CN1650014A - 用于治疗肿瘤的作为编码细胞抗原的核苷酸序列的载体的微生物 - Google Patents
用于治疗肿瘤的作为编码细胞抗原的核苷酸序列的载体的微生物 Download PDFInfo
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Abstract
本发明涉及具有编码插入了下列成分的细胞抗原的核苷酸序列的微生物，并且这些插入成分是可表达的：I)编码肿瘤细胞抗原的至少一个表位的核苷酸序列，和/或编码特异于产生了肿瘤的组织细胞抗原的至少一个表位的核苷酸序列；II)编码刺激免疫系统的细胞的蛋白质的可选择的核苷酸序列；IIIA)编码转运系统的一种核苷酸序列，它使得成分I)任意选择性地，成分II)的表达产物在细菌的外表面实现表达，和/或使得成分I)任意选择性地，成分II)的表达产物分泌；和/或IIIB)编码用于在哺乳动物细胞的胞质溶液中裂解微生物和用于胞内释放质粒的蛋白质的核苷酸，所述的质粒包含于裂解微生物内；和IV)用于表达I)到IIIB)的一种或几种成分的活化序列，所述的活化序列选自“能够在微生物中活化的，组织细胞特异性的，但是不是细胞特异性的活化序列”，从I)到IV)各个成分可以相同或不同，各个成分以一个或多个拷贝存在。还公开了这样的微生物在生产药物中的应用。
Description
发明领域
本发明涉及携带外源核苷酸序列的微生物，涉及其作为药物特别是作为疫苗的用途，涉及携带外源核苷酸序列的质粒和用于生产这样的微生物的方法。
发明背景和现有技术
对于大多数病例，恶性肿瘤疾病引起致命的后果的主要原因是身体防御系统不能检测和毁坏恶性肿瘤癌细胞。在工业高度发展的国家，癌症疾病属于具有致命病程的最普遍的疾病。仅仅在德国，每年超过210000的人死于新形成的恶性疾病(来源：WHO，1997年的数据)，相当于每100,000居民超过255人的年死亡速度。
本发明基于产生恶性畸变的分子机理的近来的新发现。在癌症已经形成的早期阶段，产生了控制细胞生长和/或细胞分化的特征性变化(Pronten，癌症存活性32：5-35，1998)。主要参与这些变化的是信号转导和细胞周期控制的蛋白质，这些蛋白质在近年得到鉴定，它们也是肿瘤抗原。
肿瘤抗原大致可以分为三组(Pardoll，Nat.Med.4：525-531，1998)：i)肿瘤特异性新抗原，它以突变的和/或过度表达的形式存在于肿瘤细胞中例如EGF-R，HER-2，ii)肿瘤特异性胚胎抗原，例如MAGE蛋白质家族的成员或CEA，iii)肿瘤组织特异性分化抗原，例如酪氨酸酶，Mart-1/Melan-A和gp100。
对于肿瘤疫苗的效果，CD8+T细胞的有效诱导是决定性的，因为在大多数病例中肿瘤细胞不表达MHC类型II分子，在大多数病例中胞内存在的肿瘤抗原是重新组装(restringiert)的MHC类型I。对于肿瘤病人，天然存在的CD8+，胞毒性T细胞(CTL)群体，明显不足以检测和去除肿瘤细胞(Jaffee，Ann.N.Y.Acad.sci.886：67-72，1999)。此外，由于机理(无反应性，耐受力，中和力)不同肿瘤特异性T细胞不能有效地攻击肿瘤组织(Smyth等人，Nat.Immunol 2：293-299，2001)。因此成功的疫苗必须打破这种无反应性或耐受力并且诱导足够量的激活的，特异性CTL以及特异性抗体。通过使用抗组(a)的肿瘤抗原的单克隆抗体(mAbs)，例如已经商品化的一种抗HER-2的mAb单克隆抗体(herceptin)，可以看到特异性抗体的作用(Colomer等人，Cancer Invest 19：49-56，2001)。
已知减毒的胞内细菌适合作为抗某些细菌感染的疫苗载体，特别是那些受所谓的Th1免疫应答的控制的(Hess and Kaufmann，FEMSImmunology & Medical Microbiology 23：165-173，1999)。这种应答的特征是CTL以及呈现特异的分泌IFN-g的CD4+T细胞(也是T辅助细胞，Th)(Abbas等人，Nature 383：787-793，1996)。其他组已经显示重组细菌可以针对异源肿瘤提供保护(Medina等人，Eur.J.Immunol.29：693-699，1999；Pan等人，Cancer Res 59：5264-5269，1999；Woodlock等人，J.Immunother.22：251-259，1999；Paglia等人，Blood，92：3172-3176，1998；Paglia等人，Eur.J.Immunol.27：1570-1575，1997；Pan等人，Nat.Med.1：471-477，1995；Pan等人，Cancer Res.55：4776-4779，1995)。但是在这些情况下，给动物免疫接种以抵抗替代抗原，然后应用表达该抗原的肿瘤细胞。
但是这些肿瘤系统不能与临床肿瘤相比，因为这些模型对肿瘤抗原没有耐受力。
相当数量的不同肿瘤疫苗已经在临床上进行研究。但是至今为止，没有任何肿瘤疫苗或免疫接种方法在肿瘤疾病的治疗中取得突破。基于这样的背景，对新的肿瘤治疗方法仍然存在迫切的需求。
