CN100366631C - IgG Fc/HIV-gp120/C3d 融合蛋白质 - Google Patents
IgG Fc/HIV-gp120/C3d 融合蛋白质 Download PDFInfo
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Abstract
本发明大体上涉及一种免疫原，特别是指一种用于诱导抗体的免疫原，该免疫原能中和大范围的HIV病毒株。本发明也涉及使用该免疫原诱导抗HIV抗体的方法。
Description
本发明主张于2002年7月23日提出的第60/397,605号临时申请的优先权，本发明结合该临时申请的完整内容作为参照。
技术领域
本发明大体上涉及一种免疫原，特别是指一种用于诱导抗体的免疫原，该免疫原能中和大范围的HIV病毒株。本发明也涉及使用该免疫原诱导抗HIV抗体的方法。
背景技术
由于HIV传染病在世界范围内的扩散，目前急需一种有效的HIV疫苗。HIV疫苗发展的一个主要障碍是HIV极端多变以及HIV突变的速度和程度。(Wain-Hobson in The Evolutionary biology of Retroviruses，SSB Morse Ed.RavenPress，NY，pgs 185-209(1994))。
麦耶斯(Myers)、可柏(Korber)及其同事分析了全球HIV病毒序列并将HIV株分为多组或多个进化枝，还为鉴定个体HIV株之间的相互进化关系奠定了基础。(Myers et al(Eds))，Human Retroviruses and AIDS(1995)，published byTheoretical Biology and Biophysics Group，T-10，Mail Stop K710，Los AlamosNational Laboratory，Los Alamos，NM 87545)。可柏等人最近也分析了含有CTL和T细胞的协助表位的HIV蛋白质区域的变异程度，在HIV株中很多CTL和T细胞协助表位被证明有序列变异。(Korber et al(Eds)，HIV Molecular ImmunologyDatabase(1995)，published by Theoretical Biology and Biophysics Group，LosAlamos National Laboratory，Los Alamos，NM 87545)。
最近，哈恩(Hahn)等通过论证进化枝中HIV的频繁重组提出了HIV变异复杂程度的一个新的标准。(Robinson et al，J.Mol.Evol.40：245-259(1995))。这些作者们提出近10％的HIV株是重组型嵌合体，暗示基于单一HIV进化枝的疫苗无法实现主体对嵌合体HIV株的免疫功能。(Robinson et al，J.Mol.Evol.40：245-259(1995))。
本发明涉及适用于HIV疫苗中的一种免疫原。该免疫原广泛诱导人体内的可交叉反应的中和抗体，并能中和大范围的HIV病毒株。
发明内容
本发明涉及一种用于诱导可中和大范围HIV病毒株抗体的免疫原。本发明也涉及使用该免疫原诱导抗HIV抗体的方法。
从下面的描述可清楚看出本发明目的和优点。
附图说明
图1为C3d-89.6gp120-hIg结构的代表示意图。
图2为C3d-89.6gp120-Ig结构的代表示意图。
具体实施方式
本发明涉及一种广泛诱导有效HIV疫苗所需要的活性中和抗体的免疫原。本发明的免疫原包括至少一种含以下三种成分的融合蛋白质：1)IgG Fc成分，2)HIV包膜成分，3)C3d成分。优选地，IgG Fc成分位于融合蛋白质对HIV包膜成分的N-末端，所述HIV包膜成分为对C3d成分的N-末端。然而，所述成分能以任何可能的顺序相连。另外，间插序列(例如连接肽)同样可出现在所述免疫原中。本发明进一步涉及编码这种融合蛋白质的核酸序列。
