元件;隐球菌真菌抗原,诸如荚膜多糖及其他隐球菌真菌抗原元件;球孢子菌真菌抗原,诸如小球体抗原及其他球孢子菌真菌抗原元件;以及癣真菌抗原,诸如发癣菌素及其他球孢子菌真菌抗原元件。
原生动物及其他寄生虫抗原的实例包括但不限于,例如,恶性疟原虫抗原,诸如裂殖子表面抗原、子孢子表面抗原、环子孢子抗原、配子母细胞/配子表面抗原、红内期抗原pf 155/RESA及其他疟原虫抗原元件;弓形体属抗原,诸如SAG-1、p30及其他弓形体属抗原元件;血吸虫属抗原,诸如谷胱甘肽-S转移酶、副肌球蛋白及其他血吸虫属抗原元件;利什曼原虫主要及其他利什曼原虫抗原,诸如gp63、磷脂聚糖及与其相关的蛋白质及其他利什曼原虫抗原元件;以及克氏锥虫抗原,诸如75-77kDa抗原、56kDa抗原及其他锥虫抗原元件。
可以使用本发明的rAb靶向的抗原通常基于许多因素选择,所述因素包括:内在化的可能性、免疫细胞特异性的水平、靶向的免疫细胞种类、免疫细胞成熟的水平和/或活化等等。用于树突细胞的细胞表面标记物的实例包括但不限于,MHC I类、MHC II类、B7-2、CD18、CD29、CD31、CD43、CD44、CD45、CD54、CD58、CD83、CD86、CMRF-44、CMRF-56、DCIR和/或ASPGR等等;而在一些情况下还缺失CD2、CD3、CD4、CD8、CD14、CD15、CD16、CD 19、CD20、CD56和/或CD57。抗原呈递细胞的细胞表面标记物的实例包括但不限于,MHC I类、MHC II类、CD40、CD45、B7-1、B7-2、IFN-γ受体及IL-2受体、ICAM-1和/或Fcγ受体。用于T细胞的细胞表面标记物的实例包括但不限于,CD3、CD4、CD8、CD14、CD20、CD11b、CD16、CD45和HLA-DR。
用于递送的细胞表面上的靶抗原包括通常来源于肿瘤组织细胞的细胞表面、细胞质、细胞核、细胞器等的肿瘤抗原特征性的那些抗原。用于本发明的抗体部分的肿瘤标靶的实例无限制地包括血液癌诸如白血病和淋巴瘤;神经肿瘤诸如星形细胞瘤或恶性胶质瘤;黑色素瘤;乳癌;肺癌;头和颈癌;胃肠肿瘤诸如胃或结肠癌;肝癌;胰腺癌;泌尿生殖器肿瘤如宫颈、子宫、卵巢癌,阴道癌,睾丸癌,前列腺癌或阴茎癌;骨肿瘤;血管肿瘤;或唇、鼻咽、咽和口腔、食道、直肠、胆囊、胆道、喉、肺和支气管、膀胱、肾、脑及神经系统的其他部分、甲状腺的癌症;霍奇金氏病;非霍奇金氏淋巴瘤;多发性骨髓瘤和白血病。
可以使用本发明单独或组合地递送至免疫细胞用于抗原呈递的抗原的实例包括肿瘤蛋白,例如突变的癌基因;与肿瘤相关的病毒蛋白;以及肿瘤粘蛋白和糖脂。抗原可以是与肿瘤相关的病毒蛋白,其可以是来自上文指出的各类别病毒的病毒蛋白。某些抗原可以是肿瘤特征性的(一个亚集,是肿瘤前体细胞通常不表达的蛋白质),或者可以是肿瘤前体细胞中通常表达的蛋白质,但是具有肿瘤特征性的突变。其它抗原包括具有改变的活性或亚细胞分布的正常蛋白质的突变型变体,例如,产生肿瘤抗原的基因突变。
肿瘤抗原的特定的非限制性实例包括:CEA,前列腺特异性抗原(PSA),HER-2/neu,BAGE,GAGE,MAGE 1-4、6和12,MUC(粘蛋白)(例如MUC-1、MUC-2等),GM2和GD2神经节苷脂,ras,myc,酪氨酸酶,MART(黑色素瘤抗原),Pmel 17(gp100),GnT-V内含子V序列(N-乙酰葡糖氨基转移酶V内含子V序列),前列腺Ca psm,PRAME(黑色素瘤抗原),β-连环蛋白,MUM-1-B(黑色素瘤遍在突变基因产物),GAGE(黑色素瘤抗原)1,BAGE(黑色素瘤抗原)2-10,c-ERB2(Her2/neu),EBNA(EB病毒核抗原)1-6,gp75,人乳头瘤病毒(HPV)E6和E7,p53,肺抗性蛋白(LRP),Bcl-2,以及Ki-67。此外,免疫原性分子可以是自身免疫性疾病的起始和/或进展中涉及的自身抗原,该自身免疫性疾病的病理学主要是由于相关靶器官、组织或细胞表达的分子特异性的抗体的活性所引起,例如SLE或MG。在这些疾病中,可能期望将进行中的针对相关自身抗原的抗体介导的(即Th2型)免疫反应指向细胞(即Th1型)免疫反应。或者,可能期望在没有感染,但是疑似易感染相关自身免疫性疾病的受试者中通过预防性诱导针对适当的自身抗原的Th1反应来防止针对自身抗原的Th2反应的起始或降低其水平。标靶自身抗原无限制地包括:(a)对于SLE,Smith蛋白、RNP核糖核蛋白、及SS-A和SS-B蛋白;以及(b)对于MG,乙酰胆碱受体的抗原。在一种或多种类型的自身免疫反应中涉及的其它各种抗原的实例包括,例如,内源性激素,诸如黄体生成素、卵泡刺激素、睾丸激素、生长激素、催乳素及其他激素。
在自身免疫疾病、过敏症和移植排斥中涉及的抗原可被用于本发明的组合物和方法。例如,在任何一种或多种下列自身免疫疾病或障碍中涉及的抗原可被用于本发明:糖尿病(diabetes、diabetes mellitus),关节炎(包括类风湿性关节炎、幼年型类风湿性关节炎、骨关节炎、银屑病关节炎),多发性硬化,重症肌无力,系统性红斑狼疮,自身免疫性甲状腺炎,皮炎(包括特应性皮炎和湿疹性皮炎),银屑病,斯耶格伦氏综合征,包括继发于斯耶格伦氏综合征的干燥性角膜结膜炎,斑秃,由于节肢动物叮咬反应的过敏反应,克罗恩氏病,口疮性溃疡,虹膜炎,结膜炎,角膜结膜炎,溃疡性结肠炎,哮喘,过敏性哮喘,皮肤红斑狼疮,硬皮病,阴道炎,直肠炎,药疹,麻疯病逆向反应,麻风结节性红斑,自身免疫性葡萄膜炎,过敏性脑脊髓炎,急性坏死性出血性脑病,特发性双侧累进性感觉神经性听力丧失,再生障碍性贫血,单纯性红细胞贫血,特发性血小板减少,多软骨炎,韦格纳氏肉芽肿病,慢性活动型肝炎,斯-约二氏综合征,自发性口炎性腹泻,扁平苔癣,克罗恩氏病,格雷夫斯眼病,结节病,原发性胆汁性肝硬化,后葡萄膜炎和间质性肺纤维化。在自身免疫性疾病中涉及的抗原的实例包括谷氨酸脱羧酶65(GAD 65)、天然DNA、髓磷脂碱蛋白、髓磷脂蛋白脂质蛋白、乙酰胆碱受体元件、甲状腺球蛋白和促甲状腺激素(TSH)受体。在过敏症中涉及的抗原的实例包括花粉抗原诸如日本柳杉花粉抗原、豚草花粉抗原、黑麦草花粉抗原,动物来源的抗原诸如灰尘螨抗原和猫科抗原,组织相容性抗原和青霉素及其他治疗性药物。在移植排斥中涉及的抗原的实例包括移植入移植物接受者的移植物的抗原性元件,诸如心脏、肺、肝脏、胰、肾和神经的移植物元件。抗原可以是对治疗自身免疫性疾病有用的改变的肽配体。
如同本文使用的,术语″表位″指的是包括与位于由病原体DNA或RNA编码的多种病原体多肽之任何一种中的表位相似的一级、二级或三级结构的肽或蛋白质抗原。相似性的水平通常达到这样的程度,即针对上述多肽的单克隆或多克隆抗体也会与该肽或蛋白质抗原结合、反应或识别该肽或蛋白质抗原。多种免疫测定方法可以和上述抗体一起使用,例如蛋白质印迹法、ELISA、RIA等,所有这些都为本领域技术人员所知。适于在疫苗中使用的病原体表位和/或它们的功能等价物的鉴定是本发明的一部分。一旦分离和鉴定,可以容易地获得功能等价物。例如,可以使用如美国专利号4,554,101中讲授的Hopp的方法,其教导根据亲水性从氨基酸序列鉴定和制备表位,该文献引入本文作为参考。其它一些论文中描述的方法及基于其的软件程序也可以用于鉴定表位核心序列(参见,例如,Jameson和Wolf,1988;Wolf等,1988;美国专利号4,554,101)。然后可以容易地通过运用肽合成或重组技术把这些″表位核心序列″的氨基酸序列引入肽中。
可以把包含编码本发明的抗原的核酸作为活性成分的疫苗组合物制剂制备为注射剂,为液体溶液或悬浮液;也可以制备适于在注射之前溶解或悬浮于液体中的固体形式。可以把制剂乳化,包封在脂质体中。通常把活性免疫原性成分与药学上可接受并与活性成分相容的载体混合。
术语″药学上可接受的载体″指的是在给予的受试者中不引起过敏反应或其它副作用的载体。合适的药学上可接受的载体包括,例如,水、盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇等及其组合中的一种或多种。此外,如果需要,疫苗可以包含少量的辅助性物质,诸如润湿或乳化剂、pH缓冲剂和/或增强疫苗效力的佐剂。可能有效的佐剂的实例包括但不限于:氢氧化铝、N-乙酰-胞壁酰-L-苏氨酰-D-异谷氨酰胺(thr-MDP)、N-乙酰-nor-胞壁酰-L-丙氨酰-D-异谷氨酰胺、MTP-PE和RIBI,其包含在2%鲨烯/Tween 80乳剂中的三种细菌提取成分,单磷酰脂质A、海藻糖二霉菌酸酯和细胞壁骨架(MPL+TDM+CWS)。佐剂的其它实例包括DDA(溴化二甲基双十八烷基铵)、弗氏完全和不完全佐剂以及QuilA。此外,免疫调节物质,诸如淋巴因子(例如,IFN-γ、IL-2和IL-12)或合成的IFN-γ诱导物(诸如聚I:C)可以和本文描述的佐剂联合使用。
如本发明所描述的,药品可以包括具有单一或多拷贝的特定核苷酸序列的裸多核苷酸,该特定核苷酸序列与存在于血浆脂蛋白上的载脂蛋白的特定DNA结合位点结合。多核苷酸可以编码生物活性肽、反义RNA或核酶并以生理学上可接受的可给药形式提供。可来自本发明的另一种药品以生理学上可接受的可给药形式包括根据本文描述的方法从患者血液或其它来源分离的高度纯化的血浆脂蛋白部分和预先结合到纯化的脂蛋白部分的、包含与存在于血浆脂蛋白上的载脂蛋白的特定DNA结合位点结合的单一或多拷贝的特定核苷酸序列的多核苷酸。
