CN101486756A - 外表面蛋白质及其基因和用途 - Google Patents
外表面蛋白质及其基因和用途 Download PDFInfo
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- CN101486756A CN101486756A CNA2008101761856A CN200810176185A CN101486756A CN 101486756 A CN101486756 A CN 101486756A CN A2008101761856 A CNA2008101761856 A CN A2008101761856A CN 200810176185 A CN200810176185 A CN 200810176185A CN 101486756 A CN101486756 A CN 101486756A
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Classifications
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Abstract
本发明涉及外表面蛋白质及其基因和用途。根据本发明，在B组链球菌中鉴定了一系列基因，其产物可能位于生物体的外表面上。该基因或其功能性片段可用于治疗物质，例如使患者免受微生物感染的疫苗的制备。
Description
本申请是分案申请，其母案申请日为1999年12月22日，申请号为2005100047117，发明名称为“外表面蛋白质及其基因和用途”。前述母案的母案是申请号为99814781.8的同名申请。
发明领域
该项发明是关于外表面蛋白质的鉴定及其基因和用途，尤其是涉及在免疫治疗和药物筛选上的应用。
发明背景
B组链球菌(GBS)也被称为无乳链球菌，是各种病的病原体。特别是，GBS可引起：
早期发作新生期感染
该感染通常开始于子宫，导致新生儿严重的败血病和肺炎，如果不能及时治疗将其致死，即使得到治疗也会有10-20％的死亡率。
晚期发作新生期感染
该感染多发于婴儿刚出生至大约3个月期间，可致败血病，90％的病例伴发脑膜炎。其它病灶性感染包括脑膜炎、脓毒性关节炎、脓肿和眼内炎。
成人感染
该感染似乎越来越常见且最频繁地发生于刚生育过婴儿的、年长的、无免疫应答的女性身上。其特征为败血病和病灶性感染，包括脑膜炎、脓毒性关节炎、脓肿和眼内炎。
尿道感染
GBS是尿道感染的成因，在妊娠期的所有感染中约占10％。
家畜感染
GBS引起奶牛的慢性乳腺炎。导致产奶量下降，因此具有值得注意的经济重要性。
虽然GBS感染可用抗生素治疗，但免疫学的方法是优选的。因此人们希望找到一种能被用于有治疗效果的疫苗中的免疫原。
发明概要
本发明基于在GBS中的一系列基因的鉴定，以及相关的生物体，该生物体的产物可能与其外表面相关联且因此可被用作免疫治疗的靶。
根据本发明的一个方面，肽由包括任意的已被鉴定为MS4、MS10、MS11、MS14和MS16的可得自GBS的基因，或其同源物或功能性片段的操纵子所编码。此种肽适合用于治疗，例如当被分离后。
此处所用的术语“功能性片段”是指一部分保留整个基因或肽活性的基因或肽。例如肽的功能性片段可用做抗原决定因子，在疫苗或抗体生产方面颇有用处。
基因片段可用于编码活性肽。另外，该基因片段在基因疗法、体内野生型基因定位来发挥治疗作用方面有实用。
本发明的肽可包含确定的任一氨基酸序列，如SEQ ID NOS.2、4、6、8、10和12，或包含上述序列的功能性片段。
因为位于细胞外或细胞表面的位置，本发明的肽可为生产抗GBS治疗上有效的疫苗的候选物。“治疗上有效的”是指包括疫苗的预防作用。例如，疫苗可包含本发明所述的肽或用于其表达的工具以治疗感染。
这种疫苗可在妇女怀孕前或怀孕期间给药来保护母亲和新生儿免受GBS感染。
根据本发明的另一方面，此肽或基因可用于筛选潜在的抗微生物药物或毒性检测。
本发明的另一个方面是在此处鉴定的任意产物的用途，用于与GBS菌株感染相关病症的治疗或预防。
虽然已经描述了此蛋白质用于病人的治疗，但该产物的兽医用途也被视为在本发明的范围之内。尤其是，该肽或疫苗可被用于慢性乳腺炎的治疗，特别是对奶牛的治疗。
发明描述
本发明与B组链球菌菌株M732有关，然而所有的GBS菌株和许多其它的细菌菌株都可能包含相关的肽或蛋白质，它们都有与M732的肽同源的氨基酸序列。可能含有此肽的生物体，包括但不仅限于此：肺炎链球菌，酿脓链球菌，猪链球菌，米氏链球菌，C组和G组链球菌，还有肠球菌。按照描述GBS的相同方法，可以开发出这些菌株中的相应疫苗。
优选地，用于生产疫苗的肽与在此鉴定的肽有超过40％的序列相似性，优选可以超过60％，最优选可多于80％的序列相似性，例如95％相似性。
在鉴定出本发明的一个基因后，可以用此基因序列在别的微生物中确定同源性。以此方式还可以确定别的微生物是否有相似的外表面产物。通过在现存的数据库例如：EMBL或Genbank中搜索，可以确定序列的同源性。
本发明的肽或蛋白质可通过本领域已知的方法被纯化和分离。特别是，确定基因序列后，可以用重组技术在合适的宿主中表达基因。活性片段和同源物可以被鉴定出来，并在治疗领域中应用。例如，肽或其活性片段可在疫苗中作为抗原决定簇，来引起免疫答应。其也可以被用于抗体的制备，用于被动免疫或诊断应用。合适的抗体包括单克隆抗体或其片段，包括单链fv片段。制备抗体的方法对本领域的技术人员来说是显而易见的。