在本领域内已知，导入细菌中的核酸序列的表达产物在这些细菌的细胞膜上表达，或者将它们从这些细菌中分泌。该技术的基础是代表格兰氏阴性细菌的I型分泌系统的原型的大肠杆菌溶血素系统HlyAs。借助于HlyAs，研制了分泌型载体，允许有效地去除肠炎沙门氏菌(Salmonella enterica)，小肠结肠炎耶尔森氏菌(Yersiniaenterocolitica)，霍乱弧菌(Vibrio cholerae)中的蛋白质抗原。这样的分泌型载体含有结合到编码下述产物的核苷酸序列上任意蛋白质抗原的cDNA，所述产物指用于溶血素分泌器的HlyA信号肽，hlyB和hlyD和hly特异性启动子，借助于该分泌载体，可以在该细菌的表面表达蛋白质。这样的遗传工程修饰的细菌作为疫苗诱导一种比细菌具有更高的免疫保护作用，其中由导入的核酸表达的蛋白质保留在细胞内(Donner等人，EP1015023A；gentschev等人，Gene，179：133-140，1996；疫苗19：2621-2618，2001；Hess等人PNAS 93：1458-1463，1996)。但是该系统的缺点是通过使用hly-特异性启动子，在该细菌的外表面表达的蛋白质的量是非常小的。
研制了借助于载体细菌，例如沙门氏菌和单核细胞增生李斯特氏菌(Listeria monocytogenes)将质粒DNA插入到哺乳动物细胞中的技术。当它们处于真核启动子控制下时，包含于这些质粒中的基因也在哺乳动物细胞中表达。将质粒导入到单核细胞增生李斯特氏菌中，所述的质粒包含任意真核启动子控制下的任意抗原的核苷酸序列。通过将该核苷酸序列导入特异性裂解基因，获得了单核细胞增生李斯特氏菌溶解于抗原呈递细胞的胞质溶液中并且释放它们的质粒，这导致随后质粒编码的蛋白质的表达、加工和呈递，并且明显增加这些蛋白质的免疫原性(Dietrich等人，Nat.Biothechnol.16：181-185，1998；Vaccine 19：2506-2512，2001)。
研制了减毒的，定居于胞内的细菌。例如单核细胞增生李斯特氏菌变种，肠炎沙门氏菌鼠伤寒沙门氏菌和伤寒沙门氏菌种(Salmonellaenterica.sv.Typhimurium和Typhi)，和牛分枝杆菌已用作为耐受力极好的抗斑疹伤寒和肺结核的活疫苗。这些细菌，包括它们的减毒突变体通常是免疫刺激的，并且可以引发良好的细胞免疫应答。例如，单核细胞增生李斯特氏菌刺激至特定程度的TH1细胞活化，胞毒性T-淋巴细胞增殖。这些细菌提供分泌的抗原直接进入抗原呈递细胞的胞质溶液(APC，巨噬细胞和树枝状的细胞)，依次表达共刺激分子并且引起T细胞的有效刺激。李斯特氏菌在吞噬区室中被部分降解，从而由这些细菌产生的抗原一方面由MHC II类分子呈递，因此导致T辅助细胞诱导。另一方面，在从吞噬区室中释放后，李斯特氏菌在APCs的胞质溶液中复制；由这些细菌产生和分泌的抗原优选的是由MHCI类途径呈递，因此诱导抗这些抗原的CTL应答。此外，可以证明通过李斯特氏菌和巨噬细胞，天然杀死细胞(NK)和中性粒细胞相互作用，诱导这些细胞因子的表达(TNF-α，IFN-γ，IL-2，IL-12；Unanue，Curr.Opin.Immunol.，9：35-43，1997；Mata & Paterson，J.Immunol.163：1449-14456，1999)，对此已检测到抗肿瘤效果。通过施用经转导以表达肿瘤抗原的单核细胞增生李斯特菌，抗原可以特异性地抑制试验肿瘤的生长(Pan等人，Nat Med 1：471-477，1995；Cancer Res.59：5264-5269，1999；Voest等，Natl.Cancer Inst.87：581-586，1995；Beatty and Paterson，J. Immunol.165：5502-5508，2000)。
将引入了编码肿瘤抗原的核苷酸序列的减毒的肠炎沙门氏菌菌株作为表达病毒抗原的细菌载体，通过口服施用后会提供针对不同试验肿瘤的特异保护(Medina等人，Eur.J.Immunol.30：768-777，2000；Zoller和Christ，J.Immunol.166：3440-34450，2001；Xiang等人，PNAS 97：5492-5497，2000)。
重组沙门氏菌菌株也可以有效地作为预防性疫苗抗病毒感染(HPV)；(Benyacoub等人，Infect Immun 67：3674-3679，1999)以及用于治疗肿瘤病毒导致的无限增殖的的小鼠肿瘤(HPV)(Revaz等人，Virology 279：354-360，2001)。
发明的技术目的
本发明的目的是提供一种药物，尤其是作为在肿瘤预防和肿瘤治疗中的一种改进疫苗，它打破对肿瘤的免疫耐受力。
发明概述
为了达到该技术目的，本发明教导具有编码细胞抗原的核苷酸序列的微生物，其基因组中插入了下列成分，并且是可表达性的：I)编码至少肿瘤细胞的一种或几种抗原的表位的核苷酸序列，和/或编码特异于产生了肿瘤的组织细胞的一种或几种抗原的至少一个表位的核苷酸序列；II)编码刺激免疫系统的细胞的蛋白质的可选择的核苷酸序列；IIIA)编码转运系统的核苷酸序列，它使得成分I)任意选择性地，II)的表达产物在细菌的外表面表达，和/或使得成分I)任意选择性地，成分II)的表达产物分泌成为可能；和/或IIIB)编码用于在哺乳动物细胞的胞质溶液中裂解微生物和用于胞内释放质粒的蛋白质的核苷酸序列，所述的质粒包含于裂解的微生物内；和IV)用于表达I)到IIIB)的一种或几种成分的一种活化序列，所述的活化序列选自“能够在微生物中活化的，组织细胞特异性的，但是不是细胞特异性的活化序列”，I)到IV)各个成分可能以一个或多个拷贝存在，并且利用这样的微生物生产药物。
因此本发明的主体是微生物，这些微生物代表了编码细胞抗原的核苷酸序列的载体，这些核苷酸可以在微生物的外膜表达或分泌，本发明还包括这些微生物用于打破针对肿瘤的免疫耐受力，本发明还包括含作为编码正常细胞和/或肿瘤细胞的细胞抗原的核苷酸的载体的所述微生物的新肿瘤疫苗。借助本发明，最终引起直接抗肿瘤的免疫反应。
