CN102864151A - Tlr9的新型合成性激动剂 - Google Patents
Tlr9的新型合成性激动剂 Download PDFInfo
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- CN102864151A CN102864151A CN2012103116903A CN201210311690A CN102864151A CN 102864151 A CN102864151 A CN 102864151A CN 2012103116903 A CN2012103116903 A CN 2012103116903A CN 201210311690 A CN201210311690 A CN 201210311690A CN 102864151 A CN102864151 A CN 102864151A
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Abstract
本发明涉及TLR9的新型合成性激动剂。本发明涉及对于调控Toll样受体(TLR)介导的免疫应答有用的合成的化学组合物。具体而言,本发明涉及产生相异的细胞因子和趋化因子谱的Toll样受体9(TLR9)激动剂。
Description
本申请是申请日为2008年7月31日,申请号为200880109852.7(国际申请号为PCT/US2008/071738),名称为“TLR9的新型合成性激动剂”的发明专利申请的分案申请。
相关申请
本申请要求2007年8月1日提交的美国临时专利申请流水号60/953,251;2007年10月30日提交的美国临时专利申请流水号60/983,601;2007年11月12日提交的美国临时专利申请流水号60/987,151;和2007年12月20日提交的美国临时专利申请流水号61/015,292的权益,通过述及将其完整内容收入本文。
发明领域
本发明涉及对于调控Toll样受体(TLR)介导的免疫应答有用的合成的化学组合物。具体而言,本发明涉及产生独特的细胞因子和趋化因子谱(profile)的TTll样受体9(TLR9)激动剂。
发明背景
Toll样受体(TLR)存在于免疫***的许多细胞上,而且已经显示出牵涉先天性免疫应答(Hornung,V.等(2002)J.Immunol.168:4531-4537)。在脊椎动物中,这个家族由称作TLR1至TLR11的11种蛋白质组成,已知它们识别来自细菌、真菌、寄生物、和病毒的病原体相关分子样式(molecular patterns)(Poltorak,a.等(1998)Science 282:2085-2088;Underhill,D.M.等(1999)Nature401:811-815;Hayashi,F.等(2001)Nature 410:1099-1103;Zhang,D.等(2004)Science 303:1522-1526;Meier,A.等(2003)Cell.Microbiol.5:561-570;Campos,M.A.等(2001)J.Immunol.167:416-423;Hoebe,K.等(2003)Nature 424:743-748;Lund,J.(2003)J.Exp.Med.198:513-520;Heil,F.等(2004)Science303:1526-1529;Diebold,S.S.等(2004)Science 303:1529-1531;Hornung,V.等(2004)J.Immunol.173:5935-5943)。
TLR是脊椎动物识别外来分子和对外来分子发动免疫应答的关键手段,而且还提供了联系先天性和适应性免疫应答的手段(Akira,S.等(2001)Nature Immunol.2:675-680;Medzhitov,R.(2001)Nature Rev.Immunol.1:135-145)。有些TLR位于细胞表面上以检测胞外病原体和对胞外病原体启动应答,而其它TLR位于细胞内以检测胞内病原体和对胞内病原体启动应答。
已知TLR9识别细菌DNA中的和合成寡核苷酸中的未甲基化CpG基序(Hemmi,H.等(2000)Nature 408:740-745)。含CpG的硫代磷酸酯寡核苷酸的其它修饰也能影响它们作为经由TLR9之免疫应答的调控物起作用的能力(参见例如Zhao等(1996)Biochem.Pharmacol.51:173-182;Zhao等(1996)Biochem Pharmacol.52:1537-1544;Zhao等(1997)Antisense Nucleic AcidDrug Dev.7:495-502;Zhao等(1999)Bioorg.Med.Chem.Lett.9:3453-3458;Zhao等(2000)Bioorg.Med.Chem.Lett.10:1051-1054;Yu,D.