CN1281625C - 经修饰的wt1肽 - Google Patents
经修饰的wt1肽 Download PDFInfo
- Publication number
- CN1281625C CN1281625C CNB028070259A CN02807025A CN1281625C CN 1281625 C CN1281625 C CN 1281625C CN B028070259 A CNB028070259 A CN B028070259A CN 02807025 A CN02807025 A CN 02807025A CN 1281625 C CN1281625 C CN 1281625C
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- Prior art keywords
- peptide
- cell
- antigen
- cancer
- hla
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Abstract
本发明公开了一种癌症抗原肽,其含有下列氨基酸序列:Cys Tyr ThrTrp Asn Gln Met Asn Leu(SEQ ID NO.3),并公开了含有该肽作为其活性成分的一种癌症疫苗,以及将编码该肽的DNA作为其活性成分的一种DNA疫苗。
Description
技术领域
本发明涉及一种基于维尔姆斯(Wilms)瘤抑制基因WT1的产物的癌抗原。该癌抗原可用作抗癌疫苗以抵抗血液癌症如白血病、骨髓增生异常综合症、多发性骨髓瘤和恶性淋巴瘤,实体癌如胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、***癌、子宫癌、***和卵巢癌以及表达WT1的任何癌。
相关领域描述
清除机体中的外来物的免疫机制一般由体液免疫(其中涉及:巨噬细胞作为抗原呈递细胞识别抗原,辅助性T-细胞通过识别上述巨噬细胞呈递的抗原并产生各种淋巴因子来活化其他T-细胞,以及B淋巴细胞在上述淋巴因子作用下分化成产生抗体的细胞;)以及细胞免疫(借此,由抗原呈递导致分化的杀伤性T-细胞(细胞毒性T-细胞(CTL)攻击并摧毁靶细胞)组成。
现今,癌症免疫被认为主要是杀伤性T-细胞参与的细胞免疫的结果。在受杀伤性T-细胞影响的癌症免疫中,识别以主要组织相容性复合物(MHC)I类(MHC I类抗原,对于人也称HLA抗原)和癌症抗原的复合物形式呈递的癌症抗原的前体T-细胞分化并增生,结果所形成的杀伤性T-细胞攻击并摧毁癌细胞。此时,癌细胞在细胞表面呈递一个MHC I类抗原和癌症抗原的复合物,其被杀伤性T-细胞所靶向(Cur.Opin.Immunol.,5,709,1993;Cur.Opin.Immunol.,5,719,1993;Cell,82,13,1995;Immunol.Rev.,146,167,1995)。
上述被作为靶细胞的癌细胞上的MHC I类抗原呈递的癌症抗原被认为是由约8-12个氨基酸组成的肽,其是由于在癌细胞内合成的抗原蛋白被细胞内的蛋白酶处理而产生的(Cur.Opin.Immunol.,5,709,1993;Cur.Opin.Immunol.,5,719,1993;Cell,82,13,1995;Immunol.Rev.,146,167,1995)。
现今,虽然进行了各种癌症的抗原蛋白的研究,但是这些抗原蛋白很少被证实是癌症特异性抗原。
已经从染色体11p13中分离出了Wilms肿瘤的肿瘤抑制基因WT1(WT1基因),基于对WAGR综合症(以Wilms肿瘤、无虹膜、泌尿生殖器异常、智力迟钝等并发症的形式出现)的分析发现该基因是Wilms肿瘤的一个致病基因(Gessler,M.等,Nature,Vol.343,p.774-778(1990))。其基因组DNA约为50kb,由10个外显子组成,然而其cDNA约为3kb。从cDNA估计的氨基酸序列见SEQ ID No.1(Mol.Cell.Biol.,11,1707,1991)。