详细地说，本发明的微生物含有下列成分：I)至少一种编码肿瘤细胞的至少一种细胞蛋白质的至少一种抗原的至少一个表位的核苷酸序列和/或任意选择性地编码至少一种特异于衍生肿瘤的组织细胞的至少一种抗原的至少一个表位的核苷酸序列；II)任意选择性地编码至少一种刺激免疫系统细胞的至少一种蛋白质的核苷酸序列；IIIA)编码用于由成分I)编码的细胞抗原在膜上表达或分泌和用于分泌由成分编码的免疫刺激蛋白质的转运系统的至少一种核苷酸序列；IIIB)任意选择性地用于在胞质溶液中裂解微生物以使包含在所述微生物中的质粒释放到胞质溶液中的核苷酸；IV)编码至少一种能够在微生物中活化的或非细胞特异性，但是肿瘤细胞特异性，组织细胞特异性或功能特异性活化以表达成分I)和II)的活化序列的核苷酸序列。
优选的具体实施方式
下文中，将详细地描述本发明的微生物成分。
成分I)
成分I)代表编码肿瘤细胞的至少一种细胞蛋白质或至少一种致瘤突变的细胞蛋白质的至少一个抗原的至少一个表位的至少一个核苷酸序列。该细胞蛋白质的致瘤突变可能已经导致其原始细胞功能的失去或获得。此外，该细胞蛋白质可以选自于下列组：“受体分子或其部分，即该受体的胞外，跨膜或胞内部分；粘附分子或其部分，即粘附分子的胞外，跨膜或胞内部分；信号转导蛋白质；控制细胞周期的蛋白质；分化蛋白质；胚胎蛋白质；和病毒诱导蛋白质”。这样的细胞抗原在细胞中起着控制细胞生长和细胞分裂的作用并且呈递到正常细胞中的细胞膜上，例如由MHC I类分子呈递。在肿瘤细胞中，这些抗原经常过量表达或特异性地突变。这样的突变可能具有致癌基因抑制剂限制功能，或结果是将原-致癌基因激活为致癌基因，可以单独或共同参与肿瘤生长中的过量表达。这样的细胞抗原呈递到肿瘤细胞的膜上，因此代表了肿瘤细胞上的抗原，但是没有导致产生影响患者肿瘤疾病的免疫反应。Rapp(US5156841)已经描述了将致癌蛋白即致癌基因的表达产物用作为肿瘤疫苗的免疫原。该文献的详述作为本文参考。
本发明所属的细胞抗原和其致癌突变的例子有I)受体，例如Her-2/neu，雄激素受体，雌激素受体，midkine受体，EGF受体，ERBB2，ERBB4，TRAIL受体，FAS，TNFα受体；ii)信号转导蛋白质和其致癌突变，例如c-Raf(Raf-1)，A-Raf，B-Raf，Ras，Bc1-2，Bc1-x，Bc1-w，Bf1-1，Brag-1，Mc1-1，A1，Bax，BAD，Bak，Bc1-Xs，Bid，Bik，Hrk，Bcr/abl，Myb，C-Met，IAP1，IAO2，XIAP，ML-IAP LIVIN，survivin，APAF-1；iii)控制细胞周期的蛋白质和其致瘤突变，例如细胞周期蛋白D(1-3)，E，A，B，H，Cdk-1，-2，-4，-6，-7，cdc25c，P16，p15，p21，p27，p18，pRb，p107，p130，E2F(1-5)，GAAD45，MDM2，PCNA，ARF，PTEN，APC，BRCA，p53和同系物；iv)转录因子和其至瘤突变，例如C-Myc，NFkB，c-Jun，ATF-2，Sp1；v)胚胎蛋白质，例如癌胚胎抗原，α-胎儿蛋白质，MAGE，PSCA；vi)分化抗原，例如MART，Gp100，酪氨酸酶，GRP，TCF-4；vii)病毒抗原，例如下面的病毒：HPV，HCV，HPV，EBV，CMV，HSV。
可选择地或另外地，成分I)可以表示编码至少特异于正常组织细胞的一种抗原的至少一种核苷酸序列，所述的细胞衍生了肿瘤。这种特定的抗原例如是I)受体，例如雄激素受体，雌激素受体，乳铁蛋白受体；ii)分化抗原，例如碱性髓磷脂，α-乳白蛋白，GFAP，PSA，纤维性酸蛋白质，酪氨酸酶，EGR-1，MUC1。
成分II)
成分II)表示编码至少一种蛋白质的至少一种核苷酸序列，该蛋白质刺激细胞的免疫系统。通过选择该蛋白质，可以加强与成分I)的表达产物的免疫反应和/或以更有利于激活Th1细胞(对于细胞的免疫反应)进行定位或以更有利于激活Th2细胞(用于体液的免疫反应)进行定位。免疫刺激蛋白质例如是I)细胞因子，例如M-CSF，GM-CSF，G-CSF；ii)干扰素，例如IFN-α，β，γ；iii)白细胞介素，例如IL-1，-2，-3，-4，-5，-6，-7，-9，-10，-11，-12，-13，-14，-15，-16，人白血病抑制因子(LIF)，iV)化学因子，例如RANTES，单细胞趋化性和活化因子(MCAF)，巨噬细胞炎症因子蛋白质-1(MIP-1-α，β)，嗜中性活化蛋白质-2(NAP-2)，IL-8。
成分IIIA)
成分IIIA)是编码至少一种转运系统的至少一种核苷酸序列，该转运系统可以使成分I)和任意选择性地II)的表达产物在微生物的外表面进行表达。相应的成分可选择性地在微生物细胞膜上进行分泌或表达，即是膜结合的。这样的转运系统例如是I)大肠杆菌溶血素转运信号(含有处于hly特异性启动子控制下的HlyA，HlyB和HlyD的核苷酸序列)；下面的转运信号可用于：在HlyB和HlyD蛋白质存在下分泌-C-末端HlyA转运信号；在HlyB蛋白质的存在下膜结合表达-C-末端HlyA转运信号，ii)大肠杆菌的溶血素转运信号(含有处于非hly特异性细菌启动子控制下的HlyA，HlyB和HlyD的核苷酸序列)，iii)新月柄杆菌(caulobacter crescentus)的S-层蛋白质(RasA)的转运信号；可以将下面的转运蛋白用于：分泌和膜结合表达-C-末端RsaA转运信号，iv)大肠杆菌的To1C蛋白质的转运信号；可以将下面的转运蛋白用于：膜结合表达-大肠杆菌的To1C的N-末端转运信号，大肠杆菌的整合膜蛋白To1C是大肠杆菌的外膜的多功能孔-形成蛋白质，除了具有例如大肠菌素E1的受体(Morona等人，J.Bacteriol.153：693-699，1983)和大肠菌素V的分泌(Fath等人，J.Bacteriol.173：7549-7556，1991)的功能以外，还具有U3噬菌体的受体的功能(Austin等人，J.Bacteriol.172：5312-5325，1990)；该蛋白质不仅存在于大肠杆菌中，而且还存在于许多的格兰氏阴性细菌中(Wiener等人，Structure Fold Des 8：R171-175，2000)；其外膜定位和广泛的存在使得To1C是提供异源抗原的理想的候选者，以便例如引起免疫反应。
