CN101056977B - 用于治疗hiv感染患者的亚型匹配的灭活全病毒疫苗 - Google Patents
用于治疗hiv感染患者的亚型匹配的灭活全病毒疫苗 Download PDFInfo
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Abstract
将灭活的特定亚型的全HIV用于制备疫苗和含有该疫苗的药物组合物。该疫苗可通过诱导抗用以制备该疫苗的相同HIV亚型的保护性细胞免疫应答治疗慢性HIV感染个体。
Description
技术领域
本发明涉及用于治疗病毒感染的疫苗，尤其是用于治疗人类HIV感染的疫苗。
背景技术
在发现人类免疫缺陷性病毒(HIV)二十年后，迄今为止还没有可利用的有效的预防性或治疗性疫苗。来自世界卫生组织和联合国艾滋病毒/艾滋病项目的最新预测表明，如果按照目前艾滋病的流行趋势，到2010年将出现4,500万新感染者1。尽管通过抗逆转录病毒治疗在延长HIV感染者的存活时间和减少母婴HIV传播方面取得了重大进展，但在长期抗逆转录病毒治疗的情况下出现药物抗性和/或与药物相关的严重副作用的患者的数目不断增加。因此急需其他的替代治疗策略以保护HIV感染个体使其免于疾病发展。
在一个大规模的人类III期试验中，一种用以诱发体液免疫以中和HIV的候选疫苗最近被证明是无效的2。这种保护作用的缺乏与已知的现有疫苗不能在体内诱发有效的抗HIV中和抗体(Nab)是一致的3。这种诱发有效的Nab的能力的缺失可能是由感染原的性质决定的。例如，迄今为止还没有用于慢性感染(例如结核、麻风和丙型肝炎病毒感染)的成功的预防性疫苗。相反，成功的疫苗可以通过诱导Nab预防急性传染病(例如脊髓灰质炎、麻疹、白喉、破伤风或天花)，其中Nab也可经胎盘或经乳汁传递以保护胎儿或新生儿免遭感染。
众所皆知，持久性细胞免疫可潜在地控制处于感染原未被清除的状态的疾病，例如结核、麻风、乙型或丙型肝炎病毒和HIV慢性感染。在这点上，已表明强烈的病毒特异性CD4+辅助性T细胞1(Th1)和效应物(穿孔素+)细胞毒性T淋巴细胞(CTL)应答与慢性HIV-1感染个体中病毒血症的控制和长期不进展有关4-10。此外，在急性感染期或急性感染后不久采用高活性抗逆转录病毒治疗(HAART)早期介入可增强HIV-1特异性CD4+Th1细胞应答11，12。相反，HAART在之后的阶段导致HIV-1特异性CD4+Th1细胞和CTL应答的降低5，13，14，这表明捕获HIV-1的抗原呈递细胞(APC)的功能活性(这是诱导免疫应答必需的)随感染进程逐渐丧失15-18。由此可见，用于诱发HIV特异性持久性细胞免疫应答的治疗性疫苗在以下两个先决条件下是可行的：1)发现能够诱发强烈、广泛和持续的保护性细胞免疫的合适的免疫原；和2)通过离体激活的APC的过继转移(即，替代策略)，或通过所述免疫原与合适的细胞因子或佐剂同时联用在体内直接激活损伤较小的树突细胞(例如郎格汉斯细胞)，重建体内损伤的APC的功能。成功的治疗性疫苗的最终目标是持续地将HIV-1感染患者的病毒载量降低至尽可能低的水平。这将阻止他们的疾病进展，并因此可以减少对有害的和昂贵的抗逆转录病毒药物的需求。此外，持续地降低HIV病毒载量可以将该病毒性传播给健康人的风险降至最小19。
根据免疫原的性质，疫苗诱导的保护性免疫应答可以完全不同。减毒活疫苗诱发体液和细胞免疫应答，而灭活病毒疫苗和纯化的合成蛋白质更倾向于诱发体液(抗体)应答。在一个旨在激发免疫系统的细胞免疫方面的多中心临床试验中，研究人员失望地发现，用含HIV基因的细菌DNA制备的实验性疫苗免疫的205个志愿者中，只有20％具有显著的HIV特异性细胞免疫应答(尽管该DNA初始免疫(DNA prime)在小鼠实验中确实表现良好)20。本申请发明人(以及其他人)最近发现其中保留了包膜蛋白gp120的构象结构的灭活的全HIV-1(例如在通过Aldrithiol-2[AT-2]处理病毒的情形)可被树突细胞(DC，最有效的APC)加工和呈递，用于体外诱导有效的HLA-I限制性CTL应答21，22。几项研究还证明灭活的全HIV-1体外负载的自体树突细胞的过继转移能够在hu-PBL-SCID小鼠中诱导保护性抗病毒免疫23，24。本申请发明人先前已证明在没有任何其他抗病毒治疗的情况下，由灭活的全猿猴免疫缺陷性病毒(SIV)株mac251(SIVmac251)负载的树突细胞制备的治疗性疫苗对已感染SIVmac251的中国恒河猴免疫两个月后，可导致显著的病毒抑制25。综上所述，这些发现表明AT灭活的全病毒可用作有效的疫苗免疫原，在慢性HIV-1感染人群中诱发保护性HIV-1特异性CTL应答。但是，HIV-1在全球范围的广泛的变异性表明将GMP级的灭活全病毒制品用作HIV-1的通用型治疗性疫苗的观念是行不通的。
