CN117653654A - 用于抑制和/或压制tlr9激活的适体 - Google Patents
用于抑制和/或压制tlr9激活的适体 Download PDFInfo
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- CN117653654A CN117653654A CN202311487145.4A CN202311487145A CN117653654A CN 117653654 A CN117653654 A CN 117653654A CN 202311487145 A CN202311487145 A CN 202311487145A CN 117653654 A CN117653654 A CN 117653654A
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Abstract
本发明涉及用于抑制和/或压制TLR9激活的适体。本发明涉及用于通过抑制或压制细胞中的TLR9激活来治疗受试者的新的适体分子,使用这样的适体分子抑制或压制细胞中的TLR9激活的方法,包含这样的适体分子的药物组合物和试剂盒,以及适体分子用于抑制或压制TLR9激活的用途。
Description
本申请是中国专利申请201780072355.3的分案申请,原申请201780072355.3的申请日为2017年10月27日,其名称为“用于抑制和/或压制TLR9激活的适体”。
技术领域
本发明涉及用于通过抑制或压制细胞中TLR9激活来治疗受试者的新适体分子,使用这样的适体分子抑制或压制细胞中的TLR9激活的方法,包含这样的适体分子的药物组合物和试剂盒,以及适体分子用于抑制或压制TLR9激活的用途。
背景技术
Toll样受体(Toll-like receptors,TLR)存在于免疫系统的许多细胞上,已经显示参与先天免疫应答(Hornung,V.等人,(2002)J.Immunol.168:4531-4537)。在脊椎动物或哺乳动物中,该家族由称为TLR1至TLR10的蛋白质组成,已知其识别来自细菌、真菌、寄生虫和病毒的病原体相关分子模式(pathogen associated molecular patterns,PAMP)(Poltorak,a.等人(1998)Science 282:2085-2088;Underbill,D.M.,等人(1999)Nature401:811-815;Hayashi,F.等人(2001)Nature 410:1099-1103;Zhang,D.等人(2004)Science303:1522-1526;Meier,A.等人(2003)Cell.Microbial.5:561 570;Campos,M.A.等人(2001)J.Immunol.167:416-423;Hoebe,K.等人(2003)Nature 424:743-748;Lund,J.(2003)J.Exp.Med.198:513-520;Heil,F.等人(2004)Science303:1526-1529;Diebold,S.S.,等人(2004)Science 303:1529-1531;Hornung,V.等人(2004)J.Immunol.173:5935-5943)。
TLR是哺乳动物识别并对外源分子产生免疫应答的关键方式,并且还提供了连接先天性和适应性免疫应答的方式(Akira,S.等人(2001)Nature Immunol.2:675-680;Medzhitov,R.(2001)Nature Rev.Immunol.1:135-145)。同样已显示TLR在包括自身免疫、传染性疾病和炎症的许多疾病的发病机理中起作用(Cook,D.N.等人(2004)NatureImmunol.5:975-979),并且使用适当的试剂调节TLR介导的激活可以提供疾病干预手段。进一步地,通过自身核酸在浆细胞样树突细胞前体(PDC)和B细胞中触发TLR9,在系统性红斑狼疮(SLE)的发病机理中具有重要作用。
作为针对细胞外和细胞内病原体的防御的一部分,TLR位于细胞表面,但也位于细胞内部。TLR2、4、5和6为保卫细胞对抗细胞外的病原体的位于细胞表面的受体,TLR3、7、8和9通常位于细胞内以支持针对细胞内病原体的防御(Dowling和Dellacasagrande,2016)Dowling,J.K.和Dellacasagrande,J.(2016)Methods Mol.Biol.Clifton NJ 1390,3-27)、(Diebold,S.S.等人(2004)Science 303:1529-1531;Liew,F.等人(2005)Nature 5:446-458;Hemmi H等人(2002)Nat Immunol 3:196-200;Jurk M等人,(2002)Nat Immunol 3:499;Lee J等人(2003)Proc.Natl.Acad.Sci.USA 100:6646-6651);(Alexopoulou,L.(2001)Nature 413:732-738)。
细菌DNA和合成DNA中存在的特定未甲基化的CpG基序已显示通过TLR9激活免疫系统并诱导抗肿瘤活性(Tokunaga T等人,J.Natl.Cancer Inst.(1984)72:955-962;ShimadaS,等人,Jpn.H cancer Res,1986,77,808-816;Yamamoto S,等人,Jpn.J.Cancer Res.,1986,79,866-73)。相反,哺乳动物DNA通常不具有免疫刺激性活性,显然是由于低频率的CG序列以及大部分的CG序列具有甲基化的胞嘧啶。因此,哺乳动物免疫系统细胞似乎是通过TLR9受体来区分细菌DNA和自身DNA的。
其他使用含有CpG二核苷酸的反义寡核苷酸的研究已显示刺激免疫应答(Zhao Q,等人(1996)Biochem.Pharmacol.26:173-182)。随后的研究表明,TLR9识别细菌DNA和合成DNA中存在的未甲基化的CpG基序(Hemmi,H.等人(2000)Nature 408:740-745)。
含有CpG的硫代磷酸酯寡核苷酸的其他修饰也可以影响它们作为通过TLR9的免疫应答的调节物的能力(参见,例如,Biochem.Pharmacol.(1996)51:173-182;Zhao等人(1996)Biochem Pharmacol.52:1537-1544;Zhao等人(1997)Antisense Nucleic AcidDrug Dev.7:495-502;Zhao等人(1999)Bioorg.Med.Chem.Lett.9:3453-3458;Zhao等人(2000)Bioorg.Med.Chem.Lett.10:1051-1054;Yu,D.等人(2000)Bioorg.Med.Chem.Lett.10:2585-2588;Yu,D.等人(2001)Bioorg.Med.Chem.Lett.11:2263-2267;以及Kandimalla,E.等人(2001)Bioorg.Med.Chem.9:807-813)。
另外,结构活性关系研究已经允许合成的基序和新的基于DNA的化合物的识别,所述基序和化合物诱导特异性免疫应答谱,这些谱与未经甲基化的CpG二核苷酸的不同(Kandimalla,E.等人(2005)Proc.Natl.Acad.Sci.US A102:6925-6930.Kandimalla,E.等人(2003)Proc.Nat.Acad.Sci.US A100:14303-14308;Cong,Y.等人(2003)BiochemBiophys Res.Commun.310:1133-1139;Kandimalla,E.等人(2003)Biochem.Biophys.Res.Commun.306:948-953;Kandimalla,E.等人(2003)Nucleic AcidsRes.31:2393-2400;Yu,D.等人(2003)Bioorg.Med.Chem.11:459-464;Bhagat,L.等人(2003)Biochem.Biophys.Res.Commun.300:853-861;Yu,D.等人(2002)Nucleic AcidsRes.30:4460-4469;Yu,D.等人(2002)J.Med.Chem.45:4540-4548.Yu,D.等人(2002)Biochem.Biophys.Res.Commun.297:83-90;Kandimalla.E.等人(2002)Bioconjug.Chem.13:966-974;Yu,D.等人(2002)Nucleic Acids Res.30:1613-1619;Yu,D.等人(2001)Bioorg.Med.Chem.9:2803-2808;Yu,D.等人(2001)Bioorg.Med.Chem.Lett.11:2263-2267;Kandimalla,E.等人(2001)Bioorg.Med.Chem.9:807-813;Yu,D.等人(2000)Bioorg.Med.Chem.Lett.10:2585-2588;Putta,M.等人(2006)Nucleic Acids Res.34:3231-3238)。