成分IIIB)
成分IIIB)是编码至少一种裂解蛋白质的核苷酸序列，它在哺乳动物细胞的胞质溶液表达并且裂解微生物以释放宿主细胞的胞质溶液中的质粒。这样的裂解蛋白质(内溶素)例如是处于李斯特启动子控制下的李斯特特异性裂解蛋白质，例如PLY551(Loessner等人，MolMicrobiol 16：1231-41，1995)和/或李斯特特异性的穴蛋白。
本发明的优选的具体实施方式是不同成分IIIB)的结合，例如裂解蛋白质和穴蛋白的结合。
成分IIIA和/或IIIB可以是组成型活化的。
成分IV)
成分IV)代表编码至少一种用于成分I)表达，任意选择性地II)的表达的活化序列的至少一种核苷酸序列。
如果表达是在微生物的外表面的膜结合的，活化序列优选的是选择那些能够在微生物中活化的。这样的活化序列例如是：I)组成型活化的启动子区域，例如大肠杆菌的β-内酰胺酶基因或tetA基因的具有“核糖体结合位点”(RBS)的启动子区域(Busby and Ebright，Cell79：743-746，1994)；ii)能够被诱导的启动子，优选的是在细胞中被接受后活化的启动子。单核细胞增生李斯特氏菌的启动子actA(Dietrich等人，Nat.Biotechnol.16：181-185，1998)或鼠伤寒沙门氏菌的pagC启动子(Bumann，Infect Immun 69：7493-7500，2001)属于这种类型。
如果裂解后质粒从微生物释放到细胞的胞质溶液，活化序列不是细胞特异的，但是组织特异的，细胞周期特异或功能特异的。优选的是选择这样的活化序列，特异地在巨噬细胞，树状细胞，淋巴细胞中活化。
本发明意义上的微生物是病毒，细菌或单细胞的寄生虫，它们通常被用于转移对微生物而言的外源的核苷酸序列。
在本发明的特定的具体实施方式中，微生物代表格兰氏阳性或格兰氏阴性细菌，优选的细菌，例如大肠杆菌，沙门氏菌，小肠结肠炎耶尔森氏菌(Yersinia enterocolitica)，霍乱弧菌(Vibriocholerae)，单核细胞增生李斯特氏菌，志贺氏菌(Shigella)。
优选的是，使用可以减毒的这样的细菌。
采用本领域技术人员已知的方法将本发明的成分导入微生物。如果该微生物代表细菌，将该成分插入到质粒，将质粒转移到细菌。本领域技术人员非常熟悉适用于该细菌和质粒的技术。
本发明的主体是含有本发明微生物或该微生物的膜包膜的药物制剂。该方法中涉及的这些膜包膜的制剂参见例如EP-A-0540525。这样的药物制剂例如是本发明的微生物溶于适用于注射的为药师所熟悉的溶液中的悬浮液。
本发明的另一方面涉及含有本发明的微生物的药物制剂的给药。局部或全身给药，例如表皮，皮下组织，肌肉系统，体腔，器官，肿瘤或血液循环。
本发明的特定方面是以本发明的药物进行经口或直肠给药以预防和/或治疗增殖疾病。给药可以一次或几次进行。在每次给药中，使用10-109本发明的微生物进行给药。如果以该数量的本发明的微生物进行给药时没有引起足够的免疫反应，则必须提高注射的量。
在以本发明的微生物给药后，破坏了对细胞呈递成分I)，例如对肿瘤细胞，或对衍生肿瘤的组织细胞的耐受力，并且激发了抗肿瘤和/或其组织细胞的胞毒性免疫反应。
基于选择的成分I)，该胞毒性免疫反应或只针对肿瘤或针对肿瘤细胞，包括衍生了肿瘤的组织细胞。
因此本发明的一个方面是将本发明的药物制剂给药以预防或治疗增殖疾病。增殖疾病是肿瘤疾病，白血病，病毒引起的疾病，慢性炎症，移植器官的排斥和自体免疫病。
在本发明的具体的实施方式中，其中成分I)代表了至少一个由肿瘤细胞和衍生肿瘤的组织细胞表达的细胞抗原，将本发明的药物给药以预防或治疗甲状腺，乳房，胃，肾，卵巢，痣，前列腺，子宫颈或膀胱、泌尿器肿瘤。
下面，将详细解释本发明，基于仅仅代表实施例的具体方式。实施例1：通过表达c-raf的沙门氏杆菌免疫接种，在BxB小鼠中诱导免疫应答
Raf是常规的胞质丝氨酸/苏氨酸激酶(PSK)，它与其他蛋白自的信号级联系统结合控制细胞生长和存活(Kerkhoff and Rapp，Oncogene 17：1457-1462，1998；Troppmair and Rapp，RecentResults Cancer Res.143：245-249，1997)。生长因子与相应的受体结合通常借助于Ras的活化，以及随后的基于PSK和酪氨酸激酶MEK和PSK ERK的几个磷酸化步骤将Raf活化以激活细胞核中的复制机理(Kerkhoff and Rapp，Oncogene 17：1457-1462，1998)。该链中的第一个连接，修饰形式的小G蛋白质Ras存在于30％的人肿瘤中(Zachos和Spandidos，Crit.Rev.Oncol.Hematol.26：65-75，1997)。Raf是Ras的一种效应因子，并且以过度表达形式在许多人肿瘤中存在(Naumann等人，Recent Results Cancer Res.143：237-244，1997)。