本发明融合蛋白质的IgG Fc成分(优选地，为人类的IgG Fc成分)为该融合蛋白质提供了更长的血清/血浆/细胞外液的半衰期。C3d成分(优选地，人类C3d成分)将融合蛋白质定位到表达CD21(C3d受体)的免疫系统的抗原呈递细胞上，从而提升抗原呈递(Ahearn et al，Adv.Immunol.46：183(1989)，Cooperet al Ann.Rev.Immunol.6：85(1988)、Dempsey et al，Science 271：348(1996)，Ross et al，AIDS Res.Hum.Retroviruses 17：829(2001))。所述HIV包膜成分优选为HIV-1gp120，然而，HIV-1gp140、gp160、gp41和gp120、gp41更小的部分也可应用。所述HIV成分可包括T辅助细胞标位，也可包括HIV gp120C4结构域的残基。(例如C4结构域16个相邻残基，例如残基421-436)(见WO03/039470中的C4结构域序列)。HIV病毒成分也能包括来自被选的gp120 V3结构域的残基，例如，使其包括一个中和抗体表位的B细胞。优选地，在V3结构域至少有23个相邻残基被用上，例如，HIV gp120的V3结构域的残基297-322。V3残基可被选择用来代表在一个种群中的高次序结构模体，该V3残基的基序可以在包膜介导HIV和宿主细胞的交互作用过程中介导V3的功能。美国洛斯阿拉莫斯国家实验室(Los Alamos National Laboratory)人类逆转录酶病毒与艾滋病数据库(见Human Retroviruses and AIDS，2000，published by TheoreticalBiology and Biophysics Group，GT-10，Mail Stop K710，Los Alamos NationalLaboratory，Los Alamos，NM)目前包含超过14000个HIV V3包膜序列。适合用于本发明的V3序列的例子包括但不限于WO 03/039470中描述的以及以下列举的：
| V3序列 |
| RPNNNTRRNIHI<u>GLGR</u>RFYAT |
| RPNNNTRRSVRI<u>GPGG</u>AMFRTG |
| RP<u>IKI</u>ERKRIPL<u>GLGK</u>AFYTTK |
| RPSVNNTRRSIHM<u>GLGR</u>AFYTTG |
| RPNRHTGKSIRM<u>GLGL</u>RAWHTTR |
| RRNIHI<u>GLG</u>RRF RRSVRI<u>GPGG</u>AM |
| RKSIRI<u>GPGR</u>AV RRRISI<u>GPGR</u>AF |
| RKSIHI<u>GPGR</u>AF RKSIHI<u>APGR</u>AF |
| RPNNNTRKGIHI<u>GPGR</u>TFFATG |
| RPNNNTRKSINI<u>GPGR</u>AFYTTG |
| RPNNNTRKSIQI<u>GPGR</u>AFYTTG |
| RPNNNTRKSIHI<u>GPGR</u>AFYTTG |
| RPNNNTRKSIHI<u>GPGR</u>AFYATE |
| RPNNNTRKRMTL<u>GPGK</u>VFYTTG |
| RPGNNTRGSIHL<u>HPGR</u>KFYYSR |
| V3共享序列 | ||
| osence名称 | 在数据库中的总片段 | 氨基酸序列 |
| 1.48162.19C62.19ΔT162.7170.634.2974.17396.223.2332.1557.236.29BAL V3 | 945952-1173994225362146 | SVENGTRPNNNTRKSIHIGPGRAFYTTGEIIGOIRCAHCNISRASVENCTRPNNNTRKSIHIGPGRAFYATERIIGOIRCAHCNISRTSVENCTRPNNNTRKSIHIGPGRAFYATETTTRIIGOIRCAHCNISRTSVENCTRPGNNTRGSIHLHFGRKFYYSRGIIGOIREAHCAINIPSVEINCTRPNNNTRRSVRIGPGGAMFRTGOIIGOIRCAHCNLSRTSIEINCTRPNNNTRKSIQIGPGRAFYTTGEIIGOIRCAHCNLSRASVEINCTRPNNNTRKRMTLGPGKVFYTTGEIIGOIRKAHCNISRASVAINCTRRNNNTRRNIHIGLGRRFYATEIIGOTKKAOCNISRASVENCTTRPKIERKRIPLLGLGKAFYTTKQVGOIKCAHCPVENCTRPNNNTRRSIHIAPGRAFYTTGQIIGOIRRAHCNISRTTVVINCTRPNRHTGXSIRMGLGRAWHTTREIGOIRKAYCTLNGTSVNINCTRPHNNTRKGIHIGPGRTFFATGOIIGOIRCAHCNLSRTCTRPNNNTRKSIHIGPGRAFYTTGEIGOIRIOAHC |