虽然TLR的激活参与免疫应答的产生,免疫系统通过TLR的不受控制的刺激可能加重特定疾病,例如在免疫受损的受试者中。因此,在通过TLR9激活引起的一般性或特异性提高的免疫应答的情况下,可期望应用TLR9拮抗剂。
近年来,几个小组已经显示合成的寡脱氧寡核苷酸(oligodeoxyoligonucleotides,ODN)作为炎性细胞因子的抑制剂的用途(Lenert,P.等人(2003)DNA Cell Biol.22(10):621-631)。
使用特定合成的ODN,Lenert等人报道了产生抑制性ODN的能力(Lenert,P.等人(2003)DNA Cell Biol.22(10):621-631)。这些抑制性ODN需要两个三联体序列,近端的“CCT”三联体和远端的“GGG”三联体。除了这些含有三联体的抑制性ODN之外,几个小组已经报道了可以通过含有CpG的ODN抑制TLR9介导的激活的其他特定的DNA序列。这些“抑制性(inhibitory)”或“压制性(suppressive)”基序富含多聚“G”(例如,“GGGG”)或“GC”序列,倾向于甲基化,并且存在于哺乳动物和特定病毒的DNA中(参见,例如,Chen,Y.,等人,GeneTher.8:1024-1032(2001);Stunz,L.L,Eur.J.Immunol.32:1212-1222(2002)。
Duramad,O.,等人,J.Immunol.,174:5193-5200(2005)和美国专利申请US2005/0239733描述了在序列内含有GGGG基序的抑制性DNA寡核苷酸的结构。Patole等人确证含有GGGG的ODN将压制系统性狼疮(Patole,P.等人(2005)J.Am.Soc.Nephrol.16:3273-3280)。另外,Gursel,I.,等人,J.Immunol.,171:1393-1400(2003)描述了在哺乳动物端粒中以高频率存在并且下调CpG诱导的免疫激活的重复的TTAGGG元件。Shirota,H.,等人,J.Immunol.,173:5002-5007(2004)确证含有TTAGGG元件的合成寡核苷酸模拟该活性并且在预防/治疗某些Th1依赖性自身免疫疾病方面可为有效的。
美国专利申请US11/549,048公开了新类别的不需要多聚G序列的TLR拮抗剂。Kandimalla等人还描述了这些新的组合物治疗和预防各种疾病和病症的应用(11/549,048;11/743,876;12/140,334;12/140,338;12/244,199)。
然而,开发其他不需要多聚G序列的TLR拮抗剂仍是一种挑战。TLR9拮抗剂的数量仍然是相当有限的,并且仍需要确认其在人类和动物中的应用的有效性和无害性。因此,期望显示有益的抑制特性的其他TLR9拮抗剂的可用性。
这种新的定制化合物和组合物将用于许多临床相关应用中,包括治疗和预防例如伴有免疫刺激成分以及疼痛和炎症的疾病和病症。目前在哮喘和过敏性鼻炎或其他过敏性病症中检测这类化合物和组合物的效力(Basith S,Manavalan B,Lee G,Kim SG,Choi S."Toll-like receptor modulators:a patent review(2006-2010)."Expert Opin TherPat.Jun 2011:927-944.)。
更多的疾病已与患者中TLR9的非期望的或非天然的激活相关联。还已知的是,心脏成纤维细胞带有TLR9受体并且心脏成纤维细胞TLR9受体的激活似乎参与支持病理情况的等病理性心脏病症例如心肌炎(Ohm IK,Alfsnes K,Belland Olsen M,Ranheim T,SandangerDahl TB,Aukrust P,Finsen AV,Yndestad A,Vinge LE."Toll-likereceptor 9mediated responses in cardiac fibroblasts."PLoS One.未注明日期:e104398.)。
在这种情况下,TLR9激活的阻断、压制或抑制可显示出如在实验性狼疮中已观察到的来自Dynavax的IRS 954的治疗效果(Pawar RD1,Ramanjaneyulu A,Kulkarni OP,LechM,Segerer S,Anders HJ."Inhibition of Toll-like receptor-7(TLR-7)or TLR-7plusTLR-9attenuates glomerulonephritis and lung injury in experimental lupus."JAm Soc Nephrol.Jun 2007:1721-1731.)。
目前仅有非常有限数量的适体可以用于调节例如自身免疫疾病中的TLR9激活并且仍需要确认其在人类患者中应用的有效性和无害性。因此期望抑制或压制TLR9激活的其他寡核苷酸序列的可用性。
因此,本发明的目的为提供一种用于通过抑制或压制细胞中TLR9激活来治疗受试者的新拮抗剂。
此外,本发明的另一个目的为提供一种使用新TLR9拮抗剂抑制或压制TLR9激活的方法。
本发明的目的还在于提供一种包含新TLR9拮抗剂的药物组合物和试剂盒。
本发明的进一步的目的为提供新TLR9拮抗剂用于抑制或压制TLR9激活的用途。
发明内容
该目的通过下文所述的本发明的各方面解决。
根据本发明所述的第一方面,提供用于通过抑制或压制细胞中的TLR9激活来治疗受试者的适体。
在本发明的第一方面的优选实施方案中,所述受试者是哺乳动物,优选地所述受试者是人类。
在本发明的第一方面的另一优选实施方案中,所述待接触的细胞和/或所述待治疗的受试者显示TLR9过量表达和/或TLR9介导的信号传导的过度活性。
在本发明的第一方面的又一优选实施方案中,在抑制所述细胞和/或受试者中的TLR9激活之前,检测所述细胞和/或待治疗的受试者的TLR9过量表达和/或TLR9介导的信号传导的过度活性。
在本发明的第一方面的优选实施方案中,所述细胞是胶质细胞、小胶质细胞、星形胶质细胞、巨噬细胞、B细胞和/或树突细胞,优选是浆细胞样树突细胞。
在本发明的第一方面的另一优选实施方案中,所述受试者患有选自自身免疫性疾病、炎性疾病、自身免疫性结缔组织病(ACTD)和/或神经变性疾病的病症,优选地所述病症选自但不限于牛皮癣、类风湿性关节炎、全身脱毛、急性播散性脑脊髓炎、阿狄森病、过敏症、强直性脊柱炎、抗磷脂抗体综合征、动脉硬化、动脉粥样硬化、自身免疫性溶血性贫血、自身免疫性肝炎、大疱性类天疱疮、南美洲锥虫病、慢性阻塞性肺病、乳糜泻、皮肤红斑狼疮(CLE)、皮肌炎、糖尿病、扩张型心肌病(DCM)、子宫内膜异位症、古德帕斯彻综合征、格雷夫斯病、格-巴综合征、桥本病、化脓性汗腺炎、特发性血小板减少性紫癜、炎性肠病、间质性膀胱炎、局限性硬皮病、多发性硬化(MS)、重症肌无力、心肌炎、发作性睡病、神经肌强直、天疱疮、恶性贫血、多肌炎、原发性胆汁性肝硬变、类风湿性关节炎(RA)、精神分裂症、斯耶格伦综合征、系统性红斑狼疮(SLE)、全身性硬皮病、颞动脉炎、脉管炎、白斑病、外阴部疼痛(vulvodynia)、韦格纳肉芽肿病、外伤性疼痛、神经性疼痛(neuropathic pain)和对乙酰氨基酚毒性。