发明概述
本发明提供一种疫苗，其包含灭活的特定亚型的灭活的全HIV，任选地还包含佐剂。该疫苗可通过诱导抗用以制备该疫苗的相同HIV亚型的保护性细胞免疫应答治疗慢性HIV感染个体。
本发明还提供一种药物组合物，其包含疫苗和药学上可接受的载体的，所述疫苗包含灭活的特定亚型的全HIV。
本发明还提供灭活的特定亚型的全HIV在制备用于治疗慢性HIV感染个体的药物中的用途。所述药物可通过诱导抗用以制备该疫苗的相同HIV亚型的保护性细胞免疫应答治疗慢性HIV感染个体。
本发明还提供一种治疗慢性HIV感染个体的方法，包括给个体施用包含灭活的特定亚型的全HIV的疫苗，任选地还包括施用一种佐剂，以在该个体中诱导抗用以制备该疫苗的相同HIV亚型的保护性细胞免疫应答。在一个实施方式中，灭活的HIV被离体负载于抗原呈递免疫细胞(APC)，然后将其施用给个体。
附图说明
图1显示本发明疫苗的细胞毒性T-淋巴细胞(CTL)的杀伤活性。
图2显示用AT-2灭活的SIVmac251皮内免疫对慢性SIVmac251感染的恒河猴的血浆病毒载量的影响。数据表示免疫前后每毫升血浆中SIVRNA拷贝数的几何平均数。P值代表Wilcoxon检验对免疫前、和免疫后第3或第6个月的配对数据的统计分析。
发明详述
由于HIV基因组经常发生突变，存在两个主要的HIV群(HIV-1和HIV-2)和许多亚群。群和亚群间的主要区别在于病毒包膜。HIV-1被分入主要亚群(M)和第十局外亚群(10th outlier subgroup)(O)，其中M亚群被分为9个亚型(分化单位)，命名为A到J28-29。HIV基因组中出现的遗传变异是突变、重组、插入和缺失的结果29。
本发明的抗HIV、优选地抗HIV-1亚型(例如亚型A、B、C或E)的疫苗显示出对亚型匹配的病毒株具有高CTL杀伤活性，但只显示出低的亚型间杀伤活性。尽管在个别情况中观察到了亚型间杀伤活性，但与亚型匹配的病毒株相比，在亚型不匹配的病毒株中CTL杀伤效力差异很大(参见下面实施例1和图1)。因此，本发明提供了由灭活的特定亚型的全HIV制品制备的抗HIV的亚型特异性治疗性疫苗。本发明的疫苗可用于治疗慢性HIV感染个体，其中所述疫苗诱导抗用以制备该疫苗的相同HIV亚型的保护性细胞免疫应答。
本申请所用术语“疫苗”指被施用以产生或者人为增加对特殊疾病的免疫性的组合物。
优选地，用不是受治疗个体自体的HIV亚型制备疫苗。事实上，发明人已证明，不是受治疗个体自体的HIV亚型疫苗能够出乎意料地显著降低所述个体的病毒载量。
根据本发明，可以治疗任何HIV亚型的慢性感染，例如选自M群的A、B、C或E(和其他)亚型以及HIV-2群和HIV O亚群的HIV病毒的慢性感染。
在一个实施方式中，本发明的组合物可包含几种灭活的HIV亚型，例如两种、三种、四种或更多种不同的灭活HIV亚型。
在本申请中，“治疗”慢性HIV感染个体意指预防、减轻或抑制HIV感染的症状；在施用疫苗后病毒载量(尤其是血浆病毒载量)降低；和/或在该个体中诱导抗HIV的CTL应答。当然“治疗”慢性HIV感染个体并不需要从个体中完全清除HIV。
在本申请中，“慢性HIV感染个体”指可被诊断为被HIV感染的个体。
在本申请中，“灭活的全HIV”指已灭活的、不再具有感染性的完整HIV颗粒。
在实施本发明时，可通过本领域技术人员已知的任何合适的技术手段(例如紫外照射、加热或化学处理(如甲醛、多聚甲醛、propiolactene或AT-2处理))灭活特定亚型的HIV。
优选地，通过化学处理灭活特定亚型的HIV，更优选用AT-2处理进行灭活。出乎意料的是，这种AT-2灭活能够维持HIV蛋白的构象结构并以非自体的HIV诱导切实有效的CTL应答。