对于在小鼠模型中的测试，使用过度表达整个分子或组成型激活激酶区域(BxB)的转基因小鼠(Kerkhoff等人，Cell Growth Differ11：185-190，2000)。其中约半年后小鼠皮下产生肺肿瘤。
对于疫苗的生产，利用PCR将人的c-Raf cDNA克隆到质粒pMOhly1HlyA读框处(附图1)。随后，将质粒pMO-Raf转移到减毒的沙门氏菌(鼠伤寒沙门氏菌SL7207)，其带有芳香代谢缺陷(Hoiseth和Stocker，Nature 291：238-239，1981)。在借助于抗c-Raf抗体的免疫印迹中，可以在PMOhy-Raf感染的SL7207细菌的细菌裂解液和培养物上清液中检测到c-Raf HlyAs融合蛋白。
以沙门氏菌(5×109)口服免疫接种7-10周龄的BxB转基因小鼠，以5天的间隔重复免疫接种2次，最后一次免疫的45天之后以5×105沙门氏菌静脉免疫接种复新免疫接种。为了控制目的，以裸露的c-Raf编码DNA肌内给药小鼠。
在最后接种之后5-7天，获取血清样品，借助于免疫印迹分析抗体应答。为此，将1∶200稀释血清与膜上的分离的蛋白质和c-Raf转染的或未转染的细菌的印迹的蛋白质杂交。借助于特异于小鼠IgG的抗体进行结合到血清抗体的检测。与对照小鼠相反，用pMOhly1-Raf转染的SL7207免疫接种，可以诱导同种型IgG的c-Raf特异性抗体。因此已经证明用上面描述的沙门氏菌进行免疫接种可以破坏自身的耐受力以及诱导CD4+T细胞，这对于抗体同种型变化为IgG是必要的。
为了分析CD8+T细胞应答，用相同的方法给C57BL-6小鼠免疫接种。在最后一次免疫接种7天之后，分离脾脏细胞，并且用Raf过表达的EL-4细胞刺激经分离的脾细胞。在刺激开始后1小时，由布雷菲德菌素A阻止泡囊的运输，在另一个4小时之后，用CD8和IFN-g-特异性抗体染色细胞，并且用流式细胞计数器分析(Mittrucker等人，Infect Immun 70：199-203，2002)。仅仅在一个小鼠pMO-Raf-免疫接种的小鼠中，可以检测到Raf特异的抗体免疫应答。
对于杀肿瘤活性的检测，杀死10，12和14月龄的免疫接种和未免疫接种的BxB小鼠，称量肺质量。肺质量是对肿瘤大小的直接测量。与对照组包括已经用编码c-Raf的裸DNA(SL-pCMV-raf)免疫接种的组相比用SL-pMO-Raf免疫接种的一组中，在14个月之后清楚地看到肺质量减少的小鼠出现的频率更高。通常，在未处理的动物中肿瘤生长是不可逆的(Kerkhoff等人，Cell Growth Differ.11：185-190，2000)。这些数据显示该实验中用SL-pMO-Raf免疫接种动物可以抵抗肿瘤的生长，本文描述的发明适用于作为肿瘤疫苗。
这些实验进一步显示作为本发明代表的载体系统主要破坏自身耐受力并且在c-Raf-耐受动物中诱导c-Raf特异性抗体应答以及T细胞应答。
借助于相同的试验系统，可以将沙门氏菌作为疫苗生产，它表达异型的C-Raf(例如B-Raf和A-Raf)突变的C-Raf，B-Raf或A-Raf，正常的或突变的C-Raf，B-Raf或A-Raf的表位，或正常和/或突变的C-Raf，B-Raf或A-Raf的表位的重组体。由于Raf活性的损失伴随的突变的例子是Ras结合的区域，激酶区域和/或预防位点的突变。
实施例2：用表达PSA的沙门氏菌免疫接种BALB/C小鼠诱导免疫应答
除了这些标记的诊断用途以外，组织特异性抗原特别是由肿瘤细胞合成和高程度表达的那些组织特异性抗原的存在也是治疗途径的可能的起始点。对于前列腺癌，至今为止，已经鉴定了三种有价值的抗原：PSA(前列腺-特异性抗原)，PSMA(前列腺特异性膜抗原)和PSCA(前列腺干细胞抗原)。PSA以过量表达方式已经存在于早期肿瘤形式(Watt等人，Proc.Natl.Acad.Sci.USA 83：3166-3170，1986；Wang等人，Prostate 2：89-96，1981)和因此可用于肿瘤诊断(Labrie等人，J. Urol.147：846-851，discussion 851-842，1992)；在大多数情况下PSCA表达仅仅在局部发展的，去分化和转移肿瘤阶段获得增加(Gu等人，Oncogene 19：1288-1296，2000；Reiter，等人，Proc.Natl.Acad.Sci.USA 95：1735-1740，1998)。器官特异性使得PSA以及PSCA成为潜在的靶抗原用于研制抗前列腺癌的免疫治疗(Reiter等人，Proc.Natl.Acad.Sci.USA 95：1735-1740，1998；Hodge等人，Int.J.Cancer 63：231-237，1995；Armbruster，Clin.Chem.39：181-195，1993)。
在该起始的试验中，计划证明基于载体pMOHLY1分泌PSA的沙门氏菌是否在BALA/c小鼠中诱导免疫应答。为此，采用聚合酶链反应(PCR)将开头的两个NsiI接头导入到PSA的c-DNA序列中，以便使得经过扩增的片段尽可能以框内形式插入到靶载体。为了扩增，选择645碱基对(bp)的片段。以5’-GTGGATTGGTGATGCATCCCTCATC-3’和5’-CAGGGCACATGCATCACTGCCCCA-3’作为引物。首先将PCR产物末端平齐化克隆到pUC18载体并且后来借助于NsiI接头连接到靶载体pMOhly1。借助于限制性酶消化确证插入正确并且通过序列分析进行证实(附图2)。