另一种药品以生理学上可接受的可给药形式包括高度纯化的血浆脂蛋白部分,该血浆脂蛋白部分包括含有单一或多拷贝的特定DNA结合基序的重组载脂蛋白片段,其预先结合到包括单一或多拷贝的特定核苷酸序列的多核苷酸上。另一种药品以生理学上可接受的可给药形式包括高度纯化的血浆脂蛋白部分,该血浆脂蛋白部分包括含有单一或多拷贝的特定DNA结合基序的重组载脂蛋白片段,其预先结合到包括单一或多拷贝的特定核苷酸序列的多核苷酸上。
给药剂量在很大程度上取决于治疗的受试者的体重和身体健康状态以及给药途径和治疗频率。包括预先结合到高度纯化的脂蛋白部分的裸多核苷酸的药物组合物可以按1μg到1mg多核苷酸和1μg到100mg蛋白质的量给药。
rAb和rAb复合物给予患者可以遵循用于化学疗法给药的一般方案,如果有的话,考虑载体的毒性。预料根据需要重复治疗周期。还考虑,多种标准治疗以及外科干预可以与所述的基因治疗联合施用。
在考虑基因治疗临床应用的情况下,需要制备复合物作为适于目的应用的药物组合物。通常这需要制备基本上不含热原以及任何其它对人或动物有害的杂质的药物组合物。通常还期望使用适当的盐和缓冲液以使复合物稳定和允许复合物被靶细胞摄取。
本发明的水性组合物可以包括有效量的化合物,其溶解或分散在药学上可接受的载体或水介质中。这些组合物也可以称作接种物。用于药物活性物质的介质和试剂的使用在本领域中为大家所熟知。任何常规介质或试剂除非与活性成分不相容,否则其在治疗组合物中的使用被考虑。补充性活性成分也可以加入组合物中。本发明的组合物可以包括典型的药物制剂。也可以在甘油、液体聚乙二醇及其混合物中和在油类中制备分散体。在通常的储存和使用条件下,这些制剂包含防腐剂以防止微生物的生长。
疾病状态。取决于要治疗的特定疾病,根据本发明的治疗组合物的给予可以经任何常规途径进行,只要经该途径可达到靶组织以使最大化递送抗原到位点来达到最大的(或在一些情况下最小的)免疫反应。通常可以经原位、皮内、皮下、肌内、腹膜内或静脉内注射给药。递送的其它部位包括:口、鼻、颊、直肠、阴道或局部的。局部给药对于皮肤癌的治疗可能是特别有益的。所述组合物通常作为包括生理学上可接受的载体、缓冲液或其它赋形剂的药学上可接受的组合物给药。
本发明的疫苗或治疗组合物可以经注射胃肠外例如皮下或肌内给予。适于其它给药方式的另外的制剂包括栓剂,以及在一些情况下口服制剂或适于分配的制剂如气雾剂。对于口服制剂,使用佐剂的T细胞亚型操作,抗原包装或添加单独的细胞因子到多种制剂中产生具有最佳化免疫反应的改良口服疫苗。对于栓剂,常规的粘合剂和载体可以包括,例如,聚亚烷基二醇或甘油三脂;这些栓剂可以由包含0.5%到10%,优选1%-2%范围内的活性成分的混合物形成。口服制剂包括通常使用的赋形剂,例如药物级的甘露糖醇、乳糖、淀粉硬脂酸镁、糖精钠、纤维素、碳酸镁等。这些组合物采取溶液、悬浮液、片剂、丸剂、胶囊、缓释制剂或散剂的形式并且包含10%-95%的活性成分,优选25-70%。
本发明的编码抗原的核酸可以作为中性的或盐的形式配制入疫苗或治疗组合物中。药学上可接受的盐包括酸加成盐(与肽的游离氨基形成的),其为与无机酸例如盐酸或磷酸或与有机酸诸如醋酸、草酸、酒石酸、马来酸等形成的盐。与游离羧基形成的盐也可以源自于无机碱例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁和有机碱诸如异丙胺、三甲胺、2-乙氨基乙醇、组氨酸、普鲁卡因等。
疫苗或治疗组合物以与给药制剂相容的方式,以及以预防和/或治疗有效的量给予。要给予的量取决于要治疗的受试者,包括例如受试者的免疫系统对合成抗体的容量,以及期望保护或治疗的程度。合适的剂量范围为每次疫苗接种具有约几百微克级的活性成分,范围为约0.1mg到1000mg,诸如约1mg到300mg的范围,以及优选约10mg到50mg的范围。合适的初始给药和强化注射方案也是变化的,但是典型的是初始给药然后是后续的接种或其他给药。给药要求的活性成分的精确量取决于医师的判断且可能为每个受试者所特有。本领域技术人员清楚,本发明的核酸分子或融合多肽的治疗有效量尤其取决于给药方案,给药抗原的单位剂量,核酸分子或融合多肽是否和其它治疗剂联合给药,接受者的免疫状态和健康状态,以及特定核酸分子或融合多肽的治疗活性。
组合物可以以单一剂量方案或以多次剂量方案提供。多次剂量方案中疫苗接种的初始时程可以包括,例如1-10个单独的剂量,随后在以维持和或加强免疫反应要求的后续时间间隔给予其它剂量,例如在1-4个月给予第二剂量,以及如果需要在数月之后给予后续剂量。需要每隔1-5年,通常3年的定期加强剂量来维持需要的保护性免疫水平。免疫时程可以继之以与ESAT6或ST-CF共培养的外周血淋巴细胞(PBL)的体外增殖测定,以及测量致敏淋巴细胞释放的IFN-γ水平。可以使用常规的标记物诸如放射性同位素、酶、荧光标记物等进行测定。这些技术为本领域技术人员所知并且可以在美国专利号3,791,932、4,174,384和3,949,064中找到,这些文献的相关部分通过引用并入本文。
模块式rAb载体和/或结合的rAb载体-(cohesion/dockerin和/或dockerin-cohesin)-抗原复合物(rAb-DC/DC-抗原疫苗)可以以一种或多种″单位剂量″提供,这取决于是否使用核酸载体,最终纯化的蛋白质,或使用的最终的疫苗形式。把单位剂量定义为包含计算以产生与该治疗组合物给药即适当的途径和治疗方式相关的期望反应的预定量的治疗组合物。给药量以及特定的途径和制剂在临床领域技术人员的范围之内。还可以评估待治疗的受试者,尤其是,受试者免疫系统的状态和需要的保护。单位剂量不需要以单一注射给药,而是可以包括经设定的一段时间内的连续输注。本发明的单位剂量可以方便地用DNA/kg(或蛋白质/Kg)体重来描述,以约0.05、0.10、0.15、0.20、0.25、0.5、1、10、50、100、1,000或更多mg/DNA或蛋白质/kg体重的范围给药。同样地,递送的rAb-DC/DC-抗原疫苗的量可以从约0.2到约8.0mg/kg体重变化。因此,在特定实施方案中,可以把0.4mg、0.5mg、0.8mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、4.0mg、5.0mg、5.5mg、6.0mg、6.5mg、7.0mg和7.5mg的疫苗递送到个体体内。给药的rAb-DC/DC-抗原疫苗的剂量在很大程度上取决于治疗的受试者的体重和身体健康状态以及给药途径和治疗频率。包括预先结合到脂质体或病毒递送载体上的裸多核苷酸的药物组合物可以按从1μg到1mg多核苷酸到1μg到100mg蛋白质的量给药。因此,特定组合物可以包括在约1μg、5μg、10μg、20μg、30μg、40μg、50μg、60μg、70μg、80μg、100μg、150μg、200μg、250μg、500μg、600μg、700μg、800μg、900μg或1,000μg之间的多核苷酸或蛋白质,该多核苷酸或蛋白质独立地与1μg、5μg、10μg、20μg、3.0μg、40μg、50μg、60μg、70μg、80μg、100μg、150μg、200μg、250μg、500μg、600μg、700μg、800μg、900μg、1mg、1.5mg、5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg或100mg载体结合。
在体外细胞系统中测试本发明,该体外细胞系统测量Flu抗原靶向的树突细胞对人Flu特异性T细胞的免疫刺激。本文显示的结果证明在该系统中单独使用无效的抗原剂量下这些抗原特异性细胞的特异性扩增。
本发明还可以用于制备模块式rAb载体,该模块式rAb载体例如是与来自蓖麻毒素、炭疽毒素和葡萄球菌B肠毒素的保护性抗原复合的重组人源化mAb(抗特异性人树突细胞受体)。该实体的潜在市场是所有军事人员的疫苗接种和储备待用给大居民点服药以应对任何与这些试剂相关的生物威胁的存储疫苗。本发明对通常用于人和动物两者的疫苗设计具有广泛的应用。感兴趣的工业包括制药和生物技术工业。
一般方法-限制性和DNA修饰酶来自于NEB。质粒和DNA片段纯化利用Qiagen产品。通过Simply Blue(Invitrogen)染色的4-12%Bis-Tris凝胶进行SDS-PAGE。层析柱和树脂来自于GE Healthcare。通过DNA测序(MCLAB)确认质粒构建体。DNA引物来自于Operon或Midland CertifiedReagent Company。通过测序仪(Gene Codes)进行序列分析。通过UV吸收(NanoDrop ND-1000)测量基于通过ProtParam工具(2005)预测所计算的消光系数的蛋白质浓度。序列在序列表SEQ ID NO.:1-39中提供,该序列表引入本文作为参考,其比对抗DCIR mAb的重链(SEQ ID NO.:1-17)和轻链的信号肽和可变区序列(SEQ ID NO.:18-39)。使用测序仪确定预测的N-末端信号肽区域,变体之间或紧密相关的序列之间的序列差异。
C-末端序列延伸到Cohesin-Flex-hMART-1-肽A-6×His蛋白质的Cohesin结构域。免疫显性肽序列肽加下划线并且结合肽的粗体残基是天然的抗原序列。C-末端His标签便于通过Ni++亲和层析法纯化。C 186 Cohesin-Flex-hMART-1-肽A-6×His:
抗原表达构建体-PCR用于扩增流感A/波多黎各/8/34/西奈山(H1N1)M1蛋白质的ORF,同时在起始密码子远端加入Nhe I位点并在终止密码子远端加入Not I位点。把消化的片段克隆入pET-28b(+)(Novagen)中,在M1 ORF框内放入His6标签,从而编码His.Flu M1蛋白。把Flu M1 ORF放入类似的载体中,该载体在Nco I位点的远端编码N-末端G蛋白前体B2结构域残基298-352(gi|124267|),继之以编码GGSGGSGGSLD(SEQ ID NO.:41)的接头残基。该载体表达具有Q246E替换的ProG.Flu M1蛋白。编码在Nco I和Nhe I位点之间插入的来自热纤梭菌(C.thermocellum)的N-末端169残基cohesin结构域的pET28b(+)衍生物表达Coh.His。为了表达Coh.FluM1.His,在上述衍生物的Nhe I和Xho I位点之间插入Flu M1 ORF。类似地制备Coh.PEP.His表达构建体,除了它们使用编码需要的序列的合成DNA之外。在大肠杆菌(E.coli)菌株BL21(DE3)(Novagen)或T7 Express(NEB)中表达蛋白质,在37℃下培养,以卡那霉素抗性(40μg/ml)选择并以200转/min振荡,直至生长到对数中期,同时添加120mg/L IPTG。3小时之后,通过离心收获细胞并存储于-80C。通过加入Sal I位点代替起始密码子并添加远端Xho I位点以用于在载体Xho I位点处的插入,在上述AP融合分泌载体中用ProG和Cohesin片段替换胞外结构域片段。通过删去胞外结构域片段制备′空′AP载体。相应地,这些构建体指导ProG.AP、Coh.AP和AP的分泌。
重组蛋白的表达和纯化-将来自各1 L发酵物的大肠杆菌细胞重悬在含有0.1 ml蛋白酶抑制剂Cocktail II(Calbiochem)的30 ml冰冷的0.1 M NaPO4(pH 7.4)(缓冲液A,用于ProG.Flu M1)或50 mM Tris、1 mMEDTA(pH8.0)(缓冲液B,用于其它所有蛋白质)中。在冰上以设置18(Fisher SonicDismembrator 60)超声处理细胞2×5 min,其中有5 min休息期,然后在4℃以17,000 r.p.m.离心(Sorvall SA-600)20 min。对于ProG.Flu M1,使上清液通过5ml在缓冲液A中平衡的Q琼脂糖,然后添加5 ml hIgG小珠到Q流过液中并在4℃混合孵育1 h。用50 ml冷的PBS洗涤小珠结合的蛋白质并用2×10ml 0.1M甘氨酸(pH 2.7)洗脱。用0.1M MES(pH 5.0)缓冲液使合并的洗脱物达到pH 5并且在1ml用50mM MES(pH 5.0)(缓冲液C)平衡的HiTrap S柱上流动。用缓冲液C广泛地洗涤柱结合的蛋白质并用在缓冲液C中的0-1M NaCl梯度洗脱。合并峰级分。对于His.Flu M1纯化,使50ml细胞溶胞产物上清液部分通过5ml Q琼脂糖小珠并把6.25ml160mM Tris、40mM咪唑、4M NaCl(pH 7.9)添加到琼脂糖流过液中。将其以4ml/min上样到5ml带有Ni++的HiTrap螯合HP柱上。用20mM NaPO4、300mM NaCl(pH 7.6)(缓冲液D)洗涤柱结合的蛋白质,随后用100mMH3COONa(pH 4.0)再次洗涤。结合的蛋白质用从100mM到1MH3COONa(pH 4.0)梯度洗脱。合并峰级分并以4ml/min上样到5ml用100mMH3COONa(pH 4.0)平衡的HiTrap S柱上,用平衡缓冲液洗涤,随后用50mMNaPO4(pH 7.5)再次洗涤。用在50mM NaPO4(pH 7.5)中的0-1M NaCl梯度洗脱结合的蛋白质。合并在大约500mM NaCl下洗脱的峰级分。His.FluM1制备物具有变量的非全长产品,推测缺失C-末端部分。对于Coh.FluM1.His纯化,如上超声处理来自2L培养物的细胞,不过在缓冲液B中。离心后,将2.5ml Triton X114添加到上清液中,在冰上孵育5min。在25℃再孵育5min后,在25℃离心之后将上清液与Triton X114分离。重复萃取,使上清液通过5ml Q琼脂糖小珠并将6.25ml 160mM Tris、40mM咪唑、4M NaCl(pH 7.9)添加到琼脂糖流过液中。然后通过如上所述的Ni++螯合层析法纯化蛋白质并用缓冲液D中的0-500mM咪唑洗脱。
嵌合小鼠/人mAb的cDNA克隆和表达-从杂交瘤细胞制备总RNA(RNeasy试剂盒,Qiagen)并使用提供的5′引物和基因特异性3′引物用于cDNA合成和PCR(SMART RACE试剂盒,BD Biosciences):mIgGκ,5′ggatggtgggaagatggatacagttggtgcagcatc3′;(SEQ ID NO.:42)mIgGλ,5′ctaggaacagtcagcacgggacaaactcttctccacagtgtgaccttc3′;(SEQ ID NO.:43)mIgG1,5′gtcactggctcagggaaatagcccttgaccaggcatc3′;(SEQ ID NO.:44)mIgG2a,5′ccaggcatcctagagtcaccgaggagccagt3′;(SEQ ID NO.:45)和mIgG2b,5′ggtgctggaggggacagtcactgagctgctcatagtgt3′.(SEQ ID NO.:46)克隆(pCR2.1TA试剂盒,Invitrogen)PCR产物并通过DNA测序鉴定。使用小鼠H和L链V区cDNA的衍生序列,用特异性引物PCR扩增信号肽和V区,同时加入侧面的限制性位点以克隆入编码下游人IgGκ或IgG4H区的表达载体。通过扩增以Xho I和Not I位点侧翼的残基401-731(gi|63101937|)并将其插入pIRES2-DsRed2(BD Biosciences)的Xho I-Not I间隙中来构建用于表达嵌合mVκ-hIgκ的载体。用PCR扩增mAb Vk区,从起始密码子开始,附加Nhe I或Spe I位点然后是CACC,到编码(例如,gi|76779294|的残基126)区域,附加Xho I位点。然后将PCR片段克隆进上述载体的NheI-Not I间隙。通过将序列5′ctagttgctggctaatggaccccaaaggctccctttcctggagaatacttctgtttctctccctggcttttgagttgtcgtacggattaattaa gggcccactcgag3′(SEQ ID NO.:47)插入上述载体的Nhe I-Xho I间隙中来构建使用mSLAM前导序列的嵌合mVκ-hIgκ载体。用PCR来扩增在预测的成熟N-末端密码子(使用SignalP 3.0服务器确定)(Bendtsen,Nielsen等2004)和mVκ区的末尾(如上所确定)之间的间隔,同时附加5′tcgtacgga3′。将用Bsi WI和Xho I消化的片段插入上述载体的相应位点中。对照hIgκ序列相应于gi|49257887|残基26-85和gi|21669402|残基67-709。对照hIgG4H载体相应于gi|19684072|的残基12-1473,其带有S229P和L236E取代,使二硫键稳定并取消残余的FcR结合(Reddy,Kinney等2000),该片段插入pIRES2-DsRed2载体BgI II和Not I位点之间,同时添加序列5′gctagctgattaattaa3′代替终止密码子。用PCR来扩增mAb VH区,从起始密码子,附加CACC然后是BgI II位点,直到编码gi|19684072|残基473的区域。然后将PCR片段克隆入上述载体的BgI II-Apa I间隙。通过将序列5′ctagttgctggctaatggaccccaaaggctccctttcctggagaatacttctgtttctctccctggcttttgagttgtcgtacggattaattaagggccc3′(SEQ ID NO.:48)插入上述载体的Nhe I-Apa I间隙来构建使用mSLAM前导序列的用于嵌合mVH-hIgG4序列的载体。用PCR来扩增预测的成熟N-末端密码子和mVκ区域的末尾之间的间隔,同时附加5′tcgtacgga3′。将用Bsi WI和Apa I消化的片段插入上述载体的相应位点中。
将以近端的Nhe I位点和远端在终止密码子之后的Not I位点侧翼的多种抗原编码序列插入H链载体的Nhe I-Pac I-Not I间隔中。由带有近端的5′gctagcgatacaacagaacctgcaacacctacaacacctgtaacaa3′(SEQ ID NO.:49)序列(Nhe I位点后面是编码cipA cohesin-cohesin接头残基的序列)和远端的5′caccatcaccatcaccattgagcggccgc3′(SEQ ID NO.:50)序列(编码His6、终止密码子和Not I位点)的甲型流感病毒(A/波多黎各/8/34(H1N1))血球凝集素gi|216931681残基82-1025(带有C982T替换)编码Flu HA1-1。以与FluHA1-1相同的序列结合的gi|50296052|甲型流感病毒(A/越南/1203/2004(H5N1))血球凝集素残基49-990编码Flu HA5-1。由带有近端的Nhe I和远端的Not I位点的gi|40671|celD残基1923-2150编码Doc。由带有近端的序列5′gctagcgatacaacagaacctgcaacacctacaacacctgtaacaacaccgacaacaacacttctagcgc3′(SEQ ID NO.:51)(Nhe I位点和cipA间隔区)和远端的Not I位点的gi|34784812|前列腺特异性抗原残基101-832编码PSA。由5′gctagccccattctgagccccctgaccaaaggcattctgggctttgtgtttaccctgaccgtgcccagcgaacgcaagggtatacttggattcgttttcacacttacttaagcggccgc3′(SEQ ID NO.:52)编码FluM1-PEP。通过带有适合克隆进Nhe I和Not I限制性H链载体或Nhe I-Xho I限制性Coh.His载体的末端的互补合成DNA片段混合物产生这个和所有其它肽编码序列。始终使用优选的人密码子,除其中需要加入限制性位点或在CipA间隔区序列中之外。