等(2000)Bioorg.Med.Chem.Lett.10:2585-2588;Yu,D.等(2001)Bioorg.Med.Chem.Lett.11:2263-2267;及Kandimalla,E.等(2001)Bioorg.Med.Chem.9:807-813)。天然存在的TLR9激动剂已经显示出产生抗肿瘤活性(例如肿瘤生长和血管发生),导致有效的抗癌应答(例如抗白血病)(Smith,J.B.和Wickstrom,E.(1998)J.Natl.Cancer Inst.90:1146-1154)。另外,TLR9激动剂已经显示出与其它已知的抗肿瘤化合物(例如西妥昔单抗(cetuximab)、伊立替康(irinotecan))协同工作(Vincenzo,D.等(2006)Clin.Cancer Res.12(2):577-583)。
某些TLR9激动剂由含有核心CpR二核苷酸的3’-3’连接的DNA结构构成,其中R为经修饰的鸟苷(美国专利号7,276,489)。另外,特定的化学修饰容许制备特定的寡核苷酸类似物,它们对免疫应答产生的相异的调控。具体而言,结构活性相关性研究容许鉴定合成基序(motif)和新的基于DNA的化合物,其产生对免疫应答的特定的调控,而且这些调控与由未甲基化的CpG二核苷酸所产生的调控是相异的(Kandimalla,E.等(2005)Proc.Natl.Acad.Sci.U S A 102:6925-6930;Kandimalla,E.等(2003)Proc.Nat.Acad.Sci.U S A100:14303-14308;Cong,Y.等(2003)Biochem Biophys Res.Commun.310:1133-1139;Kandimalla,E.等(2003)Biochem.Biophys.Res.Commun.306:948-953;Kandimalla,E.等(2003)Nucleic Acids Res.31:2393-2400;Yu,D.等(2003)Bioorg.Med.Chem.11:459-464;Bhagat,L.等(2003)Biochem.Biophys.Res.Commun.300:853-861;Yu,D.等(2002)Nucleic Acids Res.30:4460-4469;Yu,D.等(2002)J.Med.Chem.45:4540-4548;Yu,D.等(2002)Biochem.Biophys.Res.Commun.297:83-90;Kandimalla.E.等(2002)Bioconjug.Chem.13:966-974;Yu,D.等(2002)Nucleic Acids Res.30:1613-1619;Yu,D.等(2001)Bioorg.Med.Chem.9:2803-2808;Yu,D.等(2001)Bioorg.Med.Chem.Lett.11:2263-2267;Kandimalla,E.等(2001)Bioorg.Med.Chem.9:807-813;Yu,D.等(2000)Bioorg.Med.Chem.Lett.10:2585-2588;Putta,M.等(2006)Nucleic Acids Res.34:3231-3238)。
发明人出人意料地发现,独特地修饰核心CpR二核苷酸侧翼序列、核苷酸之间的连接或连接寡核苷酸的接头产生新的TLR9激动剂,其在体外和在体内产生相异的细胞因子和趋化因子谱。这种对含CpR的寡核苷酸“定制调节”(custom-tune)细胞因子和趋化因子应答的能力提供以疾病特异性的和甚至患者特异性的方式预防和/或治疗各种疾病状况的能力。如此,需要新的寡核苷酸类似物化合物来提供此类受到定制调节的应答。
发明概述
本发明提供了新的基于寡核苷酸的化合物,它们各自作为激动剂与TLR9相互作用而分别提供相异的(distinct)免疫应答谱(profile)。依照本发明的TLR9激动剂的特征在于特定的(specific)和独特的(unique)化学修饰,其提供了它们相异的(distinctive)免疫应答激活谱。
依照本发明的TLR9激动剂在多种细胞类型中且在多种体外和体内实验模型中诱导免疫应答,其中各种激动剂提供相异的免疫应答谱。依照本发明的TLR9激动剂单独、或与其它药物联合或共施用,或作为用作疫苗的抗原的佐剂,用在预防和/或治疗各种疾病中。因此,它们作为用于研究免疫***以及用于比较各种动物物种(诸如人和小鼠)的免疫***的工具是有用的。
如此,在第一个方面,本发明提供了TLR9的基于寡核苷酸的激动剂(“化合物”)。
在第二个方面,本发明提供了包含依照本发明的基于寡核苷酸的TRL9激动剂和药学可接受载体的药物配制剂。
在第三个方面,本发明提供了疫苗。依照这个方面的疫苗包含依照本发明的药物配制剂且进一步包含抗原。
在第四个方面,本发明提供了用于在个体中产生TLR9介导的免疫应答的方法,此类方法包括对个体施用依照本发明的化合物、药物配制剂或疫苗。