基于减毒微生物的疫苗的制备是本领域技术人员已知的。如需要或希望的话，疫苗组合物可与合适的载体或佐剂如明矾一起配制，并用于治疗，来提供抗B组链球菌或其它相关微生物的有效免疫作用。疫苗配剂的制备对本领域的技术人员来说是显而易见的。
通常，本发明用于治疗的活性成分的合适的量以及合适载体或赋形剂以及给药途径的选择对本领域的技术人员来说是公知的。这些因素可根据已知标准选择或确定，诸如所治疗病症的性质/严重性、受治疗者的类型或健康状况等。
本发明的产品可按如下方法鉴定：
将GBS接种于Todd-Hewitt氏链球菌肉汤培养基中，允许在37℃下培养过夜。细胞被离心收集和用磷酸盐缓冲盐水(PBS)洗涤。将细胞重新悬浮在渗透性缓冲液(20％(W/V)蔗糖，20Mm Tris-HCl pH7.0，10mM MgCl2)中，该渗透性缓冲液含有蛋白酶抑制剂(1mM PMSF，10μM碘乙酸，10mM1，10-二氮杂菲，1μM胃酶抑素A)和终浓度为4单位/微升变溶菌素，在37℃培养(振荡)2小时。
先用高速离心机除去细胞和碎屑，再用超高速离心1小时。所得到的含有细胞壁蛋白质的上清液用超滤设备加压浓缩(分子量截断值为10,000)。
样品对超高水透析后冻干。经过在填充缓冲液中再悬浮，用制备性两向凝胶电泳分离出蛋白质。电泳后，选一个单独的点用于研究。对该点进行凝胶内胰蛋白酶消化。从胶状中提取产生的肽，用微内径RP-HPLC纯化。每隔45秒收集一次级分，与紫外吸收区相应的部分用延时提取-基体辅助激光解吸-飞行时间质谱、(DE-MALDI-TOF-MS)分析。然后用Nanospray-MS/MS对在空白制剂中未观察到的肽进行测序。
使用此肽序列的信息，设计了简并低聚核苷酸，将其用于聚合酶链反应(PCR)来扩增位于所鉴定的肽序列之间的DNA片段。
PCR扩增反应的结果是产生几个多聚核苷酸片段，其中每一片段按照制造商的说明书被克隆到pCR 2.1-TOPO载体(Invitrogen BV，荷兰)中。
每一质粒中的DNA片段通过测序被鉴定，然后如下所述被用于获得全长基因序列。
用已鉴定的DNA片段，低聚核苷酸引物被设计用于基因组DNA测序。这些引物被设计以便从得到的序列“向外的”方向排序。一旦阅读，即可检查获得的序列是否已经到达基因的5’端和3’端。通过检查同源序列鉴定了这些特征的存在，对于5’末端来说，在Shine-Dalgarno共有序列之前存在AUG起始密码子(或公认的替换物)而对于3’末端来说，存在翻译终止密码子。
根据全长基因的鉴定，引物被设计用于从GBS基因组DNA扩增全长产物。所用的引物包括限制酶识别位点(在5’末端的NcoI和在3’末端的Eco0109I)，允许产物随后克隆到所用的乳球菌表达体系中。
用引物进行PCR反应，并把产物克隆到pCR 2.1克隆载体(Invitrogen)中。在确认克隆片段存在后，用限制酶NcoI和Eco0109I切除该DNA。
插入此片段的载体是pNZ8048的修饰变体(Kuipers，O.P.等人(1998)J.Biotech 64：15-21)。这种含有乳球菌复制起点、氯霉素抗性标记、可诱导的乳链菌肽启动子和多克隆位点的载体通过用2个10X组氨酸标记取代位点得以改变多克隆，侧接于带有NcoI位点的5’末端，在含有多克隆位点(包括Eco0109I位点)和His标记的3’末端的终止密码子的中间分开。
插入目的基因，这样一个10X组氨酸标记处在相对于密码区的3’位置。把重组质粒转化到乳酸乳球菌(L.lactis)(菌株NZ9000-Kuipers，O.p.等人(1998)见上文)中，形成一种400ml的液体培养物，通过将乳链菌肽加到培养物中来诱导蛋白质的翻译。培养2小时后，收获细胞并用玻珠搅打溶胞，将生成的溶胞产物离心分离，然后通过金属亲合性(Talon，clonetech)柱。在用咪唑洗脱结合的蛋白质前反复洗柱。
为了鉴定含有组氨酸标记的重组蛋白质的级分，每个级分的等分试样都用SDS-PAGE、蛋白质印迹法分析，并用抗-His抗体探测。
然后用得到的重组蛋白质免疫新西兰白兔，在免疫前收集免疫前血清。在加强免疫之后，处死白兔，收集血清，用于蛋白质印迹法、ELISA和动物保护模型。
使用获自动物研究的血清，进行免疫吸附研究。
B组链球菌在20ml Todd-Hewitt氏链球菌肉汤(THB)中培养8小时，收集后再悬浮于5ml PBS中。在96孔平板(Nunc免疫-吸附)中，用50μl等分试样覆盖加样孔，在4℃放置过夜以吸收细菌到平板上。用GBS洗平板两次，然后在37℃下用加入3％BAS的PBS封闭1小时。再次洗涤平板。在PBS中制得连续10倍的血清稀释液且50μl稀释液被加到平板的孔中，一式两份。盖上平板并在37℃培养1小时。洗涤平板，然后在每个孔中加入浓度为1：5000的50μl抗兔碱性磷酸酶缀合的第二抗体。在37℃培养1小时后，再次洗涤平板。把50μl底物(PNPP)加入每个孔，在405nm处读取吸收度前反应30min。
进行动物保护研究，检验保护作用对免疫接种兔的有效性。
GBS M732在THB中培养，直至对数中期，约需5小时。在计数室中进行细胞计数，在免疫前或试验血清中稀释细菌浓度至2 x 107/ml。取50μl通过腹膜内途径注射入出生0-1天的小鼠。在48小时内观察小鼠的存活状况。
下面的实施例阐述了本发明。
实施例1
第一个质粒被称为MS4。克隆的DNA片段被测序，核苷酸和推断的氨基酸序列(SEQ ID NO.1和2)被用于检索蛋白质数据库。