使用L-链和H链构建体各~2.5μg和上述操作流程在5ml瞬时转染物中测试rAb表达构建体的生产水平。通过抗hIgG ELISA(AffmiPure山羊抗人IgG(H+L),Jackson ImmunoResearch)分析上清液。该操作流程的测试中,对于~2倍范围的各DNA浓度(即,该系统是DNA饱和的),分泌的rAb的产生与H链和L链载体浓度无关。
CD34-DC的产生-从正常的健康供给者的外周血动员-CD34+HPC并收集,该供给者皮下接受10U/kg/天的重组G-CSF(Neupogen)5天。用CEPRATE SC干细胞浓缩系统(ISOLEX)获得CD34+-HPC。通过在补充有5%自体血清、50μM2-β-巯基乙醇、1%L-谷氨酰胺、1%青霉素/链霉素和细胞因子;GM-CSF(50ng/ml;Immunex Corp.)、FLT3-L(100ng/ml;R&D)和TNF-α(10ng/ml;R&D)的Yssel′s培养基(Irvine Scientific,CA)中以0.5×106/ml的密度培养产生CD34-DC。在培养的第5天将细胞转入补充有细胞因子的新鲜培养基中,在第9天收获细胞。
CD34-DC的分选-收获培养的第9天的CD34衍生的DC并用抗CD1aFITC(Biosource International)和抗CD 14PE(BD Biosciences)染色。用FACS Vantage(BD Biosciences)分选CD1a+CD14--LC和CD1a-CD14+-intDC。纯度常规为95-99%。
自体CD8+T细胞的纯化-从获自相同供给者的PBMC通过用CD14、CD19、CD16、CD56和CD4小珠排除后使用CD8磁珠(Miltenyi)来阳性地挑选自体CD8+T细胞。在一些实验中,记忆CD8+T细胞分选作CD8+CCR7-CD45RA-。
Flu M1蛋白通过CD34-DC亚型交叉呈递给CD8+T细胞-来自HLA-A2供给者的散堆(bulk)或分选的CD34+DC亚型,CD1a+LC或CD14+IntDC(5×104细胞/ml)与纯化的自体CD8+T细胞(1×106细胞/ml)一起在Yssel′s培养基中培养,该培养基补充有10%热灭活的合并的AB人血清、10U/mlIL-7(R&D)和减少剂量的与抗DC抗体交联的Flu M1。24h后在培养物中添加CD40L,3天后添加IL-2。8或10天后,通过使用特异性Flu M1、HLA-A201/pMI、藻红蛋白结合的iTAg MHC四聚体(Beckman Coulter)分析抗原特异性CD8+T细胞的增殖水平来评价交叉呈递效率。
抗人DCIR单克隆抗体的开发-生产受体胞外结构域.hIgG(人IgG1Fc)和HRP(辣根过氧化物酶)融合蛋白以分别用于小鼠免疫和mAb筛选。表达hDCIR胞外结构域.IgG的构建体以前已经描述(Bates,Fournier等1999),并使用小鼠SLAM(mSLAM)信号肽指导分泌(Bendtsen,Nielsen等2004)。使用PCR扩增AP残基133-1581(gb|BC009647|)同时添加近端框内的XhoI位点和远端的TGA终止密码子与Not I位点来产生hDCIR胞外结构域.AP表达载体。该Xho I-Not I片段替换上述hDCIR胞外结构域.IgG载体中的IgG编码序列。通过克隆如上定义的DCIR胞外结构域-编码区远端的gi|208493|残基14-940产生DCIR.HRP融合蛋白载体。
哺乳动物细胞分泌的重组蛋白的表达和纯化-根据厂商的操作流程(1mg总质粒DNA与1.3ml 293Fectin试剂/L转染)使用FreeStyleTM293表达系统(Invitrogen)生产融合蛋白。对于重组抗体(rAb)生产,共转染等量的编码H和L链的载体。培养转染的细胞3天,收获培养物上清液并添加新鲜的培养基,继续培养2天。通过过滤使合并的上清液澄清。通过HiTrapA蛋白亲和层析法以0.1M甘氨酸pH 2.7洗脱然后对PBS透析来纯化受体胞外结构域.hIgG。通过使用HiTrap MabSelectTM柱类似地纯化rAb。
单克隆抗体的产生-通过常规的细胞融合技术产生小鼠mAb。简要地,用20μg受体胞外结构域.hIgGFc融合蛋白与Ribi佐剂腹膜内免疫6周大的BALB/c小鼠,然后以20μg抗原10天和15天后加强。3个月后,在取出脾之前3天再次加强免疫小鼠。或者,在30-40天的周期内用在Ribi佐剂中的1-10μg抗原每3-4天注射小鼠足垫中一次。最后的加强后3-4天,收获引流的淋巴结。使用常规技术将来自脾或淋巴结细胞的B细胞与SP2/O-Ag 14细胞(Shulman,Wilde等1978)融合。对照单独的融合伴侣,或对照融合到AP的受体胞外结构域(Bates,Fournier等1999),用ELISA来筛选受体胞外结构域融合蛋白杂交瘤上清液。然后使用编码全长受体cDNA的表达质粒瞬时转染的293F细胞在FACS中筛选阳性孔。
对于抗DCIR mAb的开发,来自1000个杂交瘤克隆的上清液筛选:
90个在DCIR.Ig对Ig ELISA上是+
64个在通过FACS的DCIR-293细胞上是+
62个FACS+是ELISA+
2个是293+(并且由此对DCIR不是特异的)
刺激人DC细胞因子产生的抗DCIR mAb的生物筛选-对于DC靶向目的,可能期望具有递送抗原至DC的抗体并伴随地活化DC以刺激针对递送的抗原产生免疫反应。因此,我们对直接用于DC刺激活性的62个FACS阳性的抗DCIR杂交瘤上清液组进行筛选。CD34+衍生的人DC与杂交瘤上清液一起培养24小时并且24小时后测定DC培养物上清液中趋化因子MCP-1的存在。下面的图显示,与对照相比,许多但不是所有杂交瘤上清液引起MCP-1的特异性产生。
单细胞克隆上图中以星号标记的选择的杂交瘤(大多数,但是所有刺激MCP-1产生)并且在CELLine烧瓶(Intergra)中扩增。将杂交瘤上清液与相等体积的1.5M甘氨酸、3M NaCl、1×PBS(pH 7.8)混合并且与MabSelect树脂一起翻转。用结合缓冲液洗涤树脂并用0.1M甘氨酸(pH 2.7)洗脱。在用2M Tris中和之后,对PBS透析mAb。
纯的抗DCIR mAb的表征-首先通过ELISA(DCIR.Ig与板结合,用HRP结合的抗人Fc试剂显影)和通过DCIR.HRP捕获测定(mAb与板结合,用DCIR.HRP融合蛋白显影)测试纯的mAb。图2显示典型的测定结果,其显示mAb与结合板的DCIR的高亲合力相互作用(表明结合特异性的对照没有显示)。在DCIR.HRP捕获测定中,一些(但不是所有)mAb能够捕获可溶的DCIR.HRP至板表面。这些数据显示选择的抗DCIR mAb组具有大范围的DCIR结合亲合力和性质。
还对纯的mAb测试FACS反应性,首先测试针对用编码全长DCIR的表达质粒瞬时转染的293细胞的FACS反应性,然后测试针对多种类型的培养的和离体的人DC的FACS反应性。下图显示在FACS分析中对DCIR 293细胞滴定的一组典型的mAb(对照细胞是阴性)。
图3显示CD14+和CD1a+亚型的CD34衍生的人DC表达细胞表面DCIR。这两种DC亚型在指导体液对溶细胞性免疫反应中具有完全不同的角色-因此DCIR在两亚型上均存在表明通过DCIR靶向人DC的抗原应该引起两种类型的免疫性-直接针对例如病毒感染的疫苗的重要特征。
图4显示DCIR还在从人皮肤直接分离的3种人DC亚型上表达。该观察显示对于DCIR抗原靶向疫苗,给药进皮肤应该是有益的,因为这些DC类型都表达该受体。已知,关于它们的免疫指导性质,这些DC类型类似于以上培养的人DC,因此靶向抗原通过带有DCIR的皮肤DC对于引起期望的混合免疫反应应该是有益的。
从正常人皮肤样品纯化真皮DC和LC。于4℃在细菌蛋白酶分散酶2型中孵育样品18h,然后于37℃2h。然后将表皮和真皮层分开,切成小块(~1-10mm)并放入补充有10%胎牛血清(FBS)的RPMI 1640中。2天后,收集迁移进培养基中的细胞并使用聚蔗糖(Ficoll)-泛影葡胺(diatrizoate)梯度(1.077g/dl)进一步富集。用抗CD1a FITC和抗CD14APC mAb染色后通过细胞分选纯化DC。
DCIR在其它人组织中的存在。图5显示在人扁桃腺内围绕一个生发中心的一群细胞的DCIR特异性染色。这些细胞可能是常住的DC或者例如装载外来抗原并活化后最近迁移到该位点的DC。染色显示通过除皮肤以外的允许通向产生免疫性的器官的途径的DCIR靶向疫苗的给予对于引起免疫反应应该也是有益的。