在第五个方面,本发明提供了用于治疗性处理患有疾病或病症的患者的方法,此类方法包括对患者施用依照本发明的化合物、药物配制剂或疫苗。
在第六个方面,本发明提供了用于预防疾病或病症的方法,包括对患者施用依照本发明的化合物、药物配制剂或疫苗。
本发明可由下述段落描述:1.一种免疫调控化合物,其选自化合物No.1至No.169。
2.一种组合物,其包含依照段1的免疫调控化合物和生理学可接受的载体。
3.在个体中产生免疫应答的方法,包括对个体施用药学有效量的依照段1的化合物。
4.用于治疗性处理患有受益于免疫应答调控的疾病或病症的个体的方法,包括对个体施用药学有效量的依照段1的化合物。
5.依照段4的方法,其中所述疾病或病症是癌症、自身免疫性病症、气道炎症、炎性病症、传染病、皮肤病症、***反应、哮喘或由病原体或变应原引起的疾病。
6.依照段4的方法,进一步包括施用一种或多种化疗化合物、靶向治疗剂、疫苗、抗原、抗体、细胞毒剂、变应原、抗生素、反义寡核苷酸、TLR激动剂、激酶抑制剂、肽、蛋白质、DNA疫苗、佐剂、共刺激分子或其组合。
7.用于预防性处理患有受益于免疫应答调控的疾病或病症的个体的方法,包括对个体施用药学有效量的依照段1的化合物。
8.依照段7的方法,其中所述疾病或病症是个体中的癌症、自身免疫性病症、气道炎症、炎性病症、传染病、皮肤病症、***反应、哮喘或由病原体或变应原引起的疾病。
9.依照段7的方法,进一步包括施用一种或多种化疗化合物、靶向治疗剂、疫苗、抗原、抗体、细胞毒剂、变应原、抗生素、反义寡核苷酸、TLR激动剂、激酶抑制剂、肽、蛋白质、DNA疫苗、佐剂、共刺激分子或其组合。
附图简述
图1是本发明免疫调控化合物的线性合成的合成方案。DMTr=4,4’-二甲氧基三苯甲基;CE=氰乙基。
图2是本发明免疫调控化合物的平行合成的合成方案。DMTr=4,4’-二甲氧基三苯甲基;CE=氰乙基。
图3A-3C描绘了依照下文实施例2培养、处理和分析的表达TLR9的HEK293细胞中的NF-κB活性。简言之,将HEK293细胞用10μg/ml依照本发明的免疫调控寡核苷酸刺激18小时,并使用SEAP(分泌型人胚胎碱性磷酸酶)测定法测定NF-κB水平。
图3D-3G描绘了依照下文实施例2培养、处理和分析的表达TLR9的HEK293细胞中的NF-κB活性。将HEK293细胞用0(PBS/培养基)、0.1、0.3、1.0、3.0、或10.0μg/ml依照本发明的免疫调控寡核苷酸刺激18小时,并使用SEAP(分泌型人胚胎碱性磷酸酶)测定法测定NF-κB水平。图3A-3G更一般地证明了施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的TLR9激活谱。
图4A和4B描绘了依照下文实施例3分离、培养、处理和分析的人PBMC的细胞因子和趋化因子浓度。简言之,自新鲜获得的健康人志愿者血液分离PBMC,并用10μg/ml剂量的依照本发明的免疫调控寡核苷酸培养24小时。收集上清液,并通过Luminex多重测定法分析细胞因子和趋化因子水平。图4A和4B更一般地证明了施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的细胞因子和趋化因子谱。
图4C-4H描绘了依照下文实施例3分离、培养、处理和分析的人PBMC的细胞因子和趋化因子浓度。简言之,自新鲜获得的健康人志愿者血液分离PBMC,并用0(PBS)、0.1、0.3、1.0、3.0、或10.0μg/ml剂量的依照本发明的免疫调控寡核苷酸培养24小时。收集上清液,并通过Luminex多重测定法分析细胞因子和趋化因子水平。图4C-4H更一般地证明了施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的细胞因子和趋化因子谱。
图4I-4N描绘了依照下文实施例3分离、培养、处理和分析的人PBMC的细胞因子和趋化因子浓度。简言之,自新鲜获得的健康人志愿者血液分离PBMC,并用0(PBS)、1.0、或10.0μg/ml剂量的依照本发明的免疫调控寡核苷酸培养24小时。收集上清液,并通过Luminex多重测定法分析细胞因子和趋化因子水平。图4I-4N更一般地证明了施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的细胞因子和趋化因子谱。
图4O-4FF描绘了依照下文实施例3分离、培养、处理和分析的人PBMC的细胞因子和趋化因子浓度。简言之,自新鲜获得的健康人志愿者血液分离PBMC,并用0(PBS)、0.1、0.3、1.0、3.0、或10.0μg/ml剂量的依照本发明的免疫调控寡核苷酸培养24小时。收集上清液,并通过Luminex多重测定法分析细胞因子和趋化因子水平。图4O-4FF更一般地证明了施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的细胞因子和趋化因子谱。