所述融合蛋白质自身可以用作免疫原或是以一种复合物形式出现，其中HIV包膜成分已经被激活而暴露保守中和表位的中间构象，此表位一般只是暂时或较差地暴露于HIV病毒体表面之上。HIV包膜这种“冻结”的触发形式使特定的表位能使特定的表位呈递给B淋巴细胞。这种表位暴露的结果是抗体广泛中和HIV的产物。
所述触发包膜的构思与gp41 HR-2肽，DP178，能捕获gp41(Furata et al，Nature struct.boil.5：276(1998))的非盘曲形构象的观察报告以及经福尔马林固定之感染HIV的细胞能产生广泛的中和抗体的报告是一致的(LaCasse，Science 283：357(1997))。最近，一种逆着卷曲螺旋域的单克隆抗体在卷曲螺旋gp41结构的HR1和HR2域结合至gp41的构象决定簇上，但并没有中和HIV。(Jiang et al，J.Virol.10213(1998))。然而，后者的研究证明：如果正确的抗体可被产生，抗体是可以与卷曲螺旋域结合的。
HIV包膜上的保守中和位点可在两个域上：可以在gp41上或在gp120上。
由于(i)卷曲螺旋域的氨基酸序列是保守的；及(ii)融合包膜复合物(fusogenic envelope complex)的功能是保守的，同时该功能对于病毒致病性来说是必要的，所以所述在gp140(或gp160)的“触发”(激活)过程中暴露的gp41的域和构象可期望是保守的。所述的保守是广泛中和抗HIV抗体的产品的关键。
在一种具体实施方式中，本发明融合蛋白质具有受体(CD4)的特征-联接包膜的CCR5结合区域被暴露，这与将CD4结合位点关闭的CD4-联接的蛋白质不同。这种融合蛋白质使CD4结合位点暴露(打开)。此外，在该实施例中，融合蛋白质可以没有宿主CD4，这样避免了在对宿主的使用过程中产生潜在有害的抗CD4的抗体。
本发明融合蛋白质的gp120包膜成分可和一个配体相联，该配体被联到gp120上可由一个A32单克隆抗体(mab)识别的一个位点(Wyatt et al，J，Virol，69：5723(1995)，Boots et al，AIDS Res.Hum.Retro.13：1549(1997)，Moore et al，J.Virol.68：8350(1994))。一个A32 mab已经被显于拟态CD4上，并且当结合到gp120上时，上调(暴露)了CCR5的结合位点(Wyatt et al，J.Virol.69：5723(1995))。gp120与这样一个配体相连同样上调了CD4结合位点并且不会阻止CD4联接到gp120。
优选地，所述配体同样上调了gp41的HR-2结合位点，其可和裂开的(cleaved)gp120，未裂开的gp140和裂开的gp41相连，从而进一步将HR-2结合位点暴露于这些蛋白质前-其中每一个在作为IgFc/gp120/C3d融合蛋白质表达时都是抗HIV中和抗体的潜在目标。
该实施例的一个特殊方面就是本发明融合蛋白质的HIV-1 gp120、gp140或gp160成分和一个完整的A32mab、A32mab的Fab2片段、或是A32mab的Fab片段相连，从而导致位于gp120、gp140或gp160上的CD4结合位点、CCR5结合位点、HR-2结合位点暴露/发生上调。免疫原包含一个连在融合蛋白质gp120成分上的A32mab(或其片段)，或可包含一个和交联剂(cross-linker)，例如3％的甲醛、或双异官能团交联剂，例如DTSSP(Pierce化学公司)交联且联接到融合蛋白质的gp120成分上。一个A32 mab(或其片段)连在融合蛋白的gp120和gp140成分上从而上调或暴露gp120和gp140上的HR-2结合位点。将A32 mab(或其片段)连在gp120或gp140成分上也导致CD4结合位点和CCR5结合位点的上调。包括含有gp120的融合蛋白质的复合物、包括含有gp140的融合蛋白质的复合物和A32mab(或其片段)可以用作免疫原，该免疫原与交联剂，例如3％的甲醛或DTSSP，交联或非交联。在一个实施例中，本发明涉及包含一种融合蛋白质的免疫原，该融合蛋白质的gp140成分联接并交联于A32 mab的Fab片段，并且可选择地联接并交联于一种HR-2联接蛋白质。