亚型特异性的灭活的全病毒免疫原可用于抗原呈递免疫细胞(例如成熟的或未成熟的树突细胞(DC)或郎格汉斯细胞(LC))的离体负载(也称“脉冲式处理(pulsing)”)，以制备基于APC的治疗性疫苗；或者可用于直接皮内注射到体内以使LC在体内负载以产生无细胞疫苗。
在一个实施方式中，可采用本领域中的方法，例如通过将灭活的亚型特异性HIV直接(优选不用针)递送(例如通过皮内注射器)至患者皮肤的方式施用本发明的无细胞疫苗。用于皮内施用疫苗的无针装置是本领域技术人员公知的，包括例如US 6,933,319和国际专利申请WO2004/101025中所描述的装置，在此通过引用并入本申请。通过皮肤(皮内施用)进行免疫是特别有益的，因为表皮中含有大量LC。已知LC是DC的未成熟形式，DC位于最接近皮肤最表层(角质层)的区域。这些LC代表了一个占皮肤表面积25％的免疫细胞网络26，并在慢性HIV/SIV感染的早期或无症状期保持功能完整性27。发明人已证明皮内施用本发明的无细胞疫苗能够显著降低SIV病毒载量。
在另一个实施方式中，可通过本领域中的方法，例如通过将用灭活的亚型特异性HIV负载的APC直接递送(例如通过皮下注射器)给患者的方式施用本发明的基于APC的疫苗。
在一个实施方式中，所述方法包括在施用本发明的组合物前，检测待治疗的患者所感染的HIV亚型的预步骤。可采用本领域公知的方法实施这种检测，如通过分析所述患者的血液样品中存在的HIV对HIV序列的特定区域进行基因分型。优选地，在该HIV亚型检测步骤之后，施用本发明的基于APC的疫苗或无细胞疫苗，所述疫苗包含与感染待治疗的患者的HIV亚型相同的HIV亚型。
在另一个实施方式中，用灭活的特定亚型的HIV负载的APC治疗个体。首先用灭活的HIV离体负载APC，然后采用任何合适的技术将负载的APC施用给患者。优选地，负载的APC通过皮下、皮内或者肌内方式注射给该个体，优选采用皮下注射。更优选地，通过之前从待治疗的个体采集PBMC以分离单核细胞(CD14+)而获得APC，然后依次用未成熟的和成熟的树突细胞中已知的细胞因子进行转化。这些方法是本领域技术人员公知的，例如实施例1中描述的方法。
与细菌产物不同，灭活的全HIV单用不能有效诱导DC的成熟25，不能使这些细胞向它们在其中行使免疫刺激功能的引流淋巴结有效迁移。因此，优选将一类称作佐剂的有效分子与灭活的全HIV组合以激发最佳的免疫细胞(例如LC)的成熟，从而产生抗HIV-1的有效的细胞免疫应答。
术语“佐剂”指加入疫苗以增强免疫应答的物质。
合适的佐剂包括完全弗氏佐剂、不完全弗氏佐剂、皂苷、矿物胶如氢氧化铝、表面活性物质如溶血卵磷脂、多聚醇、聚阴离子、肽、油或碳氢化合物乳液、钥孔血蓝蛋白、二硝基酚、常规细菌产物(如霍乱毒素、热不稳定肠毒素、减毒或灭活的BCG(卡介苗(bacille Calmette-Guerin))和短小棒状杆菌，或BCG衍生蛋白)、生化分子(如TNF-α、IL-1-β、IL-6、PGE2，或CD40L)、或含CpG基序的寡脱氧核苷酸。适合在疫苗组合物中使用的材料的例子已公开，例如在Osol，A.，ed.，Remington′sPharmaceutical Sciences，Mack Publishing Co.，Easton，Pa.(1980)，第1324-1341页公开的材料，该文献通过引用以其全文并入本申请。
树突细胞在单核细胞的分化调节中，更尤其是在调节CD4-Th1模式(profile)相对于CD4-Th2模式的分化中，起关键作用。优选地，本发明的无细胞疫苗组合物包含能够刺激树突细胞以抑制CD4-Th2模式中的细胞分化的佐剂，这种模式通常在慢性感染中被诱导；同时还能够刺激树突细胞以激活CD4-Th1模式中的细胞分化。这种佐剂是本领域技术人员公知的，其包括细菌产物(例如，一些BCG衍生蛋白，如Ag85B)或化合物(如具有抗COX活性的化合物，尤其是具有抗COX2活性的化合物(例如VIOX
、CELEBREX
或RIBAVERIN
))。