可在产气荚膜梭菌、流感嗜血菌、淡黄奈瑟氏球菌和Thermatogamaritima中鉴定GBS MS4基因产物的同源物。在所有的情况下同源物都是鸟氨酸转氨甲酰酶(OCT)的基因。在真核体系中这种酶催化尿素循环的第二步反应-鸟氨酸转化为瓜氨酸，该反应需氨甲酰磷酸。在原核生物中，ODC是与精氨酸脱氨酶活性有关的三种酶之一-保护细菌不受酸侵蚀。尤其，ODC有助于瓜氨酸转为鸟氨酸和氨甲酰磷酸(与真核生物中的相反的作用)(Casiano-colon，A and Marquis，R.E.1998.Ap pl.Environ.Microbiol.54：1318-1324，Cunin，R.等人1986.Microbiol.Rev.50：314-352)。
如上所述进行了动物保护研究。结果如下：
处理 幼犬数 在时间点(hrs)存活的幼犬数
24 48
PBS 15 6 0
免疫前 41 18 1
试验 41 33 14
实施例2
第二个质粒被称为MS11。核苷酸和推断的氨基酸序列(SEQ ID NOS.3和4)被用于检索蛋白质数据库。
GBS MS11基因产物的同源物可在德氏乳杆菌，海栖热袍菌，丙酮丁醇梭菌，巨大芽孢杆菌，Triticum aestivium和集胞蓝细菌PCC6803中被鉴定。
在所有的情况下同源物都是磷酸甘油激活酶(PGK)蛋白质的基因。PGK是糖酵解途径中的主要酶，与甘油醛3-磷酸-转变为磷酸烯醇丙酮酸的反应有关。尤其，与甘油酸-1，3-二磷酸与3-磷酸-甘油酸之间反应的催化作用有关，在向前的反应中释放一个磷酸。
实施例3
第三个质粒被称为pMS16。5’和3’末端克隆DNA片段被测序且5’端片段的核苷酸和推断的氨基酸序列被显示于SEQ ID NOS.5和6，3’端片段的核苷酸和推断的氨基酸序列被显示于SEQ ID NOS.7和8。
GBS MS16基因产物的同源物可以在嗜热脂肪芽孢杆菌、枯草芽孢杆菌和生殖道枝原体中被鉴定。
在所有的情况下同源物都是编码葡萄糖-6-磷酸异构酶(GPI)蛋白质的基因。
葡萄糖-6-磷酸异构酶催化糖酵解(G6P到F6P)和糖异生(F6P到G6P)过程中的葡萄糖-6-磷酸和果糖-6-磷酸之间的反应。已证明gpi基因中的突变赋予生物体嘌呤类似物敏感性。
实施例4
第四个质粒被称为pMS14。克隆的DNA片段被测序，核苷酸和推断的氨基酸序列(SEQ ID NO.9和10)被用于检索蛋白质数据库。
GBS MS14基因产物的同源物可在嗜热脂肪芽孢杆菌，Mus musculus，Bos taurus和玉米中被鉴定。在所有的情况下同源物均为嘌呤核苷磷酸酶(PNP)蛋白质的基因。此酶的作用是在正磷酸存在时切割鸟嘌呤核苷或肌苷成为其各自的碱基和糖-1-磷酸分子。
实施例5
第五个质粒被称为pMS10。克隆的DNA片段被测序，核苷酸和推断的氨基酸序列(SEQ ID NO.11和12)被用于检索蛋白质数据库。
GBS MS10基因产物的同源物可在变异链球菌，Nicotiana Plumb，Pisum sati vum和玉米中被鉴定。在所有的情况下同源物都是非磷酸化，NADP-依赖性甘油醛-3-磷酸脱氢酶(NPGAP-3-DH)蛋白质的基因。NPGAP-3-DH已被报道作为在变异链球菌中产生NADPH用于生物合成反应的重要工具(与符合糖酵解途径要求的NAD-特异性GAP-3-DH相反)(Boyd，D.A.，Cvitkovitch，D.G.和Hamilton，I.R 1995细菌学杂志。177：2622-2727)。
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<220>
<221>CDS
<222>(1)..(1197)
<400>3
<210>4
<211>398
<212>PRT
<213>B组链球菌
<400>4
<210>5
<211>516
<212>DNA
<213>B组链球菌
<220>
<221>CDS
<222>(1)..(516)
<400>5
<210>6
<211>172
<212>PRT
<213>B组链球菌
<400>6
<210>7
<211>318
<212>DNA
<213>B组链球菌
<220>
<221>CDS
<222>(1)..(318)
<400>7
<210>8
<211>105
<212>PRT
<213>B组链球菌
<400>8
<210>9
<211>804
<212>DNA
<213>B组链球菌
<220>
<221>CDS
<222>(1)..(804)
<400>9
<210>10
<211>268
<212>PRT
<213>B组链球菌
<400>10
<210>11
<211>1428
<212>DNA
<213>B组链球菌
<220>
<221>CDS
<222>(1)..(1428)
<400>11
<210>12
<211>475
<212>PRT
<213>B组链球菌
<400>12
Claims (12)
1.一种由任一已被鉴定为MS4、MS11、MS14和MS16的可获自B组链球菌的基因所编码的肽，或与其具有至少60％序列相似性的同源物，或其保持了引发免疫应答的能力的功能性片段。
2.权利要求1的肽，其中所述同源物与由鉴定为MS4、MS11、MS14或MS16的可获自B组链球菌的基因所编码的肽具有至少80％的序列相似性。
3.根据权利要求1的肽，其任一氨基酸序列为已确定的SEQ ID NOS.2，4，6，8和10。
4.根据权利要求1-3任一项的肽，其用于医疗用途。