借助于该沙门氏菌株，现在以3周的间隔用1×107的剂量给BALB/c小鼠鼻下免疫接种3次。用Western印迹分析方法和胞内细胞因子染色方法检测免疫应答。
Claims (17)
1.具有编码细胞抗原的核苷酸序列的微生物，其基因组中插入了下列成分并且这些成分是可表达的：
I)编码肿瘤细胞的一种或几种抗原的至少一个表位的核苷酸序列和/或编码特异于衍生肿瘤的组织细胞的一种或几种抗原的至少一个表位的核苷酸序列；
II)编码刺激免疫系统的细胞的蛋白质的任意选择性核苷酸序列；
IIIA)转运系统的核苷酸序列，使得成分I)和任意选择性地成分II)的表达产物在细菌的外表面表达和/或分泌成分I)和任意选择性地成分II)的表达产物成为可能，和/或
IIIB)编码用于在哺乳动物细胞胞质溶液中裂解微生物和用于胞内释放质粒的蛋白质的核苷酸序列，所述质粒包含于裂解的微生物内；和
IV)用于表达I)到IIIB)的一个或几个成分的活化序列，所述的活化序列选自：“能够在微生物中活化的，组织特异性的，但不是细胞特异性的活化序列”。
其中从I)到IV)的各个成分可以是相同或不同，各个成分以一个或多个拷贝存在。
2.根据权利要求1所述的微生物，其中该微生物是病毒，细菌，特别是格兰氏阳性或格兰氏阴性细菌，优选的是选自：“大肠杆菌，沙门氏菌，小肠结肠炎耶尔森氏菌，霍乱弧菌，单核细胞增生李斯特氏菌，志贺氏菌”，或是单细胞的寄生虫，优选的是该微生物的毒性被降低。
3.根据权利要求1所述的微生物，其中该微生物是细菌的胞膜。
4.根据权利要求1-3任一项所述的微生物，其中成分I)是编码任意选择性地突变肿瘤细胞的一种或几种蛋白质的一种或几种抗原的一个表位或几个表位的核苷酸序列，其中该蛋白质优选地选自：“受体的胞外，跨膜或胞内部分；粘附分子的胞外，跨膜或胞内部分；信号转导蛋白质；控制细胞周期的蛋白质；转录因子，分化蛋白质；胚胎蛋白质；和病毒蛋白质”，该蛋白质优选地是致癌基因产物或阻遏基因产物，特别是c-Raf，A-Raf或B-Raf或c-Raf，A-Raf或B-Raf的同源蛋白质。
5.根据权利要求1-3任一项所述的微生物，其中成分I)是编码特异于衍生肿瘤的组织细胞的一种抗原的核苷酸，所述组织细胞特别是选自于下列组“甲状腺，乳腺，唾液腺，淋巴结，乳腺，胃粘膜，肾，卵巢，前列腺，子宫颈，浆膜，膀胱泌尿器和痣”。
6.根据权利要求1-5任一项所述的微生物，包括权利要求4的成分I)和权利要求5的成分I)。
7.根据权利要求1-6任一项所述的微生物，其中成分II)编码至少一种细胞因子，白介素，干扰素和/或细胞因子。
8.根据权利要求1-7任一项所述的微生物，其中成分IIIA)编码大肠杆菌的溶血素转运信号，编码新月柄杆菌的S-层(Rsa A)蛋白质，或大肠杆菌的To1C蛋白质。
9.根据权利要求1-8任一项所述的微生物，其中成分IIIB)编码格兰氏阳性细菌的裂解蛋白质，编码单核细胞增生李斯特氏菌的裂解蛋白质，编码单核细胞增生李斯特氏菌的PLY551和/或编码单核细胞增生李斯特氏菌的穴蛋白。
10.根据权利要求1-9任一项所述的微生物，其中成分IV)编码能够在微生物中被激活的活化序列，特别是编码肿瘤细胞特异性，组织细胞特异性，巨噬细胞特异性，树突特异性，淋巴细胞特异性，功能特异性活化序列，或被细胞非特异性激活的活化序列。
11.根据权利要求1-10任一项所述的微生物，其中成分I)编码至少两种不同蛋白质。
12.权利要求1-11的微生物在生产药物中的，特别是用于预防和/或治疗疾病中的应用，所述的疾病是由非控制性细胞分裂或感染引起的，优选的是肿瘤疾病，特别是前列腺癌，卵巢癌，乳房癌，胃癌，肾肿瘤，甲状腺肿瘤，黑素瘤，子宫颈肿瘤，膀胱排尿器肿瘤，唾液腺肿瘤或淋巴结肿瘤，白血病，病毒或细菌感染，慢性炎症，器官排斥和/或自体免疫疾病。
13.权利要求12所述的应用，用于去除肿瘤以及衍生肿瘤的健康组织。
14.权利要求12或13所述的应用，其中制备用于局部，非肠道的，口服或直肠给药的药物。
15.根据权利要求12-15之一生产药物的方法，其中制备生理有效量的权利要求1-11之一所述的微生物与一种或几种生理耐受的载体物质，用于口服，肌内的，静脉内的，腹膜内的，直肠或局部给药。
16.包括权利要求1的成分I)-IV)的质粒或表达载体。
17.用于生产权利要求1-11之一的微生物的方法，其中生产权利要求16的质粒或表达载体，用该质粒或表达载体转化微生物。
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| EP1921149A1 (en) | 2006-11-13 | 2008-05-14 | AEterna Zentaris GmbH | Microorganisms as carriers of nucleotide sequences coding for antigens and protein toxins, process of manufacturing and uses thereof |
| DK2774621T3 (en) | 2007-01-25 | 2018-05-07 | Intrexon Actobiotics Nv | TREATMENT OF IMMUNE DISEASE BY MUCOSAL ADMINISTRATION OF ANTIGENS |