本发明的疫苗可配制成用于治疗慢性HIV感染个体的药物组合物(也称为“药物”)。本发明的药物组合物优选是无菌的且不含致热原，还包括药学上可接受的载体。合适的药学上可接受的载体包括水、盐溶液(例如生理盐水)、粘度调节剂和其他常规的制备人用药物组合物所使用的药物赋形剂和/或添加剂。合适的药物赋形剂包括稳定剂、抗氧化剂、等渗调节剂、缓冲液和pH调节剂。合适的添加剂包括生理相容性缓冲液(例如盐酸氨丁三醇等)，螯合剂(例如DTPA、DTPA-双酰胺等)或螯合钙复合物(例如钙DTPA、CaNaDTPA-双酰胺等)，或者可选地，添加钙或钠盐(例如氯化钙、抗坏血酸钙、葡萄糖酸钙、乳酸钙等)。制备本发明的药物组合物是本领域公知的，例如在Remington′s Pharmaceutical Science，17th ed.，Mack Publishing Company，Easton，Pa.(1985)中所有描述的，其完整公开内容通过引用并入本申请。
一种可以通过细胞免疫应答主动疗法减轻慢性HIV感染个体症状的典型方案包括施用有效量的上述疫苗组合物，可以单次使用，或者以增强的或加强免疫(booster)剂量重复使用，治疗周期持续一周至约24个月。
根据本发明，疫苗组合物的“有效量”是指足以获得所需生物学效应(在本申请中指抗HIV的细胞或体液免疫应答中的至少一种，优选细胞免疫应答)的量。当然，有效剂量将取决于受者的年龄、性别、健康状况和体重，同期治疗的方式，如果还有就是治疗频率以及所需的疗效。下面提供的有效剂量的范围不是用于限定本发明，而是代表了优选的剂量范围。但是，最优选的剂量要因个体而定，这是本领域技术能够理解并确定的。例如，参见以下文献，Berkow(1987)，Goodman(1990)，Avery(1987)，Ebadi，Pharmacology，Little，Brown and Co.，Boston，Mass.(1985)，和Katsung(1992)，这些文献及其所引用的文献通过引用完整地并入本申请。
一般来说，用于成人的剂量范围是每剂约106至1014个灭活的全HIV颗粒，优选108至1012个。无论使用什么剂量，其都应该是如通过已知方法以及本申请所描述的方法所确定的安全和有效的剂量。
本发明将通过以下限制性的实施例进行阐述。
实施例
实施例1
方法
病毒和细胞样品
通过来自感染HIV-1亚型A(n＝10)、B(n＝10)、C(n＝10)或E(n＝10)的患者的去除CD8的外周血单个核细胞(PBMC)培养物获得HIV-1株。然后如文献21中所述，通过AT-2(Sigma，St Louis，Missouri)灭活这些HIV-1亚型(A、B、C或E)株，文献21通过引用以其整体并入本申请。在GMP条件下采用标准的7天培养25从每位患者制备衍生自单核细胞的DC。简而言之，在存在0.5％临床用人血清白蛋白(LFB，Les Ulis，France)的条件下，以106个细胞/cm2的密度将新采集的PBMC进行塑料粘附。在5％CO2、37℃的条件下温育2小时后，用无菌PBS缓冲液漂洗掉未粘附的细胞。然后，在含有添加了2000U/ml GM-CSF(Schering-Plough，Brinny，Ireland)和50ng/ml临床级IL-4(CellGenix)的临床级CellGroDC培养基的完全培养基中培养被粘附的细胞5天。在第5天，于37℃将DC暴露于AT-2灭活的自体病毒(109个病毒颗粒/ml)2小时。洗涤两次除去未结合的灭活病毒后，将细胞在添加了临床级细胞因子IL-1β(10ng/ml)(CellGenix)、IL-6(100ng/ml)(CellGenix)和TNF-α(50ng/ml)(CellGenix)的完全培养基中再培养2天。在第7天，通过流式细胞仪进行DC的质量控制(QC)25，该文献通过引用以其整体并入本申请。然后用上述文献21中所描述的共培养方案，将经QC证明的活DC扩增自体病毒特异性CTL。
细胞毒性检测
用AT-HIV-1(109/ml)脉冲式处理DC 90min，然后用CFSE(Molecular Probes，PoortGebouw，The Netherlands)(10nM)标记15min，洗涤两次。未脉冲式处理的DC用CFSE标记作为特异性对照。在存在CFSE-标记的亚型匹配的或不匹配的AT-2-HIV-1脉冲式处理的树突细胞(DC)的条件下，将HIV-1亚型株特异性CTL以E∶T比例10∶1置于MicroTubes-Bulk(Bio-Rad，Hercules，CA)中，于37℃温育4小时。温育结束时，每管加入10μl碘化丙啶(PI，Sigma)(20μg/ml)。在FACSCalibur(BDImmunocytometry System，San Jose，CA)上分析靶细胞溶解。在扣除未脉冲式处理DC的非特异性CFSE/PI染色后，通过计算CFSE/PI染色DC的百分比测定病毒特异性细胞溶解活性。