5.编码权利要求1-3任一项的肽的多核苷酸，其用于医疗用途。
6.一种被转化以表达权利要求1-3任一项的肽的宿主。
7.包含权利要求1-3任一项的肽的疫苗，或用于其表达的工具。
8.权利要求1-6中任一权利要求的产物的用途，用于与细菌感染相关的疾病治疗或预防的药物的制造。
9.根据权利要求8的用途，其中的感染是B组链球菌感染。
10.根据权利要求8或9的用途，其中的感染是病灶性感染。
11.根据权利要求8或9的用途，其中的感染是尿道感染。
12.一种抗权利要求1-3任一项的肽的抗体。
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9828346.8A GB9828346D0 (en) | 1998-12-22 | 1998-12-22 | Protein and compositions containing it |
| GBGB9901234.6A GB9901234D0 (en) | 1999-01-20 | 1999-01-20 | Protein and compositions containing it |
| GBGB9901233.8A GB9901233D0 (en) | 1999-01-20 | 1999-01-20 | Protein and compositions containing it |
| GBGB9908321.4A GB9908321D0 (en) | 1999-04-12 | 1999-04-12 | Purine nucleoside phosphatase and compositions containing it |
| GBGB9912036.2A GB9912036D0 (en) | 1999-05-24 | 1999-05-24 | Glucose-6-phosphate isomerase and compositions containing it |
| GB9828346.8 | 1999-09-23 | ||
| GB9901233.8 | 1999-09-23 | ||
| GB9901234.6 | 1999-09-23 | ||
| GB9912036.2 | 1999-09-23 | ||
| GB9922596.3 | 1999-09-23 | ||
| GB9908321.4 | 1999-09-23 | ||
| GBGB9922596.3A GB9922596D0 (en) | 1999-09-23 | 1999-09-23 | Protein and compositions containing it |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99814781A Division CN1357045A (zh) | 1998-12-22 | 1999-12-22 | 外表面蛋白质及其基因和用途 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101486756A true CN101486756A (zh) | 2009-07-22 |
Family
ID=27547330
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100047117A Pending CN1733800A (zh) | 1998-12-22 | 1999-12-22 | 外表面蛋白质及其基因和用途 |
| CN99814781A Pending CN1357045A (zh) | 1998-12-22 | 1999-12-22 | 外表面蛋白质及其基因和用途 |
| CNA2008101761856A Pending CN101486756A (zh) | 1998-12-22 | 1999-12-22 | 外表面蛋白质及其基因和用途 |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100047117A Pending CN1733800A (zh) | 1998-12-22 | 1999-12-22 | 外表面蛋白质及其基因和用途 |
| CN99814781A Pending CN1357045A (zh) | 1998-12-22 | 1999-12-22 | 外表面蛋白质及其基因和用途 |
Country Status (24)
| Country | Link |
|---|---|
| US (3) | US7217415B1 (zh) |
| EP (2) | EP1574579A3 (zh) |
| JP (1) | JP2002533065A (zh) |
| KR (4) | KR100818815B1 (zh) |
| CN (3) | CN1733800A (zh) |
| AP (1) | AP2006003504A0 (zh) |
| AT (1) | ATE297995T1 (zh) |
| AU (1) | AU758722B2 (zh) |
| BR (1) | BR9916473A (zh) |
| CA (1) | CA2354843A1 (zh) |
| CZ (1) | CZ20012174A3 (zh) |
| DE (1) | DE69925866T2 (zh) |
| DK (1) | DK1140994T3 (zh) |