在人白血病中,WT1基因高频表达,且当白血病细胞用WT1反义寡聚体处理后,细胞的生长受到抑制(日本未审查的专利申请No.9-104627)。这样,WT1基因被认为促进了白血病细胞的生长。此外,WT1也在实体癌如胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、***癌、子宫癌、***和卵巢癌中高水平表达(日本专利申请No.9-191635),并且已经证明WT1基因是白血病和实体癌中的一个新的肿瘤标志。
由WT1基因表达产物的一部分组成的几种癌症特异性抗原肽在WO00/06602中描述,一个特别有希望的肽被命名为Db,在其中描述了下列氨基酸序列:Cys Met Thr Trp Asn Gln Met Asn Leu(SEQ ID No.2)(本发明中称为“野生型WT1肽”)。
发明公开
这样,本发明的一个目的是提供一种肽,其有希望作为癌症疫苗并且其活力高于以前所知道的癌症特异性抗原肽的活力。
作为全力解决上述问题的各种研究的一个结果,本发明的发明人发现一种肽(称作“经修饰的WT1肽”)有更高的活力,其氨基酸序列是上述已知氨基酸序列(SEQ ID No.2)的第二个氨基酸Met改变为Tyr所得到的,即Cys Tyr Thr Trp Asn Gln Met Asn Leu(SEQ ID No.3),因此导致了本发明的完成。
这样,本发明提供了由9-30个氨基酸组成且含有氨基酸序列:Cys TyrThr Trp Asn Gln Met Asn Leu(SEQ ID No.3)的肽(经修饰的WT1肽)。该肽优选为由9-12个氨基酸组成且含有SEQ ID No.3所示氨基酸序列的多肽,更优选由SEQ ID No.3所示氨基酸序列组成的肽。
此外,本发明提供了具有上述经修饰的WT1肽作为活性成分的癌症疫苗。
此外,本发明还提供了将编码上述肽的DNA作为活性成分的DNA疫苗。
而且,本发明提供了在其上呈递HLA抗原(MHC I类抗原)和上述肽的复合物的抗原呈递细胞。
此外,本发明还提供了识别HLA抗原和上述肽的复合物的细胞毒性T-细胞。
附图简述
图1所示为用野生型WT1肽(SEQ ID No.2)或本发明的经修饰的WT1肽(SEQ ID No.3)刺激过的效应细胞(E)对用或未用肽脉冲的C1R2402靶细胞(T)的细胞杀伤效果(特异溶胞活力)。图中,黑色圆圈表示用经修饰的WT1肽刺激的效应细胞对用野生肽脉冲过的C1R2402靶细胞的溶胞效果,黑色方块表示用野生型WT1肽刺激的效应细胞对用野生肽脉冲过的C1R2402靶细胞的溶胞效果,白色圆圈表示用经修饰的WT1肽刺激的效应细胞对没有用野生肽脉冲过的C1R2402靶细胞的溶胞效果,白色方块表示用野生型WT1肽刺激的效应细胞对没有用野生肽脉冲过的C1R2402靶细胞的溶胞效果。
图2所示为用野生型WT1肽或本发明经修饰的WT1肽刺激过的效应细胞对内源性表达WT1抗原的急性粒细胞白血病细胞或不表达WT1抗原的急性粒细胞白血病细胞的溶胞活力。
图3所示为用野生型WT1肽或本发明经修饰的WT1肽刺激过的效应细胞对用或未用肽脉冲过的C1R2402靶细胞的细胞杀伤效果(特异性溶胞活性)。图中,黑色圆圈表示用经修饰的WT1肽刺激过的效应细胞对用野生肽脉冲过的C1R2402细胞的溶胞效果,黑色方块表示用野生型WT1肽刺激过的效应细胞对用野生肽脉冲过的C1R2402靶细胞的溶胞效果,白色圆圈表示用经修饰的WT1肽刺激过的效应细胞对没有用野生肽脉冲过的C1R2402靶细胞的溶胞效果,白色方块表示用野生型WT1肽刺激过的效应细胞对没有用野生肽脉冲过的C1R2402靶细胞的溶胞效果。
图4所示为用野生型WT1肽或本发明经修饰的WT1肽刺激过的效应细胞对内源性表达WT1或不表达WT1的肺癌细胞系的溶胞活力。
图5所示为针对用野生型WT1肽或本发明经修饰的WT1肽刺激过的效应细胞对用野生肽脉冲过的C1R2402靶细胞的细胞杀伤效果(特异性溶胞活性),抗HLA I类抗体、抗HLA II类抗体和抗CD8抗体的抑制作用。
优选实施方案的描述
本发明的肽为由9-30个氨基酸组成的肽,它含有由SEQ ID No.3所示的9个氨基酸组成的氨基酸序列。此外,从结合HLA抗原而被呈递这个观点看,该肽优选为含有SEQ ID No.3所示氨基酸序列的9-12个氨基酸组成的肽,更优选地,它是具有可通过结合HLA抗原而被呈递的抗原肽序列中的规则(基元)的肽(J.Immunol.,152,p.3913,1994;Immunogenetics,41,p.178,1995;J.Immunol.,155,p.4307,1994;J.Immunol.,155,p.4749,1995)。此外,该肽最优选为由具有SEQ ID No.3所示的9个氨基酸的氨基酸序列组成的肽。