在本发明的第一方面的优选实施方案中,所述受试者患有肿瘤/癌症,优选地所述肿瘤/癌症选自由乳腺癌、子宫颈鳞状细胞癌、胃癌、胶质瘤、肝细胞癌、肺癌、黑素瘤、前列腺癌、复发性成胶质细胞瘤、复发性非霍奇金淋巴瘤、结肠直肠癌组成的组。
在本发明的第一方面的一个优选实施方案中,所述适体包含SEQ ID No.1(GGTTGG TGT GGT TGG)的核酸序列和/或至少80%相同于SEQ ID No.1的核酸序列。
根据本发明的第二方面,提供一种抑制或压制细胞中TLR9激活的方法,其包括将表达TLR9的细胞与适体接触。
在本发明的第二方面的优选实施方案中,所述方法在体外/离体进行。
在本发明的第二方面的另一优选实施方案中,所述方法另外包含检测所述细胞的TLR9过量表达和/或TLR9介导的信号传导的过度活性的前一步骤。
在本发明的第二方面的优选实施方案中,所述细胞是哺乳动物细胞,优选地所述细胞是人类细胞。
在本发明的第二方面的一个优选实施方案中,所述适体包含SEQ ID No.1(GGTTGG TGT GGT TGG)的核酸序列和/或至少80%相同于SEQ ID No.1的核酸序列。
根据本发明的第三方面,提供一种药物组合物,其包含根据本发明的第一方面的适体和至少一种药学上可接受的赋形剂。
根据本发明的第四方面,提供一种试剂盒,其包含至少一种根据本发明的第一方面的适体和容器。
根据本发明的第五方面,提供如本文限定的适体用于抑制或压制TLR9激活的用途。
在本发明的第五方面的优选实施方案中,所述适体在体外/离体使用。
附图说明
图1显示了通过添加浓度(μM)升高的SEQ ID No.1的适体(灰色柱(grey column))对在ODN 2006(TLR 9激动剂)-刺激的HEK-BlueTM hTLR9细胞中TLR9激活的抑制。检查了在缺乏TLR9激动剂ODN 2006(SEQ ID No.2)刺激的情况下浓度升高的SEQ ID No.1的适体对TLR9激活的潜在内在作用并且显示为黑色条(black bar)。通过碱性磷酸酶的TLR9激活的表达引起光密度的改变。
图2显示了浓度升高的SEQ ID No.1的适体(μM)对用100ng TNF-α刺激的(灰色柱)和缺乏TNF-α刺激的(黑色柱)HEK-BlueTM TNF-α细胞的作用。通过碱性磷酸酶的TNF-α激活的表达引起光密度的改变。
图3显示了通过添加浓度(μM)升高的SEQ ID No.3的适体(灰色柱)对在ODN 2006(TLR9激动剂)刺激的HEK-BlueTM hTLR9细胞中TLR9激活的抑制。检查了在缺乏TLR9激动剂ODN 2006(SEQ ID No.2)刺激的情况下浓度升高的SEQ ID No.3的适体对TLR9激活的潜在内在作用并且显示为黑色条。通过碱性磷酸酶的TLR9激活的表达引起光密度的改变。
图4显示了浓度升高的SEQ ID No.3的适体(μM)对用100ng TNF-α刺激的(灰色柱)和缺乏TNF-α刺激的(黑色柱)HEK-BlueTM TNF-α细胞的作用。通过碱性磷酸酶的TNF-α激活的表达引起光密度的改变。
图5显示了通过添加浓度(ng)升高的TLR9拮抗剂CpG ODN TTAGGG(SEQ ID No.4;描述为灰色柱),对在ODN 2006(TLR9激动剂)刺激的HEK-BlueTM hTLR9细胞中TLR9激活的抑制。检查了在缺乏TLR9激动剂ODN 2006(SEQ ID No.2)刺激的情况下浓度升高的CpG ODNTTAGGG(SEQ ID No.4)对TLR9激活的潜在内在作用并且显示为黑色条。通过碱性磷酸酶的TLR9激活的表达引起光密度的改变。
具体实施方式
本发明基于识别出乎意料的结构的新寡核苷酸和核苷酸组合物,其可与真核细胞中的TLR9受体相互作用并且抑制和压制其的激活。
迄今为止,本领域中已知仅有非常有限数量的似乎对TLR9受体具有拮抗作用的适体。少数常见的结构基序为先前已知的拮抗性寡核苷酸的基础。然而,考虑到在例如人类患者的治疗中适体的药物应用的严格要求,在某些情况下这些常见结构可导致降低的生物利用率和/或其他困难。为此,高度期望提供另外的、结构上不同的用于TLR9激活的靶向调节的适体。
本发明人现在首次鉴定出作为TLR9拮抗剂的要求保护的适体,其不同于通常已知的拮抗性地作用于TLR9受体的寡核苷酸的结构基序。因此,现在变为可以提供作为TLR9拮抗剂的结构上新的寡核苷酸。
根据本发明的一个优选实施方案,应抑制或压制TLR9激活的所述受试者是脊椎动物,更优选地所述受试者是哺乳动物。在本发明的含义内,哺乳动物的组包括但不限于大鼠、小鼠、兔、猫、狗、马、肉牛(cattle)、奶牛(cow)、猪、绵羊、非人灵长类和人类。最优选地,所述受试者是人类。
在本发明的上下文中,应理解的是,任何仅提及“受试者”的公开内容可以另外理解为与提及“细胞”相同的公开内容,反之亦然,除非技术人员认为这样的公开内容没有任何技术意义。
根据本发明的另一优选实施方案,至少一种待与本发明的适体接触的细胞显示TLR9过量表达。因此,待用本发明的适体治疗的受试者在该受试者的至少某些细胞中显示TLR9过量表达。更优选地,待治疗的受试者患有通过所述受试者的至少某些细胞中的TLR9过量表达引起的病症和/或症状。
根据本发明的另一优选实施方案,至少一种待与本发明的适体接触的细胞展现TLR9介导的信号传导的过度活性。这可意味着待用本发明的适体治疗的所述受试者在该受试者的至少某些细胞中显示TLR9介导的信号传导的过度活性。更优选地,待治疗的所述受试者患有通过所述受试者的至少某些细胞中的TLR9介导的信号传导的过度活性引起的病症和/或症状。
根据本发明的一个优选实施方案,在抑制所述细胞和/或待治疗的受试者中的TLR9激活前,检测所述细胞和/或受试者的TLR9过量表达和/或TLR9介导的信号传导的过度活性。因此,根据本发明的另一优选实施方案,在与本发明的适体接触或用本发明所述的适体治疗之前,所述细胞和/或待治疗的受试者已经被表征为显示TLR9过量表达和/或TLR9介导的信号传导的过度活性。
根据本发明的另一优选实施方案,待治疗的所述受试者为对于TLR9过量表达和/或TLR9介导的信号传导的过度活性的检测为阳性。
可靠地检测和确定细胞或受试者是否显示TLR9过量表达和/或TLR9介导的信号传导的过度活性完全处于技术人员的能力之内。在这方面,示例性地参考Deering和Orange,Clin Vaccine Immunol.2006Jan;13(1):68-76的公开内容。其中,给出评价TLR9表达和/或TLR9介导的信号传导的活性的方法。TLR9表达/活性评价构成现有技术的一部分的进一步的证据可来自Invivogen,San Diego,CA,United States对TLR9测试条2216的开发。
根据本发明的一个优选实施方案,如果TLR9介导的TNFα的产生相对于健康受试者的参考值为提高,则认为TLR9过量表达和/或TLR9介导的信号传导的过度活性。根据优选的实施方案,待治疗的所述受试者的值如下确定:
通过使用TLR9介导的TNFα的产生作为替代参数,TLR9过量表达和/或TLR9介导的
信号转导的过度活性的确定
带有TLR9的外周血单核细胞(PBMC)的分离
为了估计患者的TLR9状态,使用Ficoll-Paque Plus密度梯度分离(AmershamBiosciences,Uppsala,Sweden)从肝素化血液样品中分离带有TLR9受体的患者的PBMC。分离的PBMC重悬于含有10%热灭活的胎牛血清(FBS;HyClone,Logan,UT)、0.1mM非必需氨基酸、10mM HEPES、1mM丙酮酸钠、50U/ml青霉素G、50μg/ml硫酸链霉素和2mM L-谷氨酰胺(GIBCO/BRL)的RPMI(GIBCO/BRL,Grand Island,NY),一起称为R10-FBS。
所有的培养基在制备之后通过一次性的0.2μm的过滤器(Millipore,Billerica,MA)过滤。通过将细胞重悬于0.2μm过滤灭菌的含有10%二甲亚砜(DMSO;FisherScientific,Fair Lawn,NJ)的FBS,PBMC可在含有氯丁橡胶垫片的1-ml聚丙烯小瓶(Corning,Corning,NY)中冷冻保存。使用含有甲醇的非机械的低温保存装置(Nalgene,Rochester,NY)在-80℃冷冻库中以约1℃/分钟逐渐降低小瓶的温度。在快速解冻用于实验之前,细胞保存在液氮中。