| EA (1) | EA009885B1 (zh) |
| ES (1) | ES2241352T3 (zh) |
| HK (1) | HK1039339A1 (zh) |
| HU (1) | HUP0201022A3 (zh) |
| NO (1) | NO20013101L (zh) |
| NZ (4) | NZ542777A (zh) |
| OA (1) | OA12425A (zh) |
| PL (1) | PL351027A1 (zh) |
| PT (1) | PT1140994E (zh) |
| SI (1) | SI1140994T1 (zh) |
| WO (1) | WO2000037490A2 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110669711A (zh) * | 2019-08-09 | 2020-01-10 | 中国水产科学研究院珠江水产研究所 | 基于pgk基因的重组乳酸乳球菌和无乳链球菌病疫苗 |
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|---|---|---|---|---|
| NZ542777A (en) * | 1998-12-22 | 2007-11-30 | Microscience Ltd | Genes in Group B Streptococcus (GBS), and also related organisms, the products of which are associated with the outer surface of the organism, and are useful as targets for immunotherapy |
| US6890539B2 (en) * | 1998-12-22 | 2005-05-10 | Microscience, Ltd. | Genes and proteins, and their use |
| PT1141308E (pt) * | 1998-12-22 | 2007-05-31 | Microscience Ltd | Ptroteínas de streptococcus do grupo b e sua utilização |
| EP2104512A2 (en) * | 2006-12-21 | 2009-09-30 | Emergent Product Development UK Limited | Streptococcus proteins, and their use in vaccination |
| CN103060284A (zh) * | 2012-10-31 | 2013-04-24 | 内蒙古民族大学 | 一种无乳链球菌pgk亚单位重组蛋白及其制备方法 |
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| EP0230777B1 (en) | 1985-12-28 | 1991-04-10 | Ohgen Research Laboratories Ltd., | Antitumor protein gene of streptococcus pyogenes su, plasmids containing the gene, transformant cells harboring the plasmids, and process for producing the antitumor protein |
| US5328996A (en) * | 1989-03-29 | 1994-07-12 | University Of Florida Research Foundation, Inc. | Bacterial plasmin receptors as fibrinolytic agents |
| CA2127550A1 (en) * | 1992-01-08 | 1993-07-22 | Vincent Fischetti | Multifunctional surface protein of streptococci |
| IL107458A0 (en) * | 1992-11-02 | 1994-02-27 | Gen Hospital Corp | Conjugate vaccine against group b streptococcus |
| KR100331358B1 (ko) * | 1993-03-19 | 2002-08-13 | 구나르린달 | 그룹B스트렙토코커스의많은균주들에대한면역성을제공하는세포표면단백질인Rib단백질,그단백질의정제방법,시약키트및제약조성물 |
| US6015889A (en) * | 1993-03-19 | 2000-01-18 | Gunnar Lindahl | Protein rib, a cell surface protein that confers immunity to many strains of the group B streptococcus: process for purification of the protein, reagent kit and pharmaceutical composition |