图5A和5B描绘了依照下文实施例3分离、培养、处理和分析的人类浆细胞样树突细胞(pDC)的细胞因子和趋化因子浓度。简言之,自新鲜获得的健康人志愿者血液PBMC分离pDC,并用10μg/ml剂量的依照本发明的免疫调控寡核苷酸培养24小时。收集上清液,并通过Luminex多重测定法分析细胞因子和趋化因子水平。图5A和5B更一般地证明了施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的细胞因子和趋化因子谱。
图6A-6F描绘了由依照本发明的免疫调控寡核苷酸诱导的人B细胞增殖。依照下文实施例4分离、培养、处理和分析人B细胞。简言之,将自新鲜获得的健康人志愿者血液PBMC分离的人B细胞用不同剂量的依照本发明的免疫调控寡核苷酸培养68小时,并用3H-胸苷脉冲6-8小时。使用液体闪烁计数器测定3H-胸苷摄取。图6A-6F更一般地证明了施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的细胞增殖谱,这些谱因所施用的寡核苷酸的碱基组成、独特修饰、和量而有不同。
图7A描绘了依照下文实施例5处理的C57BL/6小鼠中的血清细胞因子和趋化因子诱导。简言之,给小鼠皮下注射1mg/kg剂量的依照本发明的免疫调控寡核苷酸,2小时后收集血清,通过Luminex多重测定法分析细胞因子和趋化因子水平。
图7B描绘了依照下文实施例5处理的BALB/c小鼠中的血清细胞因子诱导。简言之,给小鼠皮下注射1mg/kg剂量的依照本发明的免疫调控寡核苷酸,2小时后收集血清,并通过ELISA分析IL-12水平。
图7C-7F描绘了依照下文实施例5处理的BALB/c小鼠中的血清细胞因子诱导。简言之,给小鼠皮下注射0.25或1mg/kg剂量的依照本发明的免疫调控寡核苷酸,2小时后收集血清,并通过ELISA分析IL-12水平。图7A-7F更一般地证明了体内施用依照本发明的含有新的碱基、接头、和/或独特修饰的免疫调控寡核苷酸产生相异的TLR9激活谱,这会在多种疾病中找到应用。
发明详述
本发明提供了新的基于寡核苷酸的化合物,它们各自作为激动剂与TLR9相互作用而分别提供相异的免疫应答谱。依照本发明的TLR9激动剂的特征在于独特的化学修饰,其提供了它们相异的免疫应答激活谱。本文中所引用的所有出版物反映了本领域的技术水平,通过述及将它们完整收入本文。这些参考文献的教导与本说明书之间的任何冲突应当以有利于后者的方式来解决。
依照本发明的TLR9激动剂在多种细胞类型中且在多种体内和体外实验模型中诱导免疫应答,其中各种激动剂提供相异的免疫应答谱。因此,它们作为用于研究免疫***以及用于比较各种动物物种(诸如人和小鼠)的免疫***的工具是有用的。依照本发明的TLR9激动剂单独、或与其它药物联合或共施用,或作为用作疫苗的抗原的佐剂,用在预防和/或治疗各种疾病中。定义
术语“2’-取代的核苷”或“2’-取代的***糖苷(arabinoside)”一般包括如下的核苷或***糖核苷,其中戊糖或***糖模块2’位置的羟基被取代而生成2’-取代的或2’-O-取代的核糖核苷。在某些实施方案中,所述取代是用含有1-6个饱和的或不饱和的碳原子的低级烃基、用卤素原子、或用具有6-10个碳原子的芳基进行的,其中所述烃基或芳基可以是未取代的或者可以是取代的,例如用卤素、羟基、三氟甲基、氰基、硝基、酰基、酰氧基、烷氧基、羧基、羰烷氧基(carboalkoxy)、或氨基取代。2’-O-取代的核糖核苷或2’-O-取代的阿糖胞苷的例子包括但不限于2’-氨基、2’-氟、2’-烯丙基、2’-O-烃基和2’-炔丙基核糖核苷或***糖苷、2’-O-甲基核糖核苷或2’-O-甲基***糖苷和2’-O-甲氧基乙氧基核糖核苷或2’-O-甲氧基乙氧基***糖苷。
术语“3’”在用于方向时一般指多核苷酸或寡核苷酸中位于同一多核苷酸或寡核苷酸中另一区域或位置3’(朝向寡核苷酸的3’位置)的区域或位置。
术语“5’”在用于方向时一般指多核苷酸或寡核苷酸中位于同一多核苷酸或寡核苷酸中另一区域或位置5’(朝向寡核苷酸的5’位置)的区域或位置。
术语“约”一般意味着确切的数目不是至关重要的。如此,寡核苷酸中核苷残基的数目不是至关重要的,而且涵盖少一个或两个核苷残基或者多一个至数个核苷残基的寡核苷酸作为上文所述每一个实施方案的等同方案。
术语“气道炎症”一般包括但不限于由变应原引起的呼吸道炎症,包括哮喘。
术语“变应原”一般指抗原或在暴露于受试者后引发***反应的分子(通常是蛋白质)的抗原性部分。典型的是,受试者对变应原是过敏的,如通过例如风团(wheal)和潮红(flare)测试或本领域已知的任何方法所指出的。即使只有一小部分受试者在暴露于该分子后展现出变应性(例如IgE)免疫应答,也说该分子是变应原。
术语“***反应”一般包括但不限于食物***反应、呼吸***反应和皮肤***反应。
术语“抗原”一般指受到抗体或T细胞抗原受体识别和选择性结合的物质。抗原可以包括但不限于肽、蛋白质、核苷、核苷酸及