在解冻时,通过台盼蓝排除法(GIBCO/BRL)来确定细胞生存力并且丢弃任何<95%生存力的样品。
激发PBMC上激动剂(配体)介导的TLR9应答
TLR9活性可以在将含有TLR9受体的PBMC与特定的激动剂/配体ODN 2216培养时估计。为了激发TLR9应答,100μl R10-FBS中的2×105个PBMC添加至每个含有双重配体的(40μg ODN 2216/mL,100μL/孔)或含有对照培养基的孔中,在37℃、5% CO2下培养24小时。无配体的培养基用于确定TNFα的基线产生。
通过酶联免疫吸附分析(ELISA)估计形成的TNFα的量
通过TNFα特异性ELISA技术估计由ODN 2216激发的患者血液或对照受试者血液的PBMC形成的TNFα的量。
为此,Immulon微量滴定板(ThermoLabSystems,Franklin,MA)与100μl单克隆抗人TNFα捕获抗体(BD Biosciences)在包被缓冲液(0.1M碳酸钠,pH9.5)中在4℃下过夜培养。在弃去上清液之后,用具有0.05%吐温20(PBST)、pH 7.4的磷酸盐缓冲盐水(PBS)清洗板三次,之后用含有10%牛血清白蛋白、pH 7.0的PBS在室温下封闭1小时。
来自TLR9配体刺激的PBMC的单个孔的上清液转移至单个抗体包被孔中。
优选的是在抗体包被孔中直接两倍稀释上清液,使得TNFα的测定量在任何情况下落入TNFα标准曲线范围内。连续稀释的TNFα标准制剂用作标准曲线(R&D Systems,Minneapolis,MN)。
在加载样品和标准曲线之后,在室温下培养板2小时,随后使用PBST清洗五次。为了检测捕获的TNFα,100μl生物素化的抗人TNFα夹心单克隆抗体(BD Biosciences)以及抗生物素蛋白-辣根过氧化酶缀合物(BD Biosciences)需要添加到每个孔中并且需要在室温下培养板1小时。
使用PBST清洗五次并与100μl四甲基联苯胺加过氧化氢底物溶液在室温下培养30分钟之后,通过添加50μl的1M硫酸终止比色反应。使用微量滴定板分光光度计(Biotek,Winooski,VT)在450nm下读取吸光度。
根据本发明的一个特定实施方案,根据上文描述的方法对待治疗的受试者测定的TNFα的值是至少50pg/ml、优选至少60pg/ml、更优选至少75pg/ml、甚至更优选至少90pg/ml、甚至更优选至少100pg/ml、甚至更优选至少110pg/ml、甚至更优选至少125pg/ml、甚至更优选至少150pg/ml、最优选至少175pg/ml。
在本发明的优选实施方案中,与本发明的适体待接触的细胞是胶质细胞、小胶质细胞、星形胶质细胞、巨噬细胞、B细胞和/或树突细胞,更优选浆细胞样树突细胞。根据另一更优选的实施方案,待接触的细胞是中枢神经系统中的胶质细胞。
在本发明的一个优选的实施方案中,所述受试者患有选自自身免疫性疾病、炎性疾病、自身免疫性结缔组织病(ACTD)和/或神经变性疾病的病症,更优选地所述病症选自但不限于牛皮癣、类风湿性关节炎、全身脱毛、急性播散性脑脊髓炎、阿狄森病、过敏症、强直性脊柱炎、抗磷脂抗体综合征、动脉硬化、动脉粥样硬化、自身免疫性溶血性贫血、自身免疫性肝炎、大疱性类天疱疮、南美洲锥虫病、慢性阻塞性肺病、乳糜泻、皮肤红斑狼疮(CLE)、皮肌炎、糖尿病、扩张型心肌病(DCM)、子宫内膜异位症、古德帕斯彻综合征、格雷夫斯病、格-巴综合征、桥本病、化脓性汗腺炎、特发性血小板减少性紫癜、炎性肠病、间质性膀胱炎、局限性硬皮病、多发性硬化(MS)、重症肌无力、心肌炎、发作性睡病、神经肌强直、天疱疮、恶性贫血、多肌炎、原发性胆汁性肝硬变、类风湿性关节炎(RA)、精神分裂症、斯耶格伦综合征、系统性红斑狼疮(SLE)、全身性硬皮病、颞动脉炎、脉管炎、白斑病、外阴部疼痛、韦格纳肉芽肿病、外伤性疼痛、神经性疼痛和对乙酰氨基酚毒性。
在更优选的实施方案中,所述受试者患有自身免疫性疾病,其选自包括系统性红斑狼疮、多发性硬化、动脉硬化、炎性肠病、糖尿病、过敏症和癌症的组,特别是自身免疫性糖尿病。
在另一更优选的实施方式中,所述受试者患有与GPCR自身抗体的存在相关的自身免疫性疾病,甚至更优选地,所述自身免疫性疾病选自包含心肌病、扩张型心肌病(DCM)、缺血性心肌病(iCM)、围产期心肌病(PPCM)、特发性心肌病、恰加斯心肌病、化疗诱导的心肌病、恰加斯巨结肠、恰加斯巨食管、恰加斯神经病、良性前列腺增生、硬皮症、雷诺氏综合征、周围动脉闭塞病(PAOD)、先兆子痫、肾同种异体移植物排斥、心肌炎、青光眼、高血压、肺动脉高压、恶性高血压、代谢综合征、脱发、斑秃、偏头痛、帕金森病、癫痫、丛集性头痛、多发性硬化、抑郁症、局部疼痛综合征、不稳定型心绞痛、系统性红斑狼疮(SLE)、精神分裂症、斯耶格伦综合征、牙周炎、心房纤颤、白斑病、溶血性尿毒性综合征、僵体综合征(stiff personsyndrome)、先天性心脏传导阻滞、I型糖尿病、牛皮癣、阿尔茨海默氏病、疲劳、神经性皮肤炎、肾脏疾病(renal kidney disease)、肌萎缩性侧索硬化症(ALS)、Leber's遗传性视神经病变(LHON综合征)、过敏性哮喘、心律不齐、难治性高血压、II型糖尿病、血管性痴呆、非恰加斯巨结肠和/或直立性高血压(orthostatic hypertension)的组。
在另一更优选的实施方案中,所述受试者患有病理性心脏病,特别是扩张型心肌病和/或心肌炎。
在本发明的另一更优选的实施方案中,所述受试者患有神经性疼痛,所述神经性疼痛是由受糖尿病或化疗药物影响的神经引起的,来自创伤、外科手术、关节炎、AIDS、烧伤、脑或腰椎疾病、纤维肌痛、缺血后疼痛、肿瘤、病毒神经痛、反射性交感神经营养不良综合征、幻肢痛和截肢后疼痛、疱疹后神经痛、复杂性局部疼痛综合征或中枢性疼痛综合征。
在本发明的另一更优选的实施方案中,所述受试者患有炎症疾病,例如类风湿性关节炎、脊柱关节病、痛风性关节炎、骨关节炎、系统性红斑狼疮、或少年关节炎。在本发明的另一更优选的实施方案中,所述受试者患有与以下相关的炎症:哮喘、过敏性鼻炎、鼻窦疾病、支气管炎、肺结核、急性胰腺炎、脓毒症、传染性疾病、经期痛性痉挛、早产、腱炎、滑囊炎,皮肤相关病症例如牛皮癣、湿疹、特异反应性皮炎、荨麻疹、皮炎、接触性皮炎和灼伤,或来自包括来自例如白内障手术和屈光手术等眼科手术的术后炎症,血管疾病、偏头疼、结节性动脉周围炎、甲状腺炎、再生障碍性贫血、霍奇金病、硬化症、风湿热、I型糖尿病、包括重症肌无力的神经肌肉接点疾病、包括多发性硬化症的白质病、结节病、肾病综合征、贝切特综合征、多发性肌炎、龈炎、肾炎、超敏反应、损伤后发生的肿胀、心肌缺血、过敏性鼻炎、呼吸窘迫综合征、全身炎症反应综合征(SIRS)、癌症相关炎症、肿瘤相关血管生成减少、内毒素休克综合征、动脉粥样硬化,眼科疾病,如视网膜炎、视网膜病、葡萄膜炎、眼畏光或眼组织急性损伤,肺部炎症,如与病毒感染或囊性纤维化、慢性阻塞性肺病、急性呼吸窘迫综合征相关的那些,组织排斥、移植物抗宿主疾病、迟发型超敏反应、以及CNS疾病的免疫介导和炎症因素,如阿尔茨海默氏症、帕金森氏症、多发性硬化症。
在本发明的另一优选的实施方案中,所述受试者患有肿瘤/癌症,优选地所述肿瘤/癌症选自由乳腺癌、子宫颈鳞状细胞癌、胃癌、胶质瘤、肝细胞癌、肺癌、黑素瘤、前列腺癌、复发性成胶质细胞瘤、复发性非霍奇金淋巴瘤、结肠直肠癌组成的组。