使用抗DCIR mAb靶向抗原至人DC。根据厂商的操作流程使用磺基琥珀酰亚胺基6-[3′(2-吡啶基二硫)-丙酰胺基]己酸(sulfo-LC-SPDP;Pierce)将Flu M1蛋白化学交联至mAb。该多步操作流程包括在室温下通过经SPDP的NHS酯基修饰其胺活化mAb 30min,随后进行对PBS的透析。随后,添加含有两个游离的巯基的流感M1蛋白并在室温下孵育过夜。通过将与mAb反应前Flu M1蛋白的量与交联后的mAb/Flu M1比值相比较评价交联反应的效率。我们计算,平均50%的mAb与一个Flu M1分子起反应。图6和7显示交叉的Flu M1蛋白和DCIR mAb的实例。经还原SDS-PAGE的分析基于染色的Flu M1/H链的比例鉴定产物每个mAb有1-2个Flu M1,并且这些制备物用于体外研究。非还原SDS-PAGE分析(下面的第二张图)显示复合物主要在Flu M1和单一mAb之间,这由低百分数的非常大的复合物所证实。
图6显示Coh.Flu M1与抗DCIR_2C9mAb的交联。通过G蛋白琼脂糖亲合性纯化的交联产物的还原SDS-PAGE分析。从左至右是2.5μg、1μgCoh.Flu M1,Coh.Flu M1与mAb以1∶1、2∶1、4∶1的比例反应的10μg产物。
图7显示His.Flu M1与mAb的交联。通过G蛋白琼脂糖亲合性纯化的交联产物的非还原SDS-PAGE分析。从左至右是5μgHis.Flu M1,接着是成对的5μg mAb(抗CD1a_OKT6、抗LANG_2G3、抗DCIR_2C9)和5μg与5μg His.Flu M1反应的mAb。
与Flu M1蛋白交联的抗DC受体mAb有效地靶向抗原至人DC-将抗DC受体mAb化学交联至Flu M1蛋白,并且将多种剂量添加到人CD34衍生的CD1a+DC与自体CD8+T细胞的共培养物中。24h后将CD40L添加至该培养物中用于DC活化,随后在第3天添加IL-2用于T细胞增殖。8-10天后,通过MHC四聚体分析来评价对Flu M1肽GILGFVFTL(SEQ ID NO.:53)特异性的T细胞。图8显示交联至抗DCIR mAb的Flu M1引起Flu M1特异性细胞的增殖,同时对于类似剂量的非交联Flu M1和mAb观察到显著更少的Flu M1特异性细胞的增殖。剂量范围显示交联的mAb比游离的FluM1至少50倍更有效地引起反应。该数据证明抗原靶向,即免疫反应的增强-在这种情况下具有特定的Flu M1表位的记忆的T细胞回忆。将CD34-DC分选为CD1a+LC或CD14+IntDC亚型。图9显示抗DCIR靶向的CD1a+LC在指导Flu M1特异性CD8+细胞的扩增上远更有效,尽管在全部两种细胞类型上具有类似的DCIR表达水平。
图8显示与抗DCIR mAb交联的Flu M1比没有与mAb连接的Flu M1蛋白更有效地诱导Flu M1特异性CD8+T细胞的扩增。将CD34衍生的CD1a+DC与CD8+T细胞和标明浓度的交联至His.Flu M1的抗DCIR_2C9mAb或与未连接的mAb一起孵育。然后对CD8+T细胞分析Flu M1特异性扩增。内部的方框标明四聚体特异性CD8+T细胞的百分数。
图9显示与抗DCIR mAb交联的Flu M1通过LC比Int-DC更有效地诱导Flu M1特异性CD9+T细胞的扩增。将来自HLA-A2供给者的LC或Int-DC和自体CD8+T细胞与标明浓度的与His.Flu M1交联的抗DCIR_2C9mAb共培养。通过Flu M1特异性CD8+T细胞的频率评价交叉呈递效率,用HLA-A201/pMI四聚体分析。内部的方框标明四聚体特异性CD8+T细胞的百分数。
开发重组抗DCIR mAb(rAb)作为原型抗原靶向疫苗。开发载体用于在瞬时转染的哺乳动物细胞中分泌的抗DC受体rAb的表达,该抗DC受体rAb是小鼠杂交瘤编码的H和L链可变(V)区以及人Igκ或人IgG4H恒定(C)区的嵌合体。将具有不同特异性的抗DC受体mAb(即来自不同的抗DCIR杂交瘤)的L和H链的可变区进行cDNA克隆,通过DNA序列分析表征,并工程化入这些载体中。图10显示编码嵌合小鼠-人rAb(相当于共转染入293细胞的许多不同的抗DCIR mAb)的H+L链载体以及通过抗人FC ELISA测定分泌入培养物上清液的rAb。
抗DCIR rAb编码~9.5kDA的dockerin结构域,在框内带有rAb H链。dockerin结构域(称为rAb.Doc)的目的是允许特异性[rAb.Doc:Coh.抗原]复合物的装配。在这种情况下,Coh.抗原指的是在~17.5kDa cohesin结构域和抗原之间的融合蛋白。用在cohesin和dockerin之间的高亲合力相互作用来装配确定的复合物,我们已经证明该复合物递送抗原至具有受体特异性的DC的表面。例如,下图显示与人DC表面结合的[抗DCIR.Doc:Coh.Flu M1]复合物(这里Coh.Flu M1是生物素酰化的并且洗涤步骤后在细胞表面上检测)。对照rAb.Doc:Coh.Flu M1复合物(在下图中用红色显示)不比单独的检测链霉抗抗生物素-PE试剂结合的多。
DCIR慢动力学地使抗原内在化,这使它不同于其它DC受体。DC受体诸如DC-SIGN具有快速的内在化动力学特性。例如,图11显示抗DC-SIGN/L.Doc使Alexa标记的Coh.Flu M1快速内在化进入GM-CSF/IFN培养的人DC中-在15min之内大部分标记进入细胞内部。相反,抗DCIR.Doc非常缓慢地使Coh.Flu M1内在化-在3小时时内部抗原和细胞表面抗原两者都有显著的数量。该结果鉴别DCIR为慢内在化DC受体,这与Bates等的结论相反,Bates等提示″在交联之后,与MMR观察到的快速动力学相反(数据未显示),DCIR仅仅在单核细胞和CD34衍生的DC中缓慢地和微弱地内在化。该发现表明通过受体介导的胞吞作用捕获Ag不是DCIR的主要功能″。
图11显示与抗DCIR.Doc rAb连接的Coh.Flu M1特异性与GM/IL-15人DC结合。将单核细胞衍生的GM-CSF/IL-15培养的人DC跟与4倍摩尔过量的生物素酰化Coh.Flu M1预混合1小时的指明浓度的抗DCIR.Doc rAb一起孵育。1小时后,洗涤细胞并与链霉抗生物素-PE一起孵育。再次洗涤后,通过FACS分析细胞以检测细胞结合的PE。绿色曲线是抗DCIR.Doc rAb,红色曲线是对照IgG4.Doc复合物。
图12显示与抗DC-SIGN/L.Doc或抗DCIR.Doc rAb连接的Coh.Flu M1结合GM-CSF/IL-4人DC并内在化入GM-CSF/IL-4人DC中。将单核细胞衍生的GM-CSF/IL-4培养的人DC跟与4倍摩尔过量的Alexa标记的Coh.FluM1预混合1小时的抗DCIR.Doc或抗DC-SIGN/L.Doc rAb一起孵育。在冰上1小时后,洗涤细胞并置于37℃。用共聚焦显微镜来分析细胞结合的抗原的细胞定位(用红色显示)。绿色标记细胞膜结合的肌动蛋白。
使Coh.Flu M1经DCIR.Doc靶向人DC鉴定DCIR为用于疫苗开发目的优异受体。将Flu M1抗原经慢内在化DCIR受体靶向人DC与经快内在化ASGPR和LOX-1受体靶向相比。监控的免疫反应是Flu M1特异性CD8+T细胞的扩增。结果显示通过DCIR的靶向比经LOX-1或ASGPR显著地更有效。在一个类似的实验中,当与CD8+T细胞一起培养之前洗涤DC不含残余的[rAb.Doc:Coh.抗原]时,经DCIR的靶向的优异性甚至更明显。该情况可能更接近体内情况,其中靶向的DC可以离开残余的给予抗原以在引流淋巴结中遇到T细胞。
图13显示抗DCIR.Doc:Coh.Flu复合物比其它[抗DC受体rAb.Doc:Coh.Flu M1]复合物更有效地扩增Flu M1特异性CD8+T细胞。CD34衍生的CD1a+DC与CD8+T细胞和8nM(顶组)或0.8nM(下组)各与Coh.Flu M1复合的[抗DCIR_2C9.Doc:Coh.Flu M1]、抗LOX115C4.Doc、抗ASGPR_49C11.Doc或IgG4.Doc对照rAb共培养。然后对于CD8+T细胞分析Flu M1特异性扩增。内部的方框表示四聚体特异性CD8+T细胞的百分数。
图14显示给予1天的抗DCIR.Doc:Coh.Flu复合物比其它[抗DC受体rAb.Doc:Coh.Flu M1]复合物更有效地扩增Flu M1特异性CD8+T细胞。除了在添加自体CD8+T细胞之前1天洗涤DC之外,研究条件与上图一样。一些抗DCIR可变区对融合在rAb H链C末端的重要抗原的分泌是特别有利的。
图15显示以与rAb H链的C末端融合的融合物表达的多种抗原对rAb.抗原的分泌有固有的影响。这里在具有两个不同的小鼠可变区特异性的嵌合hIgG4rAb上工程化相同的抗原编码区。将这些表达构建体与适当的L链小鼠V区-hIgk构建体共转染入293F细胞中并在3天后评价rAb的分泌。一些rAb抗原表达良好,其它的(包括Flu HA5-1)非常贫乏。预期每种抗原具有在rAb情况下影响分泌的固有生化特性。实际上,在测试的两种V区特异性的情况下,对表达有引人注目的平行效应。
Flu HA5是在针对禽流感的疫苗开发中重要考虑的抗原。图16显示出乎意料的发现,即不同的抗DCIR V区(来源于不同的抗DCIR mAb)大大影响需要的抗DCIR.Flu HA5疫苗的分泌。在下面显示的实施例中,当与其它DCIR V区相比时,DCIR_25A4对于这种类型的疫苗的分泌是特别有利的。