此外,上述的“含有SEQ ID No.3所示的氨基酸序列的肽”特别地指,例如含有SEQ ID No.3所示氨基酸序列且从WT1上的适当位点(SEQ IDNo.1)(位置编号235-243)或从人WT1上的相应位点(NCBI数据库登录号XP012009)以N-端和/或C-端方向延伸的具有癌症抗原肽活性的肽。
测定本发明癌症抗原肽的活力的方法的一个例子是1995年J.Immunol.154,p.2257所描述的方法。下面用HLA型的HLA-A24作为例子对该方法概要地进行说明。首先,从HLA-A24抗原阳性个体中分离外周血淋巴细胞。然后通过体外加入本发明的肽刺激外周血淋巴细胞从而诱导CTL(细胞毒性T-细胞),此CTL可特异识别被抗原呈递细胞呈递的本发明肽与HLA-A24的复合物。
CTL的诱导可通过例如测量由于CTL和抗原肽与HLA-A24的复合物反应而产生的各种细胞因子(例如,γ干扰素)的量而研究。而且,也可通过测量CTL对用51Cr或铕标记的抗原肽呈递细胞的细胞毒性来研究CTL的诱导(51Cr释放试验,Int.J.Cancer,58,p.317,1994;铕释放试验,J.Immunol.,154,p.3991,1995)。此外,也可参考后面描述的实施例研究CTL的诱导。
本发明还涉及含有上述抗原作为其活性成分的癌症疫苗。该疫苗可用于预防或治疗血液癌症如白血病、骨髓增生异常综合症、多发性骨髓瘤和恶性淋巴瘤以及实体癌如胃癌、结肠癌、肺癌、乳腺癌、生殖细胞癌、肝癌、皮肤癌、膀胱癌、***癌、子宫癌、***和卵巢癌。特别地,该疫苗可施用给HLA-A24阳性患者。该疫苗可以口服或胃肠外给药,例如,通过腹膜内、皮下、皮内、肌内、静脉内或鼻内给药。
此外,本发明疫苗的给药也可通过如下方法进行:从病人外周血中收集单核细胞,从单核细胞中提取树突细胞,将树突细胞用本发明的肽脉冲后通过皮下给药返回到病人体内等等。
该方法称作细胞治疗或树突细胞(DC)治疗,在后述题为“抗原呈递细胞”的部分将进一步做详细的介绍。
该疫苗除了作为上述活性成分给药的肽外还可以含有药学上可接受的载体如合适的辅药(Clin-Microbiol.Rev.,7,277-289,1994),其中的例子包括矿物凝胶如氢氧化铝,表面活性剂如溶血卵磷脂和pluronic polyole、聚阴离子、肽和油性乳剂。备选的,该疫苗可含有其他的混合到脂质体或掺和到多糖或该疫苗中的聚集物。典型剂量为每天0.1μg/kg到1mg/kg。
本发明中,编码上述多肽疫苗的DNA也可以用作疫苗(DNA疫苗)。即将包含编码本发明经修饰的WT1肽的核酸的核酸(优选DNA)***合适的载体(优选表达载体)中后,可通过给动物施用本载体而使其具有癌症免疫性。WO 00/6602或J.Immunol.,160,p.1717,1998等可作为用于该DNA疫苗的特定技术的参考。
此外,本发明涉及抗原呈递细胞,HLA抗原和上述肽的复合物在其上呈递。在该实例中,尽管由于本发明的肽的刺激而观察到有效的杀细胞活力,但这是由于外周血单核细胞内存在其上呈递有本发明肽和HLA抗原(HLA-A24抗原)的复合物的抗原呈递细胞以及能特异识别这些抗原呈递细胞的CTL(细胞毒性T-细胞)的诱导的结果。这些其上呈递有HLA抗原和本发明肽的复合物的抗原呈递细胞在下述细胞治疗(DC治疗)中得到有效应用。
细胞治疗中使用的抗原呈递细胞的生产方法为:从肿瘤患者分离具有呈递抗原的能力的细胞,体外用本发明的肽脉冲这些细胞,并使HLA抗原和本发明肽的复合物呈递到细胞的表面上。这里,尽管对“具有呈递抗原的能力的细胞”没有特别限制,但它们应表达能够呈递本发明肽到细胞表面上的HLA抗原,优选树突细胞,因为它们被认为有高的抗原呈递能力。
此外,用于脉冲上述有能力呈递抗原的细胞的本发明肽可以不只是肽的形式,还可以是编码所述肽的DNA或RNA的形式。