本发明通过一个连在位于gp120上的A32 mab结合位点的配体触发的融合蛋白质可以与至少另一种融合蛋白质同时使用，该另一种融合蛋白质包括另一个HIV-1 gp120(或gp140)成分，并通过一个连在不同于A32 mab结合位点的位点，例如mab 17b识别的CCR5结合位点的配体来触发。所述17b mab(Kwong etal，Nature 393：648(1998)available from the AIDS Reference Repository，NIAID，NIH)增强了CD4结合到gp120上。例如，所述第二种融合蛋白质可以包含HIV-1gp120成分，该成分可与整个17b mab、17b mab的Fab2片段或17b mab的Fab片段相连。导致CD4结合位点暴露的其他CCR5配体、包括其他抗体(或其片段)可用于代替17b mab，这一点将被重视。该第二种融合蛋白质可包括联于其上的带有17b mab或其片段(或上述的其他CCR5配体)的gp120成分，或者可包括与一种制剂，例如3％的甲醛或双异官能团交联剂，例如DTSSP(Pierce化学公司)交联且联接的带有17b mab或其片段(或上述的其他CCR5配体)的gp120成分。(所述包含与整个17b mab、17b mab的Fab2片段或17b mab的Fab片段(或其他CCR5配体)相连的HIV-1gp120成分的第二种融合蛋白质自身也能用作免疫原)。
可溶解的肽，如T649Q26L和DP178，可加入上述复合物中用以稳定所述融合蛋白质的gp120或gp140成分的表位，并能与免疫原复合物交联或非交联地一同使用。
一系列单克隆抗体(mabs)已经用来中和许多HIV病毒株，除上述的17b mab之外，其还包括：联在gp120 CD4结合位点的mab IgG1b12(Roben etal，J.Virol.68：482(1994)，Mo et al，J.Virol.71：6869(1997))，联在gp120上的构象决定簇的mab 2G12(Trkola et al，J.Virol.70：1100(1996))，以及联在gp41近膜区(membrane proximal region)的mab 2F5(Muster etal，J.Virol.68：4031(1994))。包含触发包膜成分的混合融合蛋白质能用以优化可中和大范围的HIV病毒株的抗体的诱导。这些融合蛋白质，当用于灵长类动物时，例如，无论是系统地还是在粘膜区，广泛诱导HIV病毒株的活性中和抗体。
如上所述，根据本发明，有多种途径用于“冻结”融合表位。例如，影响“冻结”可以通过添入可溶的HR-2肽，例如DP-178或T-649Q26L肽，其代表卷曲螺旋域的部分，并且当加入CD4-触发包膜时，导致融合阻止(Rimsky etal，J.Virol.72：986-993(1998))。HR-2肽可以联接(或通过DSTTP(Pierce公司)、甲醛交联)于本发明融合蛋白质的gp140成分上，并且此复合物可用作一种免疫原。“冻结”亦可通过加入0.1％-3％的甲醛或多聚甲醛来实现，这两种蛋白质交联剂加入到所述复合物后能稳定所述复合物(LaCasse et al，Science283：357-362(1999))。另外，gp120融合中间产物的“冻结”能通过加入双异官能团试剂，如DSP(dithiobis[succimidylproprionate])(Pierce公司，Rockford，ILL.，No.22585ZZ)或水溶性DTSSP(Pierce公司)，其用两个和氨基反应的NHS酯以交联并稳定CD4、CCR5、或CXCR4、gp160复合物。
HIV分化枝中的HIV株以及在不同地理位置的患者的HIV株都存在固有的不同。用于HIV疫苗发展的触发融合蛋白质可以用从多种HIV分化枝及从不同的地理位置中提取的HIV包膜成分制得。为了产生含有上述复合物特性的重组蛋白质，含有抗体或者其片段、并可上调CCR5结合位点、CD4结合位点、或者CCR5结合位点和CD4结合位点、或者抗体、或者其片段、同时为CD4可诱导的触发融合蛋白质可以在质粒中以双顺反子的方式共表达两融合蛋白质以及，例如抗体Fab域的重链和轻链来产生。
本发明的融合蛋白质可通过医药可接收载体和/或佐剂(如明矾)并用本领域熟知技术来合成。本免疫原使用的合适途径包括全身(例如肌肉或皮下)。当在粘膜免疫系统(例如鼻内)发生免疫反应时，任一种途径都可以使用。可选择地，编码融合蛋白质的结构在编码序列被表达及融合蛋白质产生的条件下可被使用。
本发明的某些方面更详细的情况以下面不受限制的例子来说明。(见WO02/024149或2001年9月24日提交的美国第09/960,717号申请，以及2003年5月8日提交的美国第10/431,596号申请，以及2003年5月19日提交的美国第60/471,327号临时申请，这里一并作为参考。)
实施例1