图16显示抗DCIR.Flu HA5rAb取决于可变区的性质以不同效率分泌。将编码经H链C末端与Doc(蓝色圆形)或HA5-1(红色三角形)融合的嵌合小鼠V区和人C区的H和L链表达质粒共转染入293细胞中并且在3天以后对于上清液的稀释物通过ELISA测定IgGFc。除了DCIR_2C9,rAb.Doc通常表达良好。然而,rAb.HA5-1的表达变化很大。
抗DCIR 25A4V区偏爱rAb.HA5-1的分泌的独特性质例示了权利要求5的应用。其是基于发明人关于特定V区可以影响rAb.抗原分泌的发明。这意味着在rAb融合蛋白的情况下特定抗原固有的贫乏分泌可以通过筛选对于分泌有利的具有需要的结合特异性的不同V区来克服。断定这对于任何分泌的rAb.融合蛋白作为一条新的一般原理。
抗DCIR增强HIV特异性CD8+T细胞的启动。图17显示抗DCIR mAb对树突细胞具有特别的作用,即增强启动-肽的摄取及它在表面MHC上呈递到对该肽抗原特异的T细胞上。该实施例显示用抗DCIR mAb与CD40L一起刺激DC产生大大增加数量的对添加到DC培养物中的免疫显性HIVgag肽特异的CD8+T细胞,CD40L是一种已知的通常通过同源T细胞递送的DC活化信号。这个性质对于成功的经抗DC受体rAb疫苗靶向的抗原是高度预言性的并且表明抗DCIR抗原疫苗是优异的。
图17显示抗DCIR mAb增强HIV抗原特异性CD8+细胞的启动。用自体IFN-DC(1×105个细胞/孔)以及HLA-A201限制性HIV肽pol(pol476-484ILKEPVHGV(SEQ ID NO.:54)、pol293-302KYTAFTIPSI(SEQ ID NO.:55))和gag(gag77-85,SLYNTVATL(SEQ ID NO.:56)、gag151-159,TLNAWVKVV(SEQ ID NO.:57))(5μM)刺激纯化的总CD8+T细胞(2×106个细胞/孔)。在24孔板中培养细胞9天,该24孔板在4c用5ug/孔于PBS(pH 9.6)中稀释的抗DCIR mAb或对照单克隆抗体预涂敷过夜并广泛地洗涤。在补充有10%人AB血清、10U/ml IL-7(R&D)和100ng/ml CD40L(R&D)的Yssel′s培养基中培养细胞。在第3天添加10U/mlIL-2。通过在培养期末计算结合肽/HLA-A201四聚体(Beckman Coulter)的细胞数目确定肽特异性CD8+T细胞的扩增。
抗DCIR mAb增强交叉启动。图18显示抗DCIR mAb对树突细胞具有特别的作用,即增强交叉启动-蛋白质的摄取以及它的正确加工和在表面MHC上的呈递,其通过对该抗原衍生的肽特异的T细胞的扩增来测定。该实施例显示用抗DCIR mAb与CD40L一起刺激DC产生大大增加数量的对来自添加到DC培养物中的Cohesin-MART-1融合蛋白的免疫显性MART-1表位特异的CD8+T细胞,CD40L是一种已知的通常通过同源T细胞递送的DC活化信号。这个性质对于经抗DC受体rAb疫苗靶向的抗原是高度期望的并且表明抗DCIR抗原疫苗是优异的。
图18显示抗DCIR mAb增强HIV抗原特异性CD8+细胞的启动。除了coh.MART-1肽融合蛋白替换肽外,上图方法与前面的图一样。
预期,在本申请中所讨论的任何实施方案可用本发明的任何方法、试剂盒、试剂或组合物实施,反之亦然。此外,本发明的组合物可用于实现本发明的方法。
图19显示在人上皮层中DCIR分布的免疫组织化学分析。绿色显示DR-FITC染色而红色显示PAB269(DCIR)-568。右上方图片显示重合的图像。蓝色染色是针对细胞核的DAPI。数字图像@40×。该细胞形态学和DR染色是表皮郎格罕氏细胞的特征-因此,该分析显示在郎格罕氏细胞上的DCIR表达-指出DCIR用于摄取施加到例如划破的皮肤上的抗DCIR.抗体结合物的应用。因此,这些数据表明郎格罕氏细胞摄取与经佐剂的DC活化相关的抗原可能产生有效的针对靶向的抗原的细胞反应。
图20A-20D显示DCIR抗原的单克隆抗体对DCIR的特异性亲合力。
DCIR抗原的固定:通过伯胺(50ug.mL-1,在10mM乙酸钠,pH 5.5中)将DCIR抗原固定到AKT_iv共价传感器表面上。使用EDC和NHS的混合物活化羧化物表面并将DCIR与所有四个通道偶联。最后,使用专利阻断剂使全部剩余的羧化物基团失活。
四种抗DCIR抗体在HBS中的亲合力的测定:为确定四种抗DCIR抗体的亲合力,从10到0.3125μgmL-1制备每种抗体的稀释物系列并且在固定的DCIR抗原上平行注射180s。在样品注射之间使用100mM盐酸的两次60s注射再生表面。在Akubio声学生物传感器上进行生物传感器测量。
表1.由四种单克隆抗体与固定的DCIR抗原的相互作用计算的动力学参数。
抗体 | ka(M-1s-1x105 | kd(s-1x10-4) | KD(pM) |
杂交瘤抗DCIR24A5.4A5 | 2.07 | 1.15 | 560 |
rAb抗DCIR24A5.4A5.DocVarlC377 | 2.38 | 3.26 | 1370 |
杂交瘤抗DCIR29E9.2E2 | 5.56 | 4.70 | 850 |
rAb抗DCIR29E9.2E2.DocVaurlC409 | 1.50 | 2.90 | 1940 |
表1显示两种优选的抗DCIR单克隆抗体24A5和9E8的高亲合力DCIR胞外结构域结合性质,并证明当嫁接到人IgG4主体上时衍生的小鼠可变区基本上保留高亲合力结合性质。考虑与人DCIR相结合的应用,该数据支持对这些可变区的序列[以及它们的′人源化′衍生物]的特定权利要求。
抗DCIR mAb与恒河猴DCIR的交叉反应性。为测试抗人DCIR mAb与恒河猴DCIR的交叉反应性,用设置入哺乳动物表达载体中的恒河猴DCIRcDNA转染233F细胞。对于抗人DCIR抗体组通过FACS测试与猴DCIR的结合,与未转染的293F细胞以及用相同的指导人DCIR表达的载体转染的293F细胞相比。人和猴DCIR序列之间的比较显示如下。那些显示在人和猴DCIR之间具有交叉反应性的抗体是特别优选的,因为当设置例如作为重组人源化抗DCIR.抗原疫苗,作为治疗剂时,NHP毒性研究也可以解决基于机制的问题[即,这些测试也可以解决相对于毒性而言的效力]。
人对猴DCIR。基本的序列显示人,在猴DCIR中看到的替换显示于人序列下面。推定的跨膜区用下划线强调。非保守替换用粗体强调显示。
MTSEITYAEVRFKNEFKSSGINTASSAASKERTAPHKSNTGFPKLLCASLLIFFLLLAISF FIAFVIFFQKYSQLLEKKT(SEQ ID NO.:58)
TKELVHTTLECVKKNMPVEETAWSCCPKNWKSFSSNCYFISTESASWQDSEKDCARMEAHLLVINTQEEQDFIFQNLQEE(SEQ ID NO.:60)
SAYFVGLSDPEGQRHWQWVDQTPYNESSTFWHPREPSDPNERCWLNFRKSPKRWGWNDVNCLGPQRSVCEMMKIHL(SEQ ID NO.:62)
图21显示抗DCIR mAb与恒河猴DCIR的交叉反应性。一个样品FACS分析显示在下面。绿色曲线显示对照IgG4.gag重组蛋白的背景结合。红色曲线是通过抗DCIR.gag蛋白的结合[二抗是PE标记的抗人IgGFc]。结果显示在用人DCIR表达质粒转染的293F细胞上的9E8和24A5mAb具有相当的结合-在用猴DCIR表达质粒转染的293F细胞上9E8结合而不是24A5结合。在一个类似的分析中,mAb 9E8、29G10、31A6、3C2与猴DCIR结合良好,但是mAb 24A5、6C8、24E7、5F9、29E9不结合。
图22是显示DCIR胞外结构域与特定聚糖结构的结合的图表。DCIR胞外结构域作为从293F细胞分泌的hIgGFc融合蛋白表达并通过A蛋白亲和层析法纯化。对于蛋白质使用3.0版的来自Consortium for FunctionalGlycomics的印刷阵列测试特定聚糖的结合-该阵列由320个聚糖(或糖形)6次重复组成。下面显示的Excel棋盘式对照表在栏A-F中分别代表聚糖数目、结构或名称、6次重复的平均RFU值、标准差、平均值的标准误(用于上面的图表中的误差棒,其代表全部数据集)和%CV。栏C-Y包括聚糖数目对平均RFU的图表,栏Z-AE是来自通过RFU(高到低)分类以提供具有最高强度结合的聚糖列表的A-F的数据。除去每组6次重复的最高和最低点,因此平均值是4个值而不是6个值的平均值。这除去一些包括单个很高点的假命中。因此,具有高%CV的点应该被认为是可疑的。使用以藻红蛋白标记的抗人IgG-Fc的检测完成分析。使用含2mM Ca和Mg、1%BSA和O.05%Tween 20的Tris-盐水结合缓冲液在PBS中稀释DCIR.IgFc至200μg/ml。
与Functional Glycomics Consortium合作严生该数据。Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-3(Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-6)Manβ1-4GlcNAcβ1-4GlcNAcβ-Spl2是最紧密结合DCIR胞外结构域的聚糖。测试的其它hIgGFc融合蛋白不显示对该聚糖的偏爱,该聚糖是在一些人血清蛋白上发现的很复杂的碳水化合物。
因此,用聚糖143或从一组相关结构中筛选的较高亲合力的衍生物装饰的抗原应该磨练抗原到DCIR并作为DC靶向疫苗或其它DCIR靶向活性剂的抗DCIR元件的代用品。在疫苗制造和存储中这可以具有成本效益。
表2.