| US6346392B1 (en) | 1996-11-27 | 2002-02-12 | Smithkline Beecham Corporation | Polynucleotides encoding a novel glutamine transport ATP-binding protein |
| WO1998018931A2 (en) * | 1996-10-31 | 1998-05-07 | Human Genome Sciences, Inc. | Streptococcus pneumoniae polynucleotides and sequences |
| US7196164B2 (en) * | 1997-07-08 | 2007-03-27 | Human Genome Sciences, Inc. | Secreted protein HHTLF25 |
| US7129340B1 (en) * | 1997-07-02 | 2006-10-31 | sanofi pasteur limited/sanofi pasteur limitée | Nucleic acid and amino acid sequences relating to streptococcus pneumoniae for diagnostics and therapeutics |
| US6800744B1 (en) * | 1997-07-02 | 2004-10-05 | Genome Therapeutics Corporation | Nucleic acid and amino acid sequences relating to Streptococcus pneumoniae for diagnostics and therapeutics |
| US6380370B1 (en) * | 1997-08-14 | 2002-04-30 | Genome Therapeutics Corporation | Nucleic acid and amino acid sequences relating to Staphylococcus epidermidis for diagnostics and therapeutics |
| US6165763A (en) * | 1997-10-30 | 2000-12-26 | Smithkline Beecham Corporation | Ornithine carbamoyltransferase |
| US6248329B1 (en) * | 1998-06-01 | 2001-06-19 | Ramaswamy Chandrashekar | Parasitic helminth cuticlin nucleic acid molecules and uses thereof |
| NZ542777A (en) * | 1998-12-22 | 2007-11-30 | Microscience Ltd | Genes in Group B Streptococcus (GBS), and also related organisms, the products of which are associated with the outer surface of the organism, and are useful as targets for immunotherapy |
| US6890539B2 (en) * | 1998-12-22 | 2005-05-10 | Microscience, Ltd. | Genes and proteins, and their use |
| PT1141308E (pt) * | 1998-12-22 | 2007-05-31 | Microscience Ltd | Ptroteínas de streptococcus do grupo b e sua utilização |
| US6605709B1 (en) * | 1999-04-09 | 2003-08-12 | Genome Therapeutics Corporation | Nucleic acid and amino acid sequences relating to Proteus mirabilis for diagnostics and therapeutics |
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- 1999-12-22 JP JP2000589559A patent/JP2002533065A/ja active Pending
- 1999-12-22 CN CNA2005100047117A patent/CN1733800A/zh active Pending
- 1999-12-22 CA CA002354843A patent/CA2354843A1/en not_active Abandoned
- 1999-12-22 EP EP05009397A patent/EP1574579A3/en not_active Withdrawn
- 1999-12-22 CZ CZ20012174A patent/CZ20012174A3/cs unknown