| KR101104077B1 (ko) | 2008-10-14 | 2012-01-11 | 건국대학교 산학협력단 | Ｅｇｒ－１의 발현을 증가시키는 활성을 갖는 신규한 엔터로박테리아속에 속하는 신규균주 및 그 균주를 포함하는 조성물의 항암제로서의 용도 |
| KR101346620B1 (ko) * | 2011-11-30 | 2014-01-06 | 전남대학교산학협력단 | 신규 박테리아 용해 단백질 및 그의 용도 |
| RU2551238C9 (ru) * | 2013-08-02 | 2016-04-10 | Федеральное государственное бюджетное учреждение "Медико-генетический научный центр" Российской академии медицинских наук | Способ индукции апоптоза клеток злокачественной опухоли колоректального рака и средство для его осуществления |
| US11576936B2 (en) | 2016-12-07 | 2023-02-14 | Salspera, Llc | Methods of synergistic treatment of cancer |
| AR114683A1 (es) * | 2018-02-09 | 2020-10-07 | Consejo Nacional De Investigaciones Cientificas Y Tecn Conicet | Polipéptidos inmunomoduladores e inmunoestimulantes para suministro de drogas |
| WO2020232389A1 (en) * | 2019-05-16 | 2020-11-19 | City Of Hope | Compositions and methods for targeting tumor-associated extracellular matrix components to improve drug delivery |
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| RU1438240C (ru) * | 1987-04-22 | 1996-03-20 | Институт биоорганической химии им.М.М.Шемякина и Ю.А.Овчинникова РАН | РЕКОМБИНАНТНАЯ ПЛАЗМИДНАЯ ДНК РТNF 22, СОДЕРЖАЩАЯ ПОЛУСИНТЕТИЧЕСКИЙ ГЕН ФАКТОРА НЕКРОЗА ОПУХОЛИ ЧЕЛОВЕКА - ПРОМЕЖУТОЧНАЯ ПЛАЗМИДА ДЛЯ КОНСТРУИРОВАНИЯ РЕКОМБИНАНТНОЙ ПЛАЗМИДНОЙ ДНК pTNF 31, КОДИРУЮЩАЯ ПОЛИПЕПТИД СО СВОЙСТВАМИ ФАКТОРА НЕКРОЗА ОПУХОЛИ ЧЕЛОВЕКА, И ШТАММ БАКТЕРИЙ ESCHERICHIA COLI - ПРОДУЦЕНТ ПОЛИПЕПТИДА СО СВОЙСТВАМИ ФАКТОРА НЕКРОЗА ОПУХОЛИ ЧЕЛОВЕКА |
| RU1438241C (ru) * | 1987-04-22 | 1996-03-20 | Институт биоорганической химии им.М.М.Шемякина и Ю.А.Овчинникова РАН | Рекомбинантная плазмидная днк ртnf 33, кодирующая полипептид со свойствами фактора некроза опухоли человека, и штамм бактерий escherichia coli - продуцент полипептида со свойствами фактора некроза опухоли человека |
| RU1445193C (ru) * | 1987-04-22 | 1996-03-20 | Институт биоорганической химии им.М.М.Шемякина и Ю.А.Овчинникова РАН | РЕКОМБИНАНТНАЯ ПЛАЗМИДНАЯ ДНК pGA 23 - ПРОМЕЖУТОЧНЫЙ ПРОДУКТ ДЛЯ КОНСТРУИРОВАНИЯ РЕКОМБИНАНТНОЙ ПЛАЗМИДНОЙ ДНК pTNF 311Δ,-/,, РЕКОМБИНАНТНАЯ ПЛАЗМИДНАЯ ДНК pTNF 311Δ,-/,, КОДИРУЮЩАЯ ПОЛИПЕПТИД СО СВОЙСТВАМИ ФАКТОРА НЕКРОЗА ОПУХОЛИ ЧЕЛОВЕКА И ШТАММ БАКТЕРИЙ ESCHERICHIA COLI - ПРОДУЦЕНТ ПОЛИПЕПТИДА СО СВОЙСТВАМИ ФАКТОРА НЕКРОЗА ОПУХОЛИ ЧЕЛОВЕКА |
| US5156841A (en) * | 1988-08-26 | 1992-10-20 | United States Of America | Anti-tumor vaccine |