在本发明的另一更优选的实施方案中,所述受试者患有急性成淋巴细胞性白血病、急性髓细胞性白血病、肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、肛门癌、阑尾癌、星形细胞瘤(儿童小脑或大脑)、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干胶质瘤、脑肿瘤(小脑星形细胞瘤、大脑星形细胞瘤/恶性胶质瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层肿瘤、视觉通路和下丘脑神经胶质瘤)、乳腺癌、支气管腺瘤/类癌、伯基特淋巴瘤、类癌肿瘤(儿童期,胃肠道)、原发性不明原因的癌、中枢神经系统淋巴瘤(原发性)、小脑星形细胞瘤、大脑星形细胞瘤/恶性胶质瘤、宫颈癌、儿童癌症、慢性淋巴细胞白血病、慢性髓细胞性白血病、慢性骨髓增生病、结肠癌、皮肤T细胞淋巴瘤、促纤维增生性小圆细胞肿瘤、子宫内膜癌、室管膜瘤、食管癌、尤因氏肿瘤家族的尤因肉瘤、颅外生殖细胞肿瘤(儿童期)、性腺外生殖细胞肿瘤、肝外胆管癌、眼癌(眼内黑素瘤、视网膜母细胞瘤)、胆囊癌、胃癌(gastric(stomach)cancer)、胃肠道类癌肿瘤、胃肠道间质瘤、生殖细胞肿瘤(儿童颅外、性腺外、卵巢)、妊娠滋养层肿瘤、胶质瘤(成人、儿童脑干、儿童脑星形细胞瘤、儿童视觉通路和下丘脑)、胃类癌、毛细胞白血病、头颈癌、肝细胞(肝)癌、霍奇金淋巴瘤、下咽癌、下丘脑和视觉通路胶质瘤(儿童期)、眼内黑素瘤、胰岛细胞癌、卡波西肉瘤、肾癌(肾细胞癌)、喉癌、白血病(急性成淋巴细胞性、急性髓性、慢性淋巴细胞性、慢性髓细胞性、毛细胞性)、唇癌和口腔癌、肝癌(原发性)、肺癌(非小细胞、小细胞)、淋巴瘤(AIDS-相关的、伯基特、皮肤T细胞、霍奇金、非霍奇金、原发性中枢神经系统)、巨球蛋白血症(瓦尔登斯特伦)、骨恶性纤维组织细胞瘤/骨肉瘤、成神经管细胞瘤(儿童期)、黑素瘤、眼内黑素瘤、默克尔细胞癌、间皮瘤(成人恶性、儿童期)、伴隐匿性原发性的转移性鳞状颈部癌症、口腔癌、多发性内分泌瘤综合征(儿童期)、多发性骨髓瘤/浆细胞赘生物、蕈样真菌病、骨髓增生异常综合征、骨髓增生异常/骨髓增生性疾病、骨髓性粒细胞性白血病(慢性)、髓细胞性白血病(成人急性、儿童急性)、多发性骨髓瘤、骨髓增生性疾病(慢性)、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口腔癌、口咽癌、骨肉瘤/骨恶性纤维组织细胞瘤、卵巢癌、卵巢上皮癌(表面上皮-间质瘤)、卵巢生殖细胞瘤、卵巢低恶性潜能肿瘤、胰腺癌、胰腺癌(胰岛细胞)、鼻窦和鼻腔癌症、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、松果体星形细胞瘤、松果体生殖细胞瘤、松质母细胞瘤和幕上原始神经外胚层肿瘤(儿童期)、垂体腺瘤、浆细胞瘤、胸膜肺母细胞瘤、原发性中枢神经系统淋巴瘤、前列腺癌、直肠癌、肾细胞癌(肾癌)、肾盂和输尿管移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤(儿童期)、唾液腺癌、肉瘤(尤因氏肿瘤家族、卡波西、软组织、子宫)、塞扎里综合征、皮肤癌(非黑素瘤、黑素瘤)、皮肤癌(美克尔细胞)、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、伴隐匿性原发性(转移性)的鳞状颈部癌症、胃癌、幕上原始神经外胚层肿瘤(儿童期)、T细胞淋巴瘤(皮肤)、睾丸癌、咽喉癌、胸腺瘤(儿童期)、胸腺瘤和胸腺癌、甲状腺癌、甲状腺癌(儿童期)、肾盂和输尿管移行细胞癌、滋养层肿瘤(妊娠)、未知原发部位(成人、儿童)、输尿管和肾盂移行细胞癌、尿道癌、子宫癌(子宫内膜)、子宫肉瘤、阴道癌、视觉通路和下丘脑神经胶质瘤(儿童期)、外阴癌、瓦尔登斯特伦巨球蛋白血症和肾母细胞瘤(儿童期)。
在本发明的一个优选的实施方案中,产生对TLR9受体的拮抗效应的本文定义的适体序列不含有胞嘧啶核苷酸。有证据表明,包含对TLR9有拮抗效应的序列的序列,可以包含其他包括胞嘧啶核苷酸的核苷酸序列。
在本发明的更优选的实施方案中,本文公开和描述的本发明的适体包含SEQ IDNo.1(GGT TGG TGT GGT TGG)的核酸序列和/或至少80%相同于SEQ ID No.1的核酸序列。在另一更优选的实施方案中,所述适体包含SEQ ID No.1(GGT TGG TGT GGT TGG)的核酸序列,特别地,所述适体由SEQ IDNo.1(GGT TGG TGT GGT TGG)的核酸序列组成。
在一个优选的实施方案中,本文公开和描述的本发明的适体包含SEQ IDNo.5(GGTTGG TGT GGT TG)的核酸序列,优选地,所述适体由SEQ ID No.5(GGT TGG TGT GGT TG)的核酸序列组成。
两个序列之间同一性百分比的确定通过使用Karlin和Altschul的数学算法根据本发明来实现(Proc.Natl.Acad.Sci.USA(1993)90:5873-5877)。这种算法是Altschul等人(J.Mol.Biol.(1990)215:403-410)的BLASTN和BLASTP程序的基础。使用BLASTN程序进行BLAST核苷酸检索。为了获得用于比较目的的有空位的比对,使用如Altschul等人(NucleicAcids Res.(1997)25:3389-3402)描述的Gapped BLAST。当使用BLAST和Gapped BLAST程序时,使用相应程序的默认参数。
根据本发明的优选实施方案,适体序列构成本发明的一部分,其包含至少85%相同于本文公开的个体化的适体序列的核酸序列或由其组成,更优选至少90%相同,甚至更优选至少95%相同。
为了本发明的目的,术语“适体”是指与靶分子特异性结合并与之具有高亲和性的寡核苷酸。在限定条件下,适体可以折叠成特定的三维结构。在本发明的一个优选的实施方案中,要求保护的适体与靶受体、更优选与TLR9受体特异性地相互作用并与之具有高亲和性。
根据优选的实施方案,本发明的适体不形成由最少两种组分组成的纳米结构的一部分,其中所述最少两种组分是多个寡核苷酸、和与多个寡核苷酸连接的多个G-四联体形成核酸(G-quadruplex forming nucleic acid),更优选地,本发明的适体不形成由最少两种组分组成的纳米结构的一部分。在该优选实施方案中,所述两种组分优选地是结构上不同的。进一步地,在该优选实施方案中,在该实施方式中否定的纳米结构中的多个寡核苷酸和与多个寡核苷酸连接的多个G-四联体形成核酸之间的连接是共价连接或非共价连接,其中所述非共价连接更优选基于静电相互作用、范德华力、π效应或疏水效应的一种或多种。
根据另一优选实施方案,本发明的适体不形成稳定自组装的核酸纳米结构的一部分,所述核酸纳米结构包含多个寡核苷酸,其中所述寡核苷酸的每个核苷酸间连键不是硫代磷酸酯键;与所述多个寡核苷酸连接的多个G-四联体形成核酸,其中所述G-四联体形成核酸不是TAGGGTT;以及与所述G-四联体形成核酸连接的多个G-四联体稳定化结构域,其中所述寡核苷酸、所述G-四联体形成核酸和所述G-四联体稳定化结构域形成多个G-四体结构(G-quad structure)。
根据另一优选实施方案,本发明的适体不形成稳定自组装的核酸纳米结构的一部分,所述核酸纳米结构包含多个寡核苷酸;与所述多个寡核苷酸连接的多个G-四联体形成核酸,其中所述G-四联体形成核酸不是TAGGGTT;以及与所述G-四联体形成核酸连接的多个G-四联体稳定化结构域,其中当所述G-四联体形成核酸的至少之一包含GG、GGG或GGGG并且所述寡核苷酸是CpG寡核苷酸时,脂质不是二酰基脂质,其中所述寡核苷酸、所述G-四联体形成核酸和所述G-四联体稳定化结构域形成多个G-四体结构。
根据又一优选实施方案,本发明的适体不形成包含与本发明的适体连接的G-四联体稳定化结构域的核酸纳米结构的一部分。
本发明的适体包含核酸分子(核苷酸)的序列、或由其组成。根据优选的实施方案,本发明的适体由本文限定的核苷酸序列组成。
本发明的适体优选包含未修饰的和/或修饰的D-和/或L-核苷酸。根据通用的核酸碱基的单字母代码,“C”代表胞嘧啶,“A”代表腺嘌呤,“G”代表鸟嘌呤,如果核苷酸序列是DNA序列则“T”代表胸腺嘧啶,如果核苷酸序列是RNA序列则“T”代表尿嘧啶核苷酸。如果下文没有相反地指示,术语“核苷酸”应指核糖核苷酸和脱氧核糖核苷酸。
本发明的适体可以包含DNA-或RNA-核苷酸序列或由其组成,因此,可以分别称为DNA适体或RNA适体。应理解的是,如果本发明的适体包含RNA核苷酸序列,在整个本发明中特定的序列基序中的“T”代表尿嘧啶。
在整个本发明中为了简明起见,仅提及明确的DNA核苷酸序列。然而,应理解的是,本发明还包含相应的RNA核苷酸序列。