- 1999-12-22 PL PL99351027A patent/PL351027A1/xx not_active IP Right Cessation
- 1999-12-22 BR BR9916473-6A patent/BR9916473A/pt not_active Application Discontinuation
- 1999-12-22 KR KR1020017007910A patent/KR100818815B1/ko not_active Expired - Fee Related
- 1999-12-22 KR KR1020067017195A patent/KR100866170B1/ko not_active Expired - Fee Related
- 1999-12-22 NZ NZ512296A patent/NZ512296A/en unknown
- 1999-12-22 ES ES99962421T patent/ES2241352T3/es not_active Expired - Lifetime
- 1999-12-22 AT AT99962421T patent/ATE297995T1/de not_active IP Right Cessation
- 1999-12-22 PT PT99962421T patent/PT1140994E/pt unknown
- 1999-12-22 US US09/868,195 patent/US7217415B1/en not_active Expired - Fee Related
- 1999-12-22 NZ NZ552871A patent/NZ552871A/en unknown
- 1999-12-22 EA EA200100701A patent/EA009885B1/ru not_active IP Right Cessation
- 1999-12-22 EP EP99962421A patent/EP1140994B1/en not_active Expired - Lifetime
- 1999-12-22 HU HU0201022A patent/HUP0201022A3/hu unknown
- 1999-12-22 AU AU18779/00A patent/AU758722B2/en not_active Ceased
- 1999-12-22 WO PCT/GB1999/004376 patent/WO2000037490A2/en not_active Application Discontinuation
- 1999-12-22 DE DE69925866T patent/DE69925866T2/de not_active Expired - Fee Related
- 1999-12-22 DK DK99962421T patent/DK1140994T3/da active
- 1999-12-22 SI SI9930811T patent/SI1140994T1/sl unknown
- 1999-12-22 CN CN99814781A patent/CN1357045A/zh active Pending
- 1999-12-22 OA OA1000162A patent/OA12425A/en unknown
- 1999-12-22 CN CNA2008101761856A patent/CN101486756A/zh active Pending
- 1999-12-22 AP AP2006003504A patent/AP2006003504A0/xx unknown
- 1999-12-22 NZ NZ525538A patent/NZ525538A/en unknown
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2001
- 2001-06-21 NO NO20013101A patent/NO20013101L/no not_active Application Discontinuation
- 2001-12-20 HK HK01108929A patent/HK1039339A1/xx not_active IP Right Cessation
-
2005
- 2005-12-29 US US11/321,475 patent/US20060104990A1/en not_active Abandoned
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2007
- 2007-01-26 KR KR1020070008368A patent/KR20070027665A/ko not_active Ceased
- 2007-08-17 US US11/892,013 patent/US20080226641A1/en not_active Abandoned
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110669711A (zh) * | 2019-08-09 | 2020-01-10 | 中国水产科学研究院珠江水产研究所 | 基于pgk基因的重组乳酸乳球菌和无乳链球菌病疫苗 |
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