用于制备本发明的抗原呈递细胞的一个特定方法可参考例如,CancerImmunol.Immunother.,46,82,1998,J.immunol.,158,p.1796,1997和Cancer Res.,59,p.1184,1999。在使用树突细胞的情况下,用Fycoll方法从肿瘤病人的外周血液中分离淋巴细胞,在GM-CSF和IL-4存在的条件下培养淋巴细胞,除去非贴壁细胞,从贴壁细胞中得到树突细胞,之后通过用本发明肽培养树突细胞以进行脉冲可以制得本发明的抗原呈递细胞。
此外,对于通过将编码本发明肽的DNA或RNA***能够呈递抗原的上述细胞中而制备本发明的抗原呈递细胞的情况,对于DNA可参考例如,Cancer Res.,56,p.5672,1996或J.Immunol.,161,p.5607,1998,而对于RNA可参考例如,J.Exp.Med.,184,p.465,1996进行***。
这些抗原呈递细胞可用作肿瘤治疗剂的活性成分。此时,为了保持抗原呈递细胞的稳定,治疗剂优选含有生理盐水、磷酸盐缓冲的盐水(PBS)或介质等等。给药方法的实例包括静脉给药、皮下给药和皮内给药。
而且,本发明还涉及可识别HLA抗原和上述肽的复合物的细胞毒性T-细胞(CTL)。本发明的CTL可有效用于下述的过继性免疫治疗。
换句话说,对于黑素瘤,通过体外培养大量的已经体外攻击肿瘤的病人T细胞,然后将它们返回到病人体内,过继性免疫治疗已经被认识到具有疗效(J.Natl.Cancer Inst.,86,1159,1994)。此外,对于小鼠黑素瘤的情况,通过体外用肿瘤抗原肽TRP-2刺激脾细胞,使特异CTL在肿瘤抗原肽中增殖,然后将所述CTL施于移植有黑素瘤的小鼠中,观察到转移受到抑制(J.Exp.Med.,185,453,1997)。这是基于使特异识别抗原呈递细胞上HLA抗原和肿瘤抗原肽所形成的复合物的CTL体外增殖所导致的结果。这样,将病人的外周血液淋巴细胞在体外用本发明的肽刺激以增加肿瘤特异CTL、然后将这些细胞返回到病人体内的这种治疗方法被认为是有用的。
以这种方式,本发明的CTL可用作肿瘤治疗剂的活性成分。此时,为了保持CTL的稳定,治疗剂优选含有生理盐水、磷酸盐缓冲的盐水(PBS)或介质等等。给药方法的实例包括静脉给药、皮下给药和皮内给药。
下面的实施例用于阐释本发明肽作为癌症抗原和癌症疫苗的有用性。
实施例1
外周血单核细胞分离自HLA-A*2402阳性供体,将其分装在24孔平板的孔中,2×106细胞/孔,然后加入野生型WT1肽或经修饰的WT1肽使其浓度为20μM并培养1周。此时所用培养基由45%RPMI,45%AIV,10%FCS,1x非必需氨基酸和SM/PCG组成。上述培养之后,将细胞调节到2×106细胞/孔并用作效应细胞。
另一方面,从相同的HLA-A*2402阳性供体中类似地分离其他外周血单核细胞,然后通过和20μM上述肽之一培养4天以进行肽脉冲。之后在30Gy下辐射,将细胞调节到4×106个细胞/孔并用作刺激细胞。
然后将以上述方式制备的效应细胞和刺激细胞混合培养1周后加入IL-2至50U/ml。结果所得细胞的状态见下表。
表1
肽 | 细胞数 | CD4 | CD8 |
野生型WT1肽 | 2.4×106/孔 | 5% | 35% |
经修饰的WT1肽 | 3.0×106/孔 | 18% | 38% |
然后,根据51Cr释放方法(J.Immunol.,164,1873,2000)进行杀伤试验。C1R2402细胞和用上述肽脉冲过的C1R2402细胞用作靶细胞。然后让前述被野生型WT1肽或经修饰的WT1肽刺激过的细胞(效应细胞(E))作用于这些靶细胞(T)的每一个,E∶T比例为1、5或20,然后测定细胞的溶解。这些结果见图1。从该图中可清除的看出,用经修饰的WT1肽刺激过的细胞比用野生型WT1肽刺激过的细胞显示出更强的细胞杀伤活力。
实施例2
根据51Cr释放方法检验用经修饰的WT1肽或野生型WT1肽刺激过的效应细胞对内源性表达WT1抗原的白血病细胞的细胞杀伤活力。WT1+/A*2402+细胞(从AML病人1#得到的白血病细胞)、WT1-/A*2402+细胞(从AML病人2#得到的白血病细胞)、WT1+/A*2402-细胞(从AML病人3#得到的白血病细胞)、WT1-/A*2402-细胞(从AML病人4#得到的白血病细胞)用作靶细胞。
将实施例1中制备的效应细胞(E)和上述靶细胞(T)以20∶1的E∶T比例混合后培养4小时,之后测定细胞的溶解程度。结果见图2。