根据一个实施方案,优选使用DNA适体。DNA适体在血浆中通常比RNA适体更稳定。然而,根据可选的实施方案,优选RNA适体。根据另一实施方案,优选单链核苷酸序列。根据另一可选的实施方案,优选双链核苷酸序列。
本发明的适体可以包含核苷酸序列,所述核苷酸序列含有2'-修饰的核苷酸,例如2'-氟-、2'-甲氧基-、2'-甲氧乙基-和/或2'-氨基-修饰的核苷酸。本发明的适体还可以包含脱氧核糖核苷酸、修饰的脱氧核糖核苷酸、核糖核苷酸和/或修饰的核糖核苷酸的混合物。分别地,术语“2'-氟-修饰的核苷酸”、“2'-甲氧基-修饰的核苷酸”、“2'-甲氧乙基-修饰的核苷酸”和/或“2'-氨基-修饰的核苷酸”是指修饰的核糖核苷酸和修饰的脱氧核糖核苷酸。
本发明的适体可以包含修饰。这样的修饰包含例如烷基化,即至少一个核苷酸的甲基化、芳基化或乙酰化,包含对映异构体和/或适体与一个或多个其他核苷酸或核酸序列的融合。这样的修饰可以包含例如5'-和/或3'-PEG-或5'-和/或3'-CAP-修饰。可选地或另外地,本发明的适体可以包含修饰的核苷酸,优选地选自锁核酸(locked-nucleic acid)、2'-氟-、2'-甲氧基-和/或2'-氨基-修饰的核苷酸。
锁核酸(LNA)代表构象已经固定的相应RNA核苷酸的类似物。锁核酸的寡核苷酸包含一个或多个双环核糖核苷,其中2'-OH基团通过亚甲基基团与C4碳原子连接。与相应的未修饰的RNA-适体对应物相比,锁核酸展现了对核酸酶的改善的稳定性。并且改善杂交性质,允许增强适体的亲和性和特异性。
其他优选的修饰是添加所谓的3'-CAP-、5'-CAP-结构和/或添加修饰的鸟苷-核苷酸(例如,7-甲基-鸟苷)至所述适体的3'-和/或5'-末端。这样的3'-和/或5'-末端的修饰具有保护所述适体免于被核酸酶快速降解的效果。
可选地或另外地,本发明的适体可以展现聚乙二醇化的3'或5'-末端。3'-或5'-PEG修饰包括添加至少一个聚乙二醇(PEG)单元,优选地所述PEG基团包含1至900个亚乙基,更优选1至450个亚乙基。在优选的实施方案中,适体包含具有HO-(CH2CH2O)n-H的线性PEG单元,其中n是1至900的整数,优选n是1至450的整数。
本发明的适体可以被完全地或部分地配置为肽核酸(PNA)。根据本发明的适体可以进一步如Keefe AD等人,Nat Rev Drug Discov.2010Jul;9(7):537-50或者Mayer G,Angew Chem Int Ed Engl.2009;48(15):2672-89或者Mayer,G.和Famulok M.,Pharmaziein unserer Zeit 2007;36:432-436中描述的进行修饰。
术语“寡核苷酸”通常是指包含多个连接的核苷单元的多聚核苷。这样的寡核苷酸可从现有的包括基因组或cDNA的核酸来源中获得,但优选通过合成方法生产。在优选的实施方案中,与野生型寡核苷酸相比,各个核苷单元可以包含各种化学修饰和取代,包括但不限于修饰的核苷碱基和/或修饰的糖单元。
化学修饰的实例是本领域技术人员已知的并且描述于例如Uhlmann,E.等人(1990)Chem.Rev.90:543;"Protocols for Oligonucleotides and Analogs"Synthesisand Properties&Synthesis and Analytical Techniques,S.Agrawal,Ed,Humana Press,Totowa,USA 1993;和Hunziker,J.等人(1995)Mod.Syn.Methods 7:331-417;和Crooke,S.等人(1996)Ann.Rev.Pharm.Tox.36:107-129。
核苷残基可以通过许多任何已知的核苷间连键相互偶联,特别是为了改善寡核苷酸对抗例如核酸酶的酶促降解的稳定性。这类核苷间连键包括但不限于磷酸二酯、硫代磷酸酯、二硫代磷酸酯、烷基膦酸酯、烷基硫代磷酸酯、磷酸三酯、氨基磷酸酯、硅氧烷、碳酸酯、烷氧羰基、乙酰胺、氨基甲酸酯、吗啉代、硼烷基、硫醚、桥连氨基磷酸酯(bridgedphosphoramidate)、桥连亚甲基膦酸酯、桥联硫代磷酸酯和砜核苷间连键。
术语“寡核苷酸”还包括具有一个或多个立体特异性核苷间连键(例如,(Rr)-或(Sr)-硫代磷酸酯、烷基磷酸酯、或磷酸三酯连键)的多聚核苷。如本文使用的,术语“寡核苷酸”和“二核苷酸”明确地旨在包括具有任何这样的核苷间连键的多聚核苷和二核苷,无论所述连键是否包含磷酸基团。在特定的优选实施方案中,这些核苷间连键可以是磷酸二酯、硫代磷酸酯或二硫代磷酸酯连键或其组合,更优选地所述核苷间连键是硫代磷酸酯。
进一步地,所述适体可包封在适合的运载体中来保护其结构完整性以及促进其在细胞内的递送。优选的运载体包括脂质体、脂质囊泡、和微粒等。
脂质囊泡类似于质膜,可以使它们与细胞膜融合。大多数脂质体和多层囊泡不容易膜融合,主要是因为囊泡曲率半径的储能是最小的。优选的脂质囊泡包括小单层囊泡。预期用于包封本发明的适体的小单层囊泡是非常膜融合的,这是因为它们具有非常紧密的曲率半径。小单层囊泡的平均直径是5nm至50nm;优选10nm至100nm,更优选20nm至60nm,包括40nm。这种尺寸允许囊泡穿过内皮细胞之间的间隙,从而囊泡在静脉内施用之后允许含有适体的囊泡的全身性递送。有用的囊泡的尺寸可很大程度地变化并且可以根据适体的具体应用进行选择。
小单层囊泡可使用本领域可用的过程(例如WO 2005/037323 A2中公开的)在体外容易地制备。形成囊泡的组合物包含作为稳定囊泡形成物(vesicle former)的磷脂,其优选与另一种极性脂质一起,并且任选地与一种或多种其他的极性脂质和/或筏形成物一起。作为稳定囊泡形成物的优选的磷脂包括1-棕榈酰-2-二十二碳六烯酰基-sn-甘油-3-磷酸胆碱和1,2-二油酰基-sn-甘油-3-磷酸胆碱。优选的极性脂质包括:1-棕榈酰-2-油酰基-sn-甘油-3-磷酸、1,2-二油酰基-sn-甘油-3-乙基磷酸胆碱、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺、1,2-二油酰基-sn-甘油-3-[磷酸-l-丝氨酸]、典型的鞘磷脂、1,2-二肉豆蔻酰基-sn-甘油和1-棕榈酰-2-羟基-sn-甘油-3-磷酸胆碱。
其他优选的极性脂质包括磷脂酰丝氨酸、磷脂酰甘油、混合链磷脂酰胆碱、磷脂酰乙醇和含有二十二碳六烯酸的磷脂。优选的筏形成物的一个实例是胆固醇。
通过上述方式之一修饰本发明的适体的一个优点是,可以稳定化所述适体来对抗例如在使用所述适体的环境中存在的核酸酶等有害影响。所述修饰还适合于调整所述适体的药理学性质。所述修饰优选不改变所述适体的亲和性或特异性。
本发明的适体还可以与载体分子和/或与报告分子缀合。载体分子包括当与适体缀合时例如通过增强稳定性和/或通过影响排出率来延长缀合适体在人血浆中的血浆半衰期的分子。适合的载体分子的一个实例是PEG。
报告分子包含允许检测缀合适体的分子。这类报告分子的实例为GFP、生物素、胆固醇、染料例如荧光染料、电化学活性报告分子和/或包含放射性残基的化合物,特别是适合于PET(电子发射断层扫描)检测的放射性核素,例如18F、11C、13N、15O、82Rb或68Ga。技术人员充分了解适合的载体和报告分子,以及如何将它们缀合到本发明的适体的方法。
本发明所述的适体对于通过抑制或压制细胞中的TLR9激活来治疗特定疾病是有用的。在本发明的上下文中,所述适体被认为是对于人类受试者以及动物受试者有用的。根据一个实施方案,所述适体用于人类受试者。根据另一个实施方案,所述适体用于动物受试者。
抑制或压制TLR9激活可以是有用的疾病为,TLR9激活在展现这种TLR9激活的受试者中引起非期望的症状或结果的这样的疾病。根据优选的实施方案,通过待治疗的受试者中的TLR9激活引起所述病症和/或疾病。根据特别优选的实施方案,所述失调和/或疾病是由针对用于G蛋白偶联受体的自身抗体治疗的受试者中的TLR9激活所引起的。
在文献中已经报道或已知与TLR9激活相关的几种疾病。本发明人考虑到这种相关性进行了进一步研究,发现可与这种TLR9激活或TLR9过度激活相关的相对于先前所报道的更多的疾病(数据未显示)。