| ZA941645B (en) * | 1994-03-09 | 1995-01-13 | South To South Co Operation In | Antibodies specifically reactive against human prostate specific antigen. |
| US6051237A (en) * | 1994-11-08 | 2000-04-18 | The Trustees Of The University Of Pennsylvania | Specific immunotherapy of cancer using a live recombinant bacterial vaccine vector |
| MXPA03004562A (es) * | 2000-11-22 | 2003-09-10 | Univ Maryland | Uso de hemolisina de clya pra la excrecion de proteinas. |
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2002
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2003
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- 2003-02-13 BR BRPI0308119A patent/BRPI0308119A2/pt not_active IP Right Cessation
- 2003-02-13 WO PCT/DE2003/000471 patent/WO2003072789A2/de not_active Ceased
- 2003-02-13 MX MXPA04008287A patent/MXPA04008287A/es unknown
- 2003-02-13 US US10/506,096 patent/US20060105423A1/en not_active Abandoned
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- 2003-02-13 AU AU2003206664A patent/AU2003206664A1/en not_active Abandoned
- 2003-02-13 IL IL16367203A patent/IL163672A0/xx unknown
- 2003-02-13 CA CA002513190A patent/CA2513190A1/en not_active Abandoned
- 2003-02-13 EP EP03704315A patent/EP1478756A2/de not_active Withdrawn
- 2003-02-13 NZ NZ535312A patent/NZ535312A/en unknown
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- 2003-02-13 PL PL03372370A patent/PL372370A1/xx not_active IP Right Cessation
- 2003-02-13 RU RU2004128929/13A patent/RU2319741C2/ru not_active IP Right Cessation
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| Publication number | Publication date |
|---|---|
| US20060105423A1 (en) | 2006-05-18 |
| ZA200407528B (en) | 2006-06-28 |
| RU2004128929A (ru) | 2005-04-10 |
| MXPA04008287A (es) | 2006-04-27 |
| NZ535312A (en) | 2008-03-28 |
| RU2319741C2 (ru) | 2008-03-20 |
| JP2005518795A (ja) | 2005-06-30 |
| AU2003206664A1 (en) | 2003-09-09 |
| WO2003072789A3 (de) | 2004-02-12 |
| IL163672A0 (en) | 2005-12-18 |
| WO2003072789A2 (de) | 2003-09-04 |
| CA2513190A1 (en) | 2003-09-04 |
| NO20043926L (no) | 2004-09-20 |
| HRP20040785A2 (en) | 2004-12-31 |
| DE10208653A1 (de) | 2003-09-18 |
| KR20040104464A (ko) | 2004-12-10 |
| BRPI0308119A2 (pt) | 2016-06-28 |
| RS75604A (sr) | 2006-12-15 |
| PL372370A1 (en) | 2005-07-25 |
| EP1478756A2 (de) | 2004-11-24 |
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