统计学分析
通过Mann-Whitney检验比较HIV-1亚型匹配的和亚型不匹配的细胞杀伤活性之间的非配对数据。
结果
本发明的对HIV-1亚型A、B、C或E具有特异性的疫苗在体外对亚型匹配的病毒株(n＝10)显示出高CTL杀伤活性(28-37％)，但仅观察到低亚型间杀伤活性(5-17％)(P＜0.001)。尽管在个别情况中观察到了亚型间杀伤活性，但与亚型匹配的病毒株(标准差/平均值＜20％)(P＜0.001)相比，在亚型不匹配的病毒株中CTL杀伤效率差异很大(标准差/平均值＞50％)(图1)。这些发现表明药用HIV-1亚型特异性治疗性疫苗可通过GMP级的灭活全病毒制品而制得。
实施例2
鉴定慢性HIV感染个体，并测定感染个体的HIV亚型。在用本发明的疫苗进行治疗之前先测定每一个体的血浆病毒载量。获得与感染个体的HIV亚型具有相同亚型的HIV，按照上述实施例1所述的方法进行培养并用AT-2进行灭活。
通过无针皮内递送方式将灭活HIV亚型施用给一组慢性感染个体，然后测量血浆病毒载量。可以预期一旦施用本发明的疫苗，所述慢性感染个体的血浆病毒载量将显著降低。
给另一组慢性感染者施用树突细胞，所述树突细胞按上述实施例1所述用AT-2灭活的HIV进行负载。给个体施用HIV负载的树突细胞。可以预期一旦施用负载过的树突细胞，所述慢性感染个体的血浆病毒载量将显著降低。
实施例3
将40只血浆病毒载量＞1000拷贝/ml的慢性(＞1年)SIVmac251感染的恒河猴随机分组，或接受自动注射枪(AKRADERMOJET，Pau，France)每月一次皮内注射(背部25cm2)SIVac LA2.1(2.5ml含1010AT-2灭活的SIVmac251的0.9％NaCl溶液)5个月(100μl/cm2/注射)(n＝20)；或接受每月一次皮内注射安慰剂(单独的2.5ml的0.9％NaCl溶液)，共5个月(n＝20)。之后每个月直至第6个月，自基线收集血浆样品，并保存于-80℃直至使用。最后，通过定量RT-PCR分析(MUPROVAMA)测定血浆SIV RNA载量。
结果
根据本发明的SIV亚型特异性的无细胞疫苗在第3个月(P＝0.037)和第6个月(P＝0.013)诱导血液病毒载量降低近30％(图2)。这些发现表明药用的亚型特异的SIV治疗性疫苗可通过GMP级灭活的全病毒制品而制得。
实施例4
将140只血浆病毒载量＞1000拷贝/ml的慢性(＞1年)SIVmac251感染的恒河猴随机分组，或接受自动注射枪(AKRADERMOJET，Pau，France)每月一次皮内注射(背部25cm2)SIVac LA2.1(2.5ml含1010AT-2灭活的SIVmac251的0.9％NaCl溶液)和不同的佐剂(105UFC减毒或热灭活BCG、BCG衍生的重组Ag85B)5个月(100μl/cm2/注射)，同时每天口服或不口服200mg CELEBREX4周(每组n＝20)；或接受每月一次皮内注射安慰剂(单独的2.5ml的0.9％NaCl溶液)，共5个月(n＝20)。之后每个月直至第6个月，自基线收集血浆样品，并保存于-80℃直至使用。最后，通过定量RT-PCR分析(MUPROVAMA)测定血浆SIVRNA载量。
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本申请中的所有参考文献(包括上述列举的文献)通过引用以其整体并入本申请。从本申请所公开的内容得出的对上述实施方式的多种修饰对本领域技术人员而言将是显而易见的。因此，在不偏离其精神或本质特征的条件下，本发明可以还包括其他特定的形式。
Claims (7)
1.通过Aldrithiol-2处理灭活的A、B、C或E亚型的全HIV-1在制备通过皮内施用治疗慢性HIV感染个体的无细胞疫苗中的用途，其中该疫苗在所述个体中诱导针对与用来制备该疫苗的HIV亚型相同的HIV亚型的保护性细胞免疫应答。