由于所要求保护的适体对TLR9的亲和性以及它们对TLR9的拮抗作用,与TLR9的激活或过度激活相关的任何疾病可用本文提出和要求保护的适体进行有效治疗。因此,原则上已经识别与TLR9(过度)激活相关的所有疾病都是使用根据本发明的适体治疗的有希望的目标疾病。
本发明的适体能够产生对TLR9受体的作用,优选对TLR9受体的拮抗作用。因此,在优选的实施方案中,所要求保护的适体作为TLR9拮抗剂。优选地,所要求保护的适体能够抑制或压制TLR9激活。根据一个优选的实施方案,本发明的适体不展现对TLR7受体的作用,更优选地它们不展现对任何其他TLR受体分子的作用。根据不同的优选实施方案,本发明的适体也展现对TLR7受体的作用。
通过抑制TLR9受体的病理性或不期望的激活或过度激活,TLR9激活的潜在负面影响被中和并降低,TLR9的永久性或暂时性激活可以消除或降低至正常水平。结果,通过TLR9激活导致的或与之相关的疾病的程度和严重性可以显著降低。因此,本发明提供了适用于治疗与TLR9激活或过度激活相关的疾病的适体。
根据本发明的另一实施方案,提供了一种抑制或压制细胞中的TLR9激活的方法,其包括将表达TLR9的细胞与适体接触。
在本发明的优选实施方案中,所述方法在体外/离体进行。更优选地,根据本发明的方法的与适体接触的细胞不形成整个生物体的一部分。在一个实施方案中,可以在细胞培养物中培养待接触的细胞。可以按照本领域通常进行的那些进行个体细胞或细胞群体的这类培养。
在本发明的方法的另一优选实施方案中,所述方法可以在体内进行,和/或在形成整个生物体的一部分的细胞上进行。根据该实施方案,所述方法优选包含另外的、检测待接触的个体细胞/细胞群的TLR9激活的前一步骤,更优选地,检测所述个体细胞/细胞群对TLR9的过量表达和/或TLR9介导的信号传导的过度活性。
在本发明的第二方面的优选实施方案中,所述细胞是哺乳动物细胞,优选地所述细胞是人类细胞。
本发明还涉及一种药物组合物,其包含本发明的至少一种适体以及任选地至少一种药学上可接受的赋形剂。本发明还涉及一种药物组合物,其包含本发明的适体或本发明的不同适体的混合物,以及药学上可接受的赋形剂如适合的载体或稀释剂等。
优选地,本发明的适体构成所述药物组合物的活性成分和/或以有效量存在。术语“有效量”表示具有对疾病或病理状况的预防、诊断或治疗相关效果的本发明适体的量。预防效果防止疾病的暴发。治疗相关效果在一定程度上减轻疾病的一种或多种症状,或者使疾病或病理状况的原因或与之相关的一种或多种生理学或生物化学参数部分地或完全地回到正常。
施用本发明的适体的相应的量足够高来实现期望的预防、诊断或治疗效果。技术人员应理解的是,向任何特定哺乳动物施用的特定剂量水平、频率和时间将取决于多种因素,包括所采用的特定组分的活性、年龄、体重、一般健康状况、性别、饮食、施用时间、施用途径、药物组合、以及特定治疗的严重程度。使用公知的方式和方法,精确的量可以由本领域技术人员按照常规的实验来确定。
根据本发明的药物组合物的一个实施方案,总的适体含量的至少20%由本发明的适体组成,优选至少50%、更优选至少75%、最优选至少95%。
当用于治疗时,所述药物组合物一般将作为与一种或多种药学上可接受的赋形剂相关的制剂来施用。本文使用术语“赋形剂”来描述除本发明的适体以外的任何成分。赋形剂的选择将在很大程度上取决于特定的施用方式。赋形剂可以是适合的载体和/或稀释剂。
本发明的药物组合物可以口服给药。口服给药可涉及吞咽,从而使组合物进入胃肠道,或者可以采用口腔含化给药或舌下含化给药,由此组合物直接由口进入血流。
适合于口服给药的制剂包括:固体制剂例如片剂;包衣片剂,含有颗粒、液体或粉末的胶囊剂;锭剂(包括填充液体);和咀嚼剂;复合粒(multi-particulate)和纳米粒;凝胶剂;固溶体;脂质体;薄膜剂、珠形剂(ovules)、喷雾剂和液体制剂。
液体制剂包括悬浮液、溶液、糖浆和酏剂。这类制剂可用作软胶囊或硬胶囊中的填料,并且通常包括载体,例如,水、乙醇、聚乙二醇、丙二醇、甲基纤维素或适合的油,以及一种或多种乳化剂和/或悬浮剂。液体制剂也可以通过例如从小袋中重构固体来制备。
对于片剂剂型,根据剂量,本发明的适体可以占剂型的0.1重量%至80重量%,更通常占剂型的5重量%至60重量%。除了本发明的适体之外,片剂通常含有崩解剂。
崩解剂的实例包括羟甲基淀粉钠、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲纤维素钠、交聚维酮、聚乙烯吡咯烷酮、甲基纤维素、微晶纤维素、低级烷基-取代的羟丙基纤维素、淀粉、预凝胶化淀粉和海藻酸钠。
通常,所述崩解剂将包含剂型的1重量%至25重量%,优选5重量%至20重量%。
片剂可包含另外的赋形剂,例如粘合剂、表面活性剂、润滑剂和/或其他可能的成分,例如抗氧化剂、着色剂、调味剂、防腐剂和/或掩味剂等。
片剂混合物可以直接压制或通过辊压制成片剂。在压片之前,片剂共混物或共混物的一部分可选地可以是湿法、干法或熔融制粒、熔融凝结的或挤出的。最终制剂可包括一层或多层,并可为包被或不包被的;其甚至可以是被封装的。
用于口服给药的固体制剂可以配制成即刻释放和/或调节释放。调节释放制剂包括延迟释放、持续释放、脉冲释放、受控释放、靶向释放和程序释放。
本发明的药物组合物还可以直接施用至血流、肌肉或内脏器官中。肠胃外给药的适合的方式包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内和皮下。用于肠胃外给药的适合的设备包括针头(包括显微针)注射器、无针头注射器和输注技术。
肠胃外制剂通常是水溶液,其可以含有赋形剂,例如盐、碳水化合物和缓冲剂(优选pH为3至9),但是,对于一些应用,它们可以更合适配制成无菌非水性溶液,或配置成与合适的载体如无菌无热原水一起使用的干燥形式。
在无菌条件下制备肠胃外制剂,例如通过冷冻干燥,可以使用本领域技术人员熟知的标准制药技术容易地完成。
通过使用适当的制剂技术,例如混入溶解度增强剂,可以增加用于制备肠胃外溶液的本发明药物组合物的溶解度。
用于肠胃外给药的制剂可以配制成即刻释放和/或调节释放。调节释放制剂包括延迟释放、持续释放、脉冲释放、受控释放、靶向释放和程序释放。因此,本发明的化合物可以配制为固体、半固体或触变性液体,用于作为植入的贮库施用,提供活性化合物的调节释放。这类制剂的实例包括药物涂层支架和PGLA聚(dl-乳酸-共-乙醇酸)(poly(dl-lactic-coglycolic)acid,PGLA)微球。
本发明的药物组合物还可以局部施用至皮肤或粘膜,即皮肤或经皮给药。用于该目的的典型制剂包括凝胶、水凝胶、洗剂、溶液、乳霜、软膏、撒粉(dusting powder)、敷料、泡沫、薄膜、皮肤贴剂、薄片、植入物、海绵、纤维、绷带和微乳剂。
还可以使用脂质体。典型的载体包括醇、水、矿物油、液体石蜡、白凡士林、甘油、聚乙二醇和丙二醇。可以混入渗透促进剂。其他局部施用方式包括通过电穿孔、离子电渗、超声透入、超声促渗和微针或无针(例如Powderject(TM),Bioject(TM)等)注射来递送。用于局部施用的制剂可以配制成即刻释放和/或调节释放。调节释放制剂包括延迟释放、持续释放、脉冲释放、受控释放、靶向释放和程序释放。
对于向人类患者施用,本发明的适体和/或本发明的药物组合物的总日剂量通常在0.001mg至5000mg的范围内,当然这取决于施用的方式。例如静脉内的日剂量可仅需要0.001mg至40mg。总日剂量可以以单次或分次的剂量施用,并且在医师的判断下可以超出本文给出的通常范围。
这些剂量是基于具有约75kg至80kg体重的平均人类受试者。医师将能够容易地确定体重超出这一范围的受试者例如婴儿和老年人的剂量。
在本发明的上下文中,适体优选可与一种或多种疫苗、抗原、抗体、细胞毒性剂、过敏原、抗生素、反义寡核苷酸、TLR拮抗剂、肽、蛋白质、基因治疗载体、DNA疫苗、佐剂或激酶抑制剂组合施用。
本发明还包括试剂盒,其包含本发明的适体、容器和任选的书面使用说明书和/或施用装置。
对于疾病的治疗和/或诊断,不论施用途径如何,本发明的适体以每个治疗周期的日剂量不超过20mg/kg体重来施用,优选不超过10mg/kg体重,更优选选自1μg/kg至20mg/kg体重的范围,最优选选自0.01至10mg/kg体重范围。