几内亚猪通过使用IgG-89.6gp120-C3d融合蛋白质而实现了免疫。这种蛋白质被用在弗氏完全佐剂和弗氏不完全佐剂中。合成的中和抗体(Nab)的滴定量如表1中所示。(SHIV-89.6P是中和抗体所对准的病毒。)
使用IgG-89.6gp120-C3d融合蛋白质时几内亚猪的免疫情况
使用在CFA中继而在IFA中的50微克蛋白质使动物免疫
| Nab滴定量：<sup>＊</sup> | ||||
| 动物 | 抽血日期 | 接种数量 | SHIV-89.6 | SHIV-89.6P |
| GP356GP357GP358 | 03-26-0104-27-0105-18-0106-07-0103-26-0104-27-0105-18-0106-07-0103-26-0104-27-0105-18-0106-07-01 | Pre2x3x4xPre2x3x4xPre2x3x4x | ＜1044157781＜10194941＜10357361 | ＜20＜2095/114110/90＜2023＜20＜20＜20302062 |
*Nab滴定量是通过中性红摄取量测量的血清稀释度的倒数，其50％的细胞免于病毒诱导杀害(virus-induced ki1ling)。
为了产生c3d-gp12089.6Ig构象(图1)，以下利用标准分子技术的步骤被采用(图2)：
1)为了便于克隆，一种具有NheI限制酶的5’引物(Nhel-c3d-3064/F1，CCGTGC TAG CCC ACC TCA TTG TGA CCC CCT CG)，和具有BamHI限制酶区的3’引物(CTA TTG GAT CCC GGC GGC TGG GCA GTT GGA GGG ACA C)，同从补体C3中得到并被合成。
2)一个含有c3d编码序列的DNA片段通过使用质粒pC3d(源自DavidMontifiori)的PCR而生成，其包含作为模版的整个C3 cDNA和引物Nhe1-c3d-3064/F1和BamHI-c3d-3946/R1。
3)PCR产物用NheI和BamHI消化并与包含CD5隐性序列的质粒CD-19-Rg相连。
4)带有CD5隐性信号序列(scrational signal sequence)的c3dDNA片段随后从具有XhoI和BamI的合成质粒上被切取，并克隆进包含人类Ig基因的CDM8质粒内的XhoI-BamHI位点。
5)为了克隆89.6gp120，一种5’引物(Bam89.6/F1：CTA TTG GAT CCA GCAAAA GAA AAA ACG TGG GTC ACA ATC)和一种具有BamHI限制酶区的3’引物(Bam89.6gp120R1：CTC TGG ATC CCG TCT TTT TTC TCT TTG CAC TGT TCT TCT C)从HIV 89.6 env中得到并被合成。
6)HIV 89.6包膜gp120 DNA(源自Bob Dome)通过使用作为模版的89.6gp120质粒和引物Bam89.6/F1和Bam89.6gp120R1的PCR而生成。
7)HIV 89.6包膜gp120 PCR产物随后用NheI和BamHI消化质粒CDM8-c3dDNA相联。具有HIV 89.6包膜gp120基因正确方向的克隆通过测序进行识别。
上面引用的所有文件以其整体作为参考。
熟悉本领域技术的人将从此披露文件中获取有用信息，并可在不偏离本发明实质范围的形式和内容的进行改动。
Claims (19)
1.一种融合蛋白质，包括：
i)IgG Fc成分；
ii)HIV包膜成分；以及
iii)C3d成分。
2.如权利要求1所述的融合蛋白质，其特征在于：所述IgG Fc成分出现于所述融合蛋白质相对于HIV包膜成分的N-末端。
3.如权利要求1所述的融合蛋白质，其特征在于：所述HIV包膜成分出现于所述融合蛋白质相对于所述C3d成分的N-末端。
4.如权利要求1所述的融合蛋白质，其特征在于：所述IgG Fc成分出现于所述融合蛋白质相对于HIV包膜成分的N-末端；所述HIV包膜成分出现于所述融合蛋白质相对于所述C3d成分的N-末端。
5.如权利要求1所述的融合蛋白质，其特征在于：所述蛋白质进一步包括在至少两个所述成分之间的至少一个间插序列。
6.如权利要求1所述的融合蛋白质，其特征在于：所述IgG Fc成分为人类IgG Fc成分。
7.如权利要求1所述的融合蛋白质，其特征在于：所述C3d成分为人类C3d。
8.如权利要求1所述的融合蛋白质，其特征在于：所述C3d成分将所述融合蛋白质定位到表达CD21的抗原呈递细胞上，进而提升免疫抗原的呈递。