2.权利要求1的用途，其中所述灭活的特定亚型的全HIV-1不是受治疗的慢性HIV感染个体自体的。
3.权利要求1的用途，其中所述疫苗还包含佐剂。
4.权利要求3的用途，其中所述佐剂刺激树突细胞的成熟。
5.权利要求3的用途，其中所述佐剂能够刺激树突细胞以抑制CD4-Th2模式中的细胞分化。
6.权利要求5的用途，其中所述佐剂能够刺激树突细胞以激活CD4-Th1模式中的细胞分化。
7.权利要求4的用途，其中所述树突细胞是郎格汉斯细胞。
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| EP2821082A1 (en) * | 2013-07-05 | 2015-01-07 | Laboratoire Biodim | Method of producing an inactivated lentivirus, especially HIV, vaccine, kit and method of use |
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| Lapenta Caterina ET-AL.Potent immune respone against HIV-1 and protection fromvirus challenge in hu-PBL-SCID mice immunizd withinactivated virus-pulsed dendritic cells generated in thepresence of IFN-alpha.The Journal of Experimental Medicine198 2.2003,198(2),361-367. |
| Lapenta Caterina ET-AL.Potent immune respone against HIV-1 and protection fromvirus challenge in hu-PBL-SCID mice immunizd withinactivated virus-pulsed dendritic cells generated in thepresence of IFN-alpha.The Journal of Experimental Medicine198 2.2003,198(2),361-367. * |
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| IL182440A (en) | 2011-01-31 |
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| AU2005290930A1 (en) | 2006-04-13 |
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| WO2006038124A1 (en) | 2006-04-13 |
| ATE401392T1 (de) | 2008-08-15 |
| EP1797175B1 (en) | 2008-07-16 |
| DE602005008264D1 (de) | 2008-08-28 |
| IL182440A0 (en) | 2007-07-24 |
| AU2005290930B2 (en) | 2010-12-16 |
| US20060093623A1 (en) | 2006-05-04 |
| ES2310848T3 (es) | 2009-01-16 |
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| CN101056977A (zh) | 2007-10-17 |
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| BRPI0516314A (pt) | 2008-09-02 |
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