在本发明的优选实施方案中,所述适体可以在体外/离体使用。在可选的优选实施方案中,所述适体可以在体内使用。
本发明的适体的制造或大量生产是本领域公知的,并且仅代表常规活动。
除非本领域技术人员认为这样的组合没有任何技术意义,否则认为本文所述的本发明的所有实施方案可以按任何组合进行组合。
实施例
用于评价本发明的适体对TLR9受体的拮抗作用的功能分析
建立了可识别寡核苷酸对TLR9受体的拮抗作用的功能分析,以评价抑制或压制TLR9激活的能力。
这种功能分析使用重组HEK-293细胞系和已建立的TLR9激动剂/拮抗剂分析(HEK-BlueTM hTLR9,来自InvivoGen,San Diego,CA,USA)。所用的细胞系带有与报告基因偶联的功能性过量表达的人类TLR9受体,所述报告基因是通过NFkB诱导型启动子在信号传导时分泌的碱性磷酸酶。TLR9激活的信号是增加的光密度值(OD)。
带有报告基因而不是TLR9受体的重组HEK-293细胞作为对照(HEK-BlueTM TNF-α细胞,来自InvivoGen,San Diego,CA,USA)。在此,报告基因通过TNFα活化。使用该对照细胞,可区分效果是特异于TLR9受体还是由信号级联的干扰引起的。
实施例1:
在该实施例中,检查SEQ ID No.1(GGT TGG TGT GGT TGG)对TLR9受体的抑制效果。HEK-BlueTM hTLR9细胞与不同浓度的SEQ ID No.1的适体(0、0.37、1.1、3.3、10和20μM的适体)预培养60分钟,之后添加300ng/ml(38.86nM)公知的TLR 9激动剂ODN 2006(SEQ IDNo.2:TCG TCG TTT TGT CGT TTT GTC GTT),进一步培养细胞18小时。随后,使用标准的碱性磷酸酶分析测定光密度。这一分析的结果在图1中以灰色柱显示。还在缺乏激动剂ODN2006的情况下检测SEQ ID No.1对涉及TLR9的信号级联的潜在内在效果,在图1中以黑色柱描述。
作为对照,采用上文描述的HEK-BlueTM TNF-α细胞作为对照并使用相同的实验设置。这些TNF-α敏感细胞与不同浓度的SEQ ID No.1的适体预培养(0、0.37、1.1、3.3、10和20μM的适体)60分钟,之后将100ng/ml的TNF-α(MW17484道尔顿;TNF-α的终浓度:5.7nM)与细胞进一步培养18小时。随后,测定光密度。这一分析的结果在图2中以灰色柱显示。还在缺乏刺激分子TNF-α的情况下检测SEQ ID No.1对涉及TNF-α的信号级联的潜在内在效果,在图2中以黑色柱描述。
从这些实验和图1和2中显示的结果可以看出,SEQ ID No.1(GGT TGG TGT GGTTGG)的适体对于激动剂/拮抗剂分析或报告物表达没有内在的或非特异性的效果,但是显示了对TLR9激活的清楚的抑制和压制。
实施例2:
作为进一步的对照实验,使用上文和实施例1中描述的分析来测定不同的寡核苷酸序列的潜在抑制效果。为此,使用SEQ ID No.3(TGG AGG TGG A)代替SEQ ID No.1进行如实施例1中阐述的包括对照的相同实验用于对比。
分别地,使用SEQ ID No.3在ODN 2006刺激的HEK-BlueTM hTLR9细胞上获得的结果在图3中示出,在TNF-α刺激的HEK-BlueTM TNF-α细胞上获得的结果在图4中显示。
从这组对照实验可以看出,试验的10mer的SEQ ID No.3不显示TLR9抑制效果,而是展现了在缺乏(参见图3中的黑色条)或存在(参见图3中的灰色条)激动剂ODN 2006的情况下对TLR9的独立的和额外的刺激作用。再一次地,使用SEQ ID No.3的适体没有观察到对信号级联的影响(参见图4)。
实施例3:
作为对上述实施例1和2中使用的分析的数值和有效性的对照,如上文描述的,使用已建立的TLR9拮抗剂CpG ODN TTAGGG(SEQ ID No.4:TTA GGG TTA GGG TTA GGG TTAGGG;MW7575Da)以递增的浓度(0、30、100、300、1000和3000ng的TLR9拮抗剂;分别相应于0、3.96、13.2、39.6、132和396nM)代替实施例1或2的适体进行分析对照。
使用对照拮抗剂对ODN 2006刺激的HEK-BlueTM hTLR9细胞获得的结果在图5中显示。正如预期的,已建立的TLR99拮抗剂可抑制和/或压制TLR9激活(参见图5中的灰色条),并且在缺乏TLR9激动剂ODN 2006的情况下不产生显著的内在效果(参见图5中的黑色条)。
Claims (20)
1.一种适体在制备用于通过抑制或压制细胞中的TLR9激活来治疗受试者的药物组合物或试剂盒中的用途,其中所述适体包含SEQ ID No.1(GGT TGG TGT GGT TGG)的核酸序列。
2.根据权利要求1所述的用途,其中所述受试者是哺乳动物。
3.根据权利要求2所述的用途,其中所述受试者是人类。
4.根据前述权利要求任一项所述的用途,其中待治疗的所述受试者显示TLR9过量表达和/或TLR9介导的信号传导的过度活性。
5.根据前述权利要求任一项所述的用途,其中待治疗的所述受试者对于TLR9过量表达和/或TLR9介导的信号传导的过度活性的检测为阳性。
6.根据权利要求4或5所述的用途,其中如果TLR9介导的TNFα的产生相对于健康受试者的参考值为提高,则得出受试者中TLR9过量表达和/或TLR9介导的信号传导的过度活性。
7.根据权利要求6所述的用途,其中待治疗的所述受试者的值使用说明书中描述的方法测定,并且是至少50pg/ml。
8.根据权利要求7所述的用途,其中待治疗的所述受试者的值是至少75pg/ml。
9.根据权利要求7所述的用途,其中待治疗的所述受试者的值是至少100pg/ml。
10.根据权利要求7所述的用途,其中待治疗的所述受试者的值是至少125pg/ml。
11.根据前述权利要求任一项所述的用途,其中所述受试者患有选自自身免疫性疾病、炎性疾病、自身免疫性结缔组织病(ACTD)和/或神经变性疾病的病症,或者,其中所述受试者患有肿瘤/癌症。
12.根据权利要求11所述的用途,其中所述病症选自牛皮癣、类风湿性关节炎、全身脱毛、急性播散性脑脊髓炎、阿狄森病、过敏症、强直性脊柱炎、抗磷脂抗体综合征、动脉硬化、动脉粥样硬化、自身免疫性溶血性贫血、自身免疫性肝炎、大疱性类天疱疮、南美洲锥虫病、慢性阻塞性肺病、乳糜泻、皮肤红斑狼疮(CLE)、皮肌炎、糖尿病、扩张型心肌病(DCM)、子宫内膜异位症、古德帕斯彻综合征、格雷夫斯病、格-巴综合征、桥本病、化脓性汗腺炎、特发性血小板减少性紫癜、炎性肠病、间质性膀胱炎、局限性硬皮病、多发性硬化(MS)、重症肌无力、心肌炎、发作性睡病、神经肌强直、天疱疮、恶性贫血、多肌炎、原发性胆汁性肝硬变、类风湿性关节炎(RA)、精神分裂症、斯耶格伦综合征、系统性红斑狼疮(SLE)、全身性硬皮病、颞动脉炎、脉管炎、白斑病、外阴部疼痛、韦格纳肉芽肿病、外伤性疼痛、神经性疼痛和对乙酰氨基酚毒性。
13.根据权利要求11所述的用途,其中所述肿瘤/癌症选自由乳腺癌、子宫颈鳞状细胞癌、胃癌、胶质瘤、肝细胞癌、肺癌、黑素瘤、前列腺癌、复发性成胶质细胞瘤、复发性非霍奇金淋巴瘤、结肠直肠癌组成的组。
14.一种抑制或压制细胞中的TLR9激活的方法,其包括将表达TLR9的细胞与适体接触,其中所述方法在体外/离体进行,和其中所述适体包含SEQ ID No.1(GGT TGG TGT GGTTGG)的核酸序列。
15.根据权利要求14所述的方法,其中所述的方法另外包含检测所述细胞的TLR9过量表达和/或TLR9介导的信号传导的过度活性的前一步骤。
16.根据权利要求14或15所述的方法,其中所述细胞是哺乳动物细胞。
17.根据权利要求16所述的方法,其中所述细胞是人类细胞。
18.根据前述权利要求1至13任一项所述的用途,其特征在于,所述药物组合物包含至少一种药学上可接受的赋形剂。
19.根据前述权利要求1至13任一项所述的用途,其特征在于,所述试剂盒包含容器。
20.根据权利要求1中限定的适体用于抑制或压制TLR9激活的用途,其中所述适体在体外/离体使用。
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