9.如权利要求1所述的融合蛋白质，其特征在于：所述HIV包膜成分为HIV-1 gp120、gp140、gp160、gp41、或者为gp120或gp41的免疫原部分。
10.如权利要求1所述的融合蛋白质，其特征在于：所述HIV包膜成分包括gp120的V3结构域的残基和B细胞中和抗体表位。
11.一种免疫原组合物，包含至少一个如权利要求1所述的融合蛋白质。
12.如权利要求11所述的组合物，其特征在于：所述组合物进一步包括一个载体。
13.一种复合物，包括如权利要求1所述的融合蛋白质，其中所述融合蛋白质的所述HIV包膜成分被激活以致所述HIV包膜成分的保守中和表位的中间构象被暴露。
14.一种复合物，包括如权利要求1所述的融合蛋白质，其中所述HIV包膜成分与上调所述HIV包膜成分的CD4结合位点和CCR5结合位点中的至少一个的配体相连。
15.如权利要求14所述的复合物，其特征在于：所述配体是抗体、或其Fab2或Fab片段。
16.如权利要求14所述的复合物，其特征在于：所述配体结合到所述HIV包膜成分的CCR5结合位点并上调所述HIV包膜成分的CD4结合位点。
17.如权利要求16所述的复合物，其特征在于：所述配体上调位于所述HIV包膜成分上的CCR5和CD4结合位点。
18.一种核酸，编码如权利要求1所述的融合蛋白质。
19.一种表达载体，包括可操作地连接到启动子的如权利要求19所述的核酸。
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| CA2775564A1 (en) * | 2009-10-09 | 2011-04-14 | New York Blood Center, Inc. | Immunopotentiator-linked oligomeric influenza immunogenic compositions |
| WO2011126576A2 (en) * | 2010-04-09 | 2011-10-13 | Duke University | Genetic signatures in the envelope glycoprotein of hiv-1 |
| CN103037962A (zh) | 2010-05-24 | 2013-04-10 | 独立行政法人农业·食品产业技术综合研究机构 | 造粒方法及造粒装置 |
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| EP2706356A1 (en) * | 2012-09-06 | 2014-03-12 | Laboratorios Del. Dr. Esteve, S.A. | Methods for identifying HIV neutralizing antibodies |
| BR112018005931A2 (pt) * | 2015-09-24 | 2018-10-09 | Abvitro Llc | composições de anticorpo para hiv e métodos de uso |
| KR20230019227A (ko) * | 2017-11-17 | 2023-02-07 | 그리폴스 다이어그노스틱 솔루션즈 인크. | 신규한 포유동물 발현 인간 면역결핍 바이러스 외피 단백질 항원 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225538A (en) * | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE207760T1 (de) * | 1993-05-07 | 2001-11-15 | Akzo Nobel Nv | Hiv immunogene komplexe |
| BR0114094A (pt) | 2000-09-22 | 2003-07-22 | Univ Duke | Imunógeno |
| EP1461077A4 (en) | 2001-11-07 | 2006-01-25 | Univ Duke | POLYVALENT IMMUNOGEN |
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2003