从该图中可以清楚的看出,尽管用野生型WT1肽或经修饰的WT1肽刺激过的细胞都显示出对WT1+/A*2402细胞的细胞毒活力,但经修饰的WT1肽刺激过的细胞的活力水平较高。
实施例3
使用从不同HLA-A*2402阳性健康供体的外周血液制得的效应细胞进行与实施例1相同的实验。其结果见图3。
从该图中可以清楚的看出,和实施例1类似,用经修饰的WT1肽刺激过的细胞比用野生型WT1肽刺激过的细胞显示出更强的细胞毒活力。
实施例4
用51Cr释放方法检验用野生型WT1肽或经修饰的WT1肽刺激过的效应细胞对内源性表达WT1抗原的、与肺癌有关的癌细胞系(靶细胞)的细胞毒性活力。RERF-LCAI(WT1+/A*2402+),LC1sq(WT1+/A*2402+),11-18(WT1-/A*2402+)和LK87(WT1+/A*2402-)细胞用作靶细胞。
将使用与实施例1相同的方式制备的效应细胞(E)和上述用51Cr标记的靶细胞(T)以E∶T为20∶1的比例按和实施例2相同的方式培养4小时后测定细胞的溶解程度。结果见图4。
从图中可以清楚的看出,尽管用野生型WT1肽或经修饰的WT1肽刺激过的细胞都显示出仅对WT1+/A*2402+细胞的细胞毒活力,但经修饰的WT1肽刺激过的细胞的活力水平更高。
实施例5
利用抗体通过阻断试验(blocking assay)确认用野生型WT1肽或经修饰的WT1肽刺激过的效应细胞是和HLA I类结合的CD8阳性杀伤细胞。所用抗体由抗HLA I类抗体、抗HLA II类抗体和抗CD8抗体组成。将用与实施例1相同的方式制备的效应细胞(E)和用51Cr标记过的靶细胞(T)(C1R2402细胞或用野生肽脉冲过的C1R2402细胞)以E∶T为20∶1的比例与抗体混合后,培养4小时,然后根据51Cr释放方法测定细胞溶解的程度。其结果见图5。
从图中可以清楚的看出,对于用野生型WT1肽或经修饰的WT1肽刺激过的细胞,其细胞毒活力都被抗HLA I类抗体和抗CD8抗体所阻断,这表明显示出细胞毒活力的细胞是和HLA I类结合的CD8阳性杀伤细胞。
实施例6
我们研究了经修饰的WT1肽和野生型WT1肽结合HLA-A*2402的亲和力。在用缓冲液(131mM柠檬酸,66mM磷酸钠,290m渗透压摩尔,pH3.3)处理C1RA2402细胞1分钟后,向这些细胞加入含0.5%牛血清白蛋白的DMEM培养基以进行中和。用该培养液洗涤细胞后,将其悬浮于含200nM β2-微球蛋白(Sigma)和0.5%牛血清白蛋白的DMEM培养基中,使细胞浓度为2×106个细胞/ml。将15μl细胞悬浮液和含不同浓度WT1肽的50μl培养基混合,在室温下培养4小时。洗涤细胞后,将它们用FITC标记的抗HLA-A24单克隆抗体(克隆名:7A12)染色,用流式细胞仪FACS***分析表现出的HLA-A24量。用相似的步骤研究已报道结合HLA-A*2402的黑素瘤抗原pmel 15的抗原肽(Ala Tyr Gly Leu Asp Phe Tyr Ile Leu)(SEQID No.4)(J.Immunol.,154,5994,1995),用此作为标准,根据文献(Immunogenetics,51,816,2000)描述的方法计算得到WT1肽的解离常数(Kd)。这些结果见表2。
表2
肽 | 解离常数Kd(M) |
野生型WT1肽 | 1.82×10-5 |
经修饰的WT1肽 | 6.40×10-7 |
从该表可清楚的看出,经修饰的WT1肽比野生型W孔肽显示出对HLA-A*2402更强的结合亲和力。
基于上述结果,证明本发明的肽无疑可起癌症抗原的作用,并且能引起针对癌细胞的杀伤性T-细胞(癌细胞的细胞毒性T-细胞)的诱导和增殖。这样,本发明的癌症抗原肽可用作癌症疫苗,抵抗伴有WT1基因表达增加的白血病和实体癌。
序列表
<110>杉山 治夫(Haruo Sugiyama)
<120>经修饰的WT1肽
<130>J939
<150>JP 2001-83250
<151>2001-03-22
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Claims (8)
1.一种癌症抗原肽,其由9-12个氨基酸组成且含有下列氨基酸序列:Cys Tyr Thr Trp Asn Gln Met Asn Leu(序列ID NO.3),其特征在于:
(1)其由序列ID NO.3的氨基酸序列组成;或
(2)其由序列ID NO.3的氨基酸序列以及序列ID NO.1的WT1上自序列ID NO.3的对应位置235-243向N端和/或C端延伸的一个或多个额外氨基酸组成。
2.根据权利要求1的癌症抗原肽,其由序列ID NO.3所示的氨基酸序列组成。
3.一种癌症疫苗,其含有权利要求1或2的肽作为活性成分。
4.一种DNA,其编码权利要求1或2的肽。
5.一种表达载体,其包含权利要求4的DNA。
6.一种抗癌的DNA疫苗,其包含权利要求5的表达载体作为活性成分。
7.HLA抗原和权利要求1或2的肽的复合物。
8.抗原呈递细胞,其上呈递有HLA抗原和权利要求1或2的肽的复合物。
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JP2001083250 | 2001-03-22 | ||
JP83250/2001 | 2001-03-22 |
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EP (1) | EP1371664B1 (zh) |
JP (2) | JP3728439B2 (zh) |
KR (1) | KR100863853B1 (zh) |
CN (1) | CN1281625C (zh) |
AT (1) | ATE383375T1 (zh) |
BR (1) | BRPI0208183B8 (zh) |
CA (1) | CA2440303C (zh) |
DE (1) | DE60224508T2 (zh) |
ES (1) | ES2298353T3 (zh) |
HK (1) | HK1070078A1 (zh) |
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Publication number | Publication date |
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US20040097703A1 (en) | 2004-05-20 |
DE60224508D1 (de) | 2008-02-21 |
CA2440303A1 (en) | 2002-10-10 |
WO2002079253A1 (fr) | 2002-10-10 |
TWI318630B (en) | 2009-12-21 |
JP3819930B2 (ja) | 2006-09-13 |
US20090325886A1 (en) | 2009-12-31 |
ES2298353T3 (es) | 2008-05-16 |
DE60224508T2 (de) | 2008-12-24 |
JP2006034296A (ja) | 2006-02-09 |
CA2440303C (en) | 2013-03-19 |
BRPI0208183B1 (pt) | 2018-08-28 |
ATE383375T1 (de) | 2008-01-15 |
HK1070078A1 (en) | 2005-06-10 |
KR100863853B1 (ko) | 2008-10-15 |
CN1531553A (zh) | 2004-09-22 |
KR20030084970A (ko) | 2003-11-01 |
JP3728439B2 (ja) | 2005-12-21 |
EP1371664A4 (en) | 2006-03-22 |
BR0208183A (pt) | 2004-03-02 |
US8105604B2 (en) | 2012-01-31 |
JPWO2002079253A1 (ja) | 2004-07-22 |
EP1371664A1 (en) | 2003-12-17 |
EP1371664B1 (en) | 2008-01-09 |
BRPI0208183B8 (pt) | 2021-05-25 |
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