***聚糖#143是Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-3(Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-6)Manβ1-4GlcNAcβ1-4GlcNAcβ-Spl2。
图23A到23C显示DCIR是对于所有血液DC亚型普遍的标靶。在血液中鉴定了两种DC亚型:CD11c+mDC和BDCA2+pDC。DCIR是在两种DC亚型上都发现的稀有凝集素型受体之一。从细胞分离术纯化mDC和pDC,并且将各DC亚型与自体纯化的CD8T细胞和减少浓度的Flu-MP的四种重组形式一起培养,所述Flu-MP的四种重组形式为Flu-MP、与IgG4融合的Flu-MP以及与两种不同的重组抗DCIR抗体:24A5和9E8融合的Flu-MP。
显示于下面图23A中的结果表明两种重组DCIR-Flu-MP融合蛋白都能够使Flu-MP有效靶向mDC,因为这两种蛋白能够在低至80pM的浓度下诱导1.78%至2.18%的四聚体阳性细胞,在80pM的浓度下Flu-MP本身和IgG4-Flu-MP不能诱导抗原特异性T细胞的扩增。pDC也能在8nM下交叉呈递重组Flu-MP的四种形式。在0.8nM和80pM下,两种DCIR-Flu-MP构建体被交叉呈递而两种其它Flu-MP构建体未被(下面的图B)。
总之,这些数据表明DCIR有效靶向蛋白质用于通过两种血液mDC和pDC的交叉呈递。在人中LC和IntDC能够优先地、分别地启动细胞免疫和体液免疫。靶向抗原至pan-DC分子如DCIR可能通过靶向多种DC亚型诱导广泛的体液和细胞免疫反应。这与亚型特异性抗原递送载体诸如抗Langerin相反。
图23A显示用各8nM、0.8nM或80pM的aDCIR-Flu-MP(a#24A5和b#9E8)、IgG4-Flu-MP或Flu-MP靶向来自HLA-A2供给者的血液衍生的mDC,用CD40L使其成熟并与自体CD8+T细胞共培养。10d之后,通过特异性HLA-A2-M1四聚体染色[纵轴]评估T细胞扩增。
图23B显示用各8nM、0.8nM或80pM的aDCIR-Flu-MP(a#24A5和b#9E8)、IgG4:Flu-MP或Flu-MP靶向来自HLA-A2供给者的血液衍生的pDC,用CD40L使其成熟并与自体CD8+T细胞共培养。10d之后,通过特异性HLA-A2-M1四聚体染色[纵轴]评估T细胞扩增。
图23C显示DCIR允许蛋白质通过LC和真皮CD14+DC的交叉呈递。用各8nM的抗DCIR:Flu-MP、抗Langerin:Flu-MP或IgG4:Flu-MP靶向来自HLA-A2供给者的皮肤衍生的DC,用CD40L使其成熟并与自体CD8+T细胞共培养。10d之后,通过特异性HLA-A2-M1四聚体染色[纵轴]评估T细胞扩增。
图24显示证实用DCIR-FluM1疫苗接种允许产生FluM1特异的记忆CD8+T细胞免疫性的结果。用来自HLA-A*0201+健康供给者的3×106CD34+HPC移植亚致死量照射的NOD/SCID β2m-/-免疫缺陷小鼠,并在移植后4-8星期通过20×106自体T细胞的过继转移重建。小鼠用5倍剂量的人重组FLT3配体(FLT3-L)预处理10天以动员DC。于两个时间点即第1天和第7天经两个部位:i.p.和i.v.以50mcg/小鼠聚IC作为佐剂递送总共30mcgDCIR-FluM1疫苗。通过用基质蛋白1:FluM158-66(GILGFVFTL)(SEQ IDNO.:64)肽负载的四聚体染色血液和组织来评价流感特异性免疫应答的诱导。如图1所示,4/5的用DCIR-FluM1接种的小鼠证明,在疫苗接种后第11天,结合FluM1四聚体的循环人CD8+T细胞:0.63%、0.34%、0.21%和0.62%。用负载HIV gag肽的对照四聚体染色几乎是阴性的。在独立的小鼠组中确认了这些初步结果并且在总共9/12接种的小鼠中观察到高亲合力FluM1四聚体结合的CD8+T细胞的扩增。这些结果证明用DCIR-FluM1疫苗接种允许产生FluM1特异的记忆CD8+T细胞免疫性。
应理解,本文描述的特定实施方案以例证的方式显示而不作为本发明的限制。不背离本发明的范围的前提下,可以在多种实施方案中使用本发明的基本特征。本领域技术人员将识别或仅使用常规实验能够确定本文描述的特定操作的许多等价物。这样的等价物被认为是在本发明的范围之内并被权利要求书所覆盖。
在说明书中提到的所有出版物和专利申请指示了本发明所属领域技术人员的技能水平。所有出版物和专利申请均引入本文作为参考,其程度如同各单个出版物或专利申请特别且单独地指出引入本文作为参考一样。
词语″一″当和术语″包括″、“包含”、“含有”在权利要求书和/或说明书中一起使用时可以表示″一个(种)″,但是也与″一个(种)或多个(种)″、″至少一个(种)″和″一个(种)或一个(种)以上″的意思一致。在权利要求书中术语″或″的使用用于表示″和/或″,除非尽管公开的内容支持指代唯一的替换物以及″和/或″的定义,但是权利要求书中明确指出指的是唯一的替换物或替换物是相互排斥的。贯穿本申请,术语″大约″用于表示数值包括装置、使用来测定该值的方法的固有误差变异,或存在于研究受试者之中的变化。
如本说明书和权利要求书中所用,词语″包括″(及其任何形式)、″具有″(及其任何形式)、″包含″(及其任何形式)或″含有″(及其任何形式)是包含的或开放的并且不排除另外的、未列举的元件或方法步骤。
本文使用的术语″或其组合″指在该术语之前列举的项目的所有排列与组合。例如,″A、B、C或其组合″意指包含A、B、C、AB、AC、BC或ABC至少一个,以及如果在特定的情况下顺序是重要的,还包含BA、CA、CB、CBA、BCA、ACB、BAC或CAB。继续这个例子,明确包括的是包含一个或多个项目或术语的重复的组合,诸如BB、AAA、MB、BBC、AAABCCCC、CBBAAA、CABABB等等。熟练的技术人员可以理解在任何组合中通常没有对项目或术语数目的限制,除非从上下文中是显然的。
按照本申请公开的内容而不需要过度的实验,能够制备及实施本文公开及请求保护的所有组合物和/或方法。虽然本发明的组合物和方法已经就优选的实施方案进行了描述,但是本领域技术人员清楚,在不背离本发明的构思、精神及范围的前提下,可以将变化应用于本文所描述的组合物和/或方法以及本文所描述的方法的步骤中或步骤的序列中。所有这样的对本领域技术人员而言显而易见的类似替代和修改被认为在所附的权利要求书所定义的本发明的精神、范围及构思的范围之内。
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Trumpfheller,C.,J.S.Finke,et al.(2006).″Intensified and protective CD4+Tcell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine.″J Exp Med 203(3):607-17.
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序列表
<110>贝勒研究院
G·祖拉夫斯基
J·F·班彻罗
<120>基于靶向抗原至抗原呈递细胞上表达的DCIR的疫苗
<130>BHCS:2096
<150>US 60/888,032
<151>2007-02-02
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Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Thr Gly Tyr Thr Phe
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Glu Trp Ile Gly Glu Ile Leu Pro Gly
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Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Thr Arg Ser Pro
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Val Ser Ala Ala Lys Thr Lys Gly
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Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Phe
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Lys Asp Pro Ser Ser Asn Gln Val Phe Leu Arg Ile Thr Ser Val Asp
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Thr Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg Asn Ser His Tyr Tyr
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Val Thr Val Ser Ser Ala Lys Thr Lys Gly
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Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser
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Thr Ala Asp Ala Ala Thr Tyr Tyr Cys Ala Arg Ser Ser His Tyr Tyr
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Gly Tyr Gly Tyr Gly Gly Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr
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Val Thr Val Ser Ser Ala Lys Thr Lys Gly
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Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
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Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
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Val Asp Ser Tyr Gly Ile Ser Phe Met His Trp Tyr Gln Gln
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
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Gly Ser Thr Gly Asp Ile Val Leu Ile Gln Ser Pro Ala Ser Leu Ala
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Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Gly Val Pro
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Gly Ser Thr Gly Asn Ile Val Leu Thr Gln Ser Pro Thr Ser Phe Thr
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Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
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Gly Ser Thr Gly Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
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Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
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Ile His Ser Tyr Gly Asn Ser Phe Leu His Trp Tyr Gln Gln
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Met Asp Phe Arg Val Gln Ile Phe Ser Phe Leu Leu Met Ser Ala Ser
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Val Ile Met Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Leu
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Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
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Ser Asn Ile Ser Tyr Met Tyr Trp Tyr Gln Gln
50 55
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Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Met Ser Ala Ser
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Val Ile Met Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Leu
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Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
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Ser Asn Ile Ser Tyr Met Tyr Trp Tyr Gln Gln
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Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr
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Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Ala Ser Val Gly Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Gly Asn
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Ile His Asn Tyr Leu Ala Trp Tyr Gln Gln Glu
50 55
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Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr
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Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser
20 25 30
Ala Ser Val Gly Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Gly Asn
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Ile Arg Asn Tyr Leu Ala Trp Tyr Gln Gln
50 55
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Met Thr Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys
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Val Ser Asp Ser Arg Ala Glu Thr Thr Val Thr Gln Ser Pro Ala Ser
20 25 30
Leu Ser Met Ala Ile Gly Glu Lys Val Thr Ile Arg Cys Val Thr Ser
35 40 45
Thr Asp Ile Asp Asp Asp Val Asn Trp Tyr Gln Gln
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Met Thr Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys
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Val Ser Asp Ser Arg Ala Glu Thr Thr Val Thr Gln Ser Pro Ala Ser
20 25 30
Leu Ser Met Ala Ile Gly Glu Lys Val Thr Ile Arg Cys Val Thr Ser
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Thr Asp Ile Asp Asp Asp Val Asn Trp Tyr Gln Gln
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Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Gln
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Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp
20 25 30
Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr
35 40 45
Tyr Cys Gln Gln Ser Asn Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr
50 55 60
Lys Leu
65
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Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Gln
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Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp
20 25 30
Phe Thr Pro Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr
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Tyr Cys Gln Gln Ser Asn Glu Asp Pro Leu Thr Phe Gly Ala Gly Thr
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Lys Leu
65
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Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Val Ser Asn Leu
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Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp
20 25 30
Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr
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Tyr Cys Gln Gln Ser Asn Glu Asp Pro Phe Thr Phe Gly Ser Gly Thr
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Lys Leu
65
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Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Val
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Glu Ser Gly Val Pro Ala Lys Phe Ser Gly Ser Gly Ser Arg Thr Asp
20 25 30
Phe Thr Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr
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Tyr Cys Gln Gln Asn Ser Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr
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Lys Leu
65
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Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Val
1 5 10 15
Glu Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp
20 25 30
Phe Thr Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr
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Tyr Cys Gln Gln Asn Ser Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr
50 55 60
Lys Leu
65
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Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu
1 5 10 15
Glu Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp
20 25 30
Phe Thr Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr
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Tyr Cys Gln Gln Asn Asn Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr
50 55 60
Lys Leu
65
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Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr Leu Thr Ser Asn Leu
1 5 10 15
Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser
20 25 30
Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr
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Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr Phe Gly Ala Gly Thr
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Lys Leu
65
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Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr Leu Thr Ser Asn Leu
1 5 10 15
Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser
20 25 30
Tyr Ser Leu Thr Thr Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr
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Cys Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr Phe Gly Ala Gly Thr
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Lys Leu
65
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Lys Gln Gly Lys Ser Pro Gln Leu Leu Val Tyr Asn Ala Lys Thr Leu
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Ala Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln
20 25 30
Tyr Ser Leu Lys Ile Asn Thr Leu Gln Pro Glu Asp Phe Gly Ser Tyr
35 40 45
Tyr Cys Gln His Phe Trp Asp Ser Trp Thr Phe Gly Gly Gly Thr Lys
50 55 60
Leu
65
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Lys Gln Gly Lys Ser Pro Gln Leu Leu Val Tyr Asn Ala Lys Thr Leu
1 5 10 15
Ala Asp Gly Val Pro Ser Arg Phe Gly Gly Ser Gly Ser Gly Thr Gln
20 25 30
Tyr Ser Leu Lys Ile Asn Ser Leu Gln Pro Glu Asp Phe Gly Asn Tyr
35 40 45
Tyr Cys Gln His Phe Trp Ser Ser Pro Tyr Thr Phe Gly Gly Gly Thr
50 55 60
Lys Leu
65
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Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile Ser Glu Gly Asn Thr Leu
1 5 10 15
Arg Pro Gly Val Pro Ser Arg Phe Ser Ser Ser Gly Tyr Gly Thr Asp
20 25 30
Phe Val Phe Thr Ile Glu Asn Met Leu Ser Glu Asp Val Ala Asp Tyr
35 40 45
Tyr Cys Leu Gln Ser Gly Asn Leu Pro Tyr Thr Phe Gly Gly Gly Thr
50 55 60
Lys Leu
65
<210>39
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Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile Ser Glu Gly Asn Thr Leu
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Arg Ala Gly Val Pro Ser Arg Phe Ser Ser Ser Gly Tyr Gly Thr Asp
20 25 30
Phe Val Phe Thr Ile Glu Asn Met Leu Ser Glu Asp Val Ala Asp Tyr
35 40 45
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Claims (25)
1.一种用于增加表达DCIR的抗原呈递细胞的抗原呈递效力的方法,包括分离和纯化DCIR特异性抗体或其片段的步骤,其中靶试剂与所述DCIR特异性抗体或其片段结合形成抗体-试剂复合物,其中已与所述抗体-试剂复合物接触的抗原呈递细胞使该分子内在化。
2.权利要求1的方法,其中抗原呈递细胞包括树突细胞。
3.权利要求1的方法,其中DCIR特异性抗体或其片段与Coherin/Dockerin对的一半结合。
4.权利要求1的方法,其中DCIR特异性抗体或其片段与Coherin/Dockerin对的一半结合而靶试剂与Coherin/Dockerin对的互补性一半结合,形成复合物。
5.权利要求1的方法,其中所述靶试剂选自肽、蛋白质、脂质、碳水化合物、核酸及其组合。
6.权利要求1的方法,其中所述靶试剂包括一种或多种细胞因子。
7.权利要求6的方法,其中所述靶试剂包括一种或多种细胞因子,所述细胞因子选自白细胞介素,转化生长因子(TGF),成纤维细胞生长因子(FGF),血小板衍生生长因子(PDGF),表皮生长因子(EGF),结缔组织活化肽(CTAP),成骨因子及这些生长因子的生物活性类似物、片段和衍生物,B/T细胞分化因子,B/T细胞生长因子,促有丝分裂细胞因子,趋化细胞因子,集落刺激因子,血管生成因子,IFN-α,IFN-β,IFN-γ,IL1,IL2,IL3,IL4,IL5,IL6,IL7,IL8,IL9,IL10,IL11,IL12,IL13,IL14,IL15,IL16,IL17,IL18等,瘦素,肌肉生长抑制素,巨噬细胞刺激蛋白,血小板衍生生长因子,TNF-α,TNF-β,NGF,CD40L,CD137L/4-1BBL,人淋巴毒素-β,G-CSF,M-CSF,GM-CSF,PDGF,IL-1α,IL1-β,IP-10,PF4,GRO,9E3,促红细胞生成素,内皮抑素,血管抑素,VEGF,包括β转化生长因子(例如TGF-β1、TGF-β2、TGF-β3)在内的转化生长因子(TGF)超基因家族;骨形态发生蛋白(例如BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9);肝素结合生长因子(成纤维细胞生长因子(FGF),表皮生长因子(EGF),血小板衍生生长因子(PDGF),胰岛素样生长因子(IGF));抑制素(例如抑制素A、抑制素B);生长分化因子(例如GDF-1);以及活化素(例如活化素A、活化素B、活化素AB)。
8.权利要求1的方法,其中所述靶试剂包括细菌蛋白、病毒蛋白、真菌蛋白、原生动物蛋白或癌蛋白。
9.一种用于增加树突细胞的抗原呈递效力的方法,所述方法包括结合DCIR特异性抗体或其片段,其中抗原与所述DCIR特异性抗体或其片段结合形成抗体-抗原复合物,其中已与所述抗体-抗原复合物接触的树突细胞加工并呈递该抗原。
10.针对DCIR的抗体或其它特异性结合分子用于递送抗原至抗原呈递细胞以引起保护性或治疗性免疫反应的用途。
11.对DCIR特异的抗原靶向性试剂用于经皮肤的疫苗接种的用途。
12.对DCIR特异的抗原靶向性试剂与共给药或连接的佐剂相结合用于疫苗接种的用途。
13.能够作为重组抗原-抗体融合蛋白表达的特异性抗原用于抗原靶向(疫苗接种)目的的用途。
14.一种用于增加树突细胞效力的方法,包括:
分离患者的树突细胞;
使所述树突细胞暴露于活化量的抗DCIR抗体或该抗体片段和抗原,形成负载了抗原的活化树突细胞;和
将所述负载抗原的活化树突细胞再引入所述患者中。
15.权利要求14的方法,其中所述抗原包括细菌蛋白、病毒蛋白、真菌蛋白、原生动物蛋白或肿瘤蛋白。
16.抗DCIR免疫球蛋白或其部分,其由哺乳动物细胞分泌且抗原与该免疫球蛋白结合。
17.权利要求16的免疫球蛋白,其中所述免疫球蛋白与cohesin/dockerin结构域的一半结合。
18.权利要求16的免疫球蛋白,其进一步包括与抗原结合的cohesin-dockerin结合对的互补性一半,其中该抗原与模块式rAb载体形成复合物。
19.权利要求16的免疫球蛋白,其进一步包括与抗原构成融合蛋白的cohesin-dockerin结合对的互补性一半。
20.权利要求16的免疫球蛋白,其中抗原特异性结构域包括全长抗体、抗体可变区结构域、Fab片段、Fab′片段、F(ab)2片段、Fv片段、Fabc片段和/或具有部分Fc结构域的Fab片段。
21.权利要求16的免疫球蛋白,其中所述免疫球蛋白与毒素结合,其中所述毒素选自放射性同位素、金属、酶、肉毒杆菌毒素、破伤风、蓖麻毒素、霍乱、白喉、黄曲霉毒素、产气荚膜梭菌毒素、真菌毒素、志贺菌毒素、葡萄球菌肠毒素B、T2、seguitoxin、蛤蚌毒素、相思豆毒素、cyanoginosin、α毒素、河豚毒素、aconotoxin、蛇毒和蜘蛛毒。
22.权利要求16的免疫球蛋白,其中所述抗原是与所述免疫球蛋白构成的融合蛋白。
23.一种疫苗,其包括DCIR特异性抗体或其片段,其中抗原与所述DCIR特异性抗体或其片段结合形成抗体-抗原复合物,其中所述抗原由已与所述抗体-抗原复合物接触的树突细胞加工并呈递。
24.权利要求23的疫苗,其中所述抗原包括DCIR。
25.一种T细胞抗原,其包括:
与聚糖的至少一部分结合的抗原性T细胞表位肽,该聚糖包括与DCIR特异性结合的Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-3(Neu5Acα2-3Galβ1-4GlcNAcβ1-2Manα1-6)Manβ1-4GlcNAcβ1-4GlcNAcβ-Sp12。
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Cited By (7)
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CN108864261A (zh) * | 2011-11-23 | 2018-11-23 | 拜奥文斯瑞有限公司 | 重组蛋白及其治疗用途 |
CN110241080A (zh) * | 2011-12-12 | 2019-09-17 | 细胞药物有限公司 | 扩大t细胞的方法 |
CN103045627A (zh) * | 2012-11-09 | 2013-04-17 | 逢甲大学 | 于细胞内制造融合蛋白质的方法 |
CN103045627B (zh) * | 2012-11-09 | 2015-04-15 | 逢甲大学 | 于细胞内制造蛋白复合物的方法 |
CN103409451A (zh) * | 2013-06-28 | 2013-11-27 | 扬州维克斯生物科技有限公司 | 一种向树突状细胞dc靶向加载肿瘤抗原肽的方法 |
WO2017201635A1 (zh) * | 2016-05-23 | 2017-11-30 | 蔡胜和 | 透明质酸酶的细胞表达及其在实体瘤细胞治疗中的应用 |
WO2020119048A1 (zh) * | 2017-12-13 | 2020-06-18 | 苏州康聚生物科技有限公司 | 一种包含肿瘤抗原识别受体的免疫细胞及其应用 |
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CA2715044A1 (en) | 2008-08-14 |
KR20090114430A (ko) | 2009-11-03 |
US9102730B2 (en) | 2015-08-11 |
BRPI0807160A2 (pt) | 2018-09-25 |
JP2010517538A (ja) | 2010-05-27 |
CN101679508B (zh) | 2014-11-05 |
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EP2115002A4 (en) | 2010-09-01 |
AU2008214032A1 (en) | 2008-08-14 |
EP2115002B1 (en) | 2014-08-20 |
HK1141812A1 (zh) | 2010-11-19 |
EP2527363A1 (en) | 2012-11-28 |
JP5377330B2 (ja) | 2013-12-25 |
ZA200905347B (en) | 2010-04-28 |
TWI446921B (zh) | 2014-08-01 |
US8586052B2 (en) | 2013-11-19 |
AU2008214032B2 (en) | 2012-06-28 |
US9234040B2 (en) | 2016-01-12 |
US20130295120A1 (en) | 2013-11-07 |
MX2009008140A (es) | 2009-10-26 |
EP2115002A2 (en) | 2009-11-11 |
US20120004643A1 (en) | 2012-01-05 |
US20140134168A1 (en) | 2014-05-15 |
US8057798B2 (en) | 2011-11-15 |
TW200902061A (en) | 2009-01-16 |
WO2008097866A2 (en) | 2008-08-14 |
US20120237513A1 (en) | 2012-09-20 |
NZ578696A (en) | 2012-01-12 |
US8449888B2 (en) | 2013-05-28 |
WO2008097866A3 (en) | 2008-12-24 |
US20080241170A1 (en) | 2008-10-02 |
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