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- 2003-07-23 WO PCT/US2003/022917 patent/WO2004009785A2/en active Application Filing
- 2003-07-23 NZ NZ537345A patent/NZ537345A/en not_active IP Right Cessation
- 2003-07-23 EP EP10013160A patent/EP2374811A1/en not_active Withdrawn
- 2003-07-23 JP JP2004523297A patent/JP2006509496A/ja not_active Withdrawn
- 2003-07-23 EP EP03765923A patent/EP1523492A4/en not_active Withdrawn
- 2003-07-23 CN CNB038171961A patent/CN100366631C/zh not_active Expired - Fee Related
- 2003-07-23 US US10/518,523 patent/US20060014148A1/en not_active Abandoned
- 2003-07-23 BR BR0312808-3A patent/BR0312808A/pt not_active IP Right Cessation
- 2003-07-23 CA CA002493706A patent/CA2493706A1/en not_active Abandoned
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2004
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2005
- 2005-01-17 IL IL16634305A patent/IL166343A0/xx unknown
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2009
- 2009-10-02 JP JP2009230429A patent/JP2010057490A/ja not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5225538A (en) * | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
| US5428130A (en) * | 1989-02-23 | 1995-06-27 | Genentech, Inc. | Hybrid immunoglobulins |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2006509496A (ja) | 2006-03-23 |
| WO2004009785A3 (en) | 2004-08-05 |
| AU2003256671A1 (en) | 2004-02-09 |
| EP1523492A2 (en) | 2005-04-20 |
| AU2003256671B2 (en) | 2008-10-16 |
| ZA200410324B (en) | 2006-07-26 |
| EP1523492A4 (en) | 2006-05-10 |
| CN1668633A (zh) | 2005-09-14 |
| MXPA05000874A (es) | 2005-03-23 |
| CA2493706A1 (en) | 2004-01-29 |
| WO2004009785A2 (en) | 2004-01-29 |
| KR20050036960A (ko) | 2005-04-20 |
| NZ537345A (en) | 2007-12-21 |
| US20060014148A1 (en) | 2006-01-19 |
| JP2010057490A (ja) | 2010-03-18 |
| BR0312808A (pt) | 2005-04-19 |
| EP2374811A1 (en) | 2011-10-12 |
| IL166343A0 (en) | 2006-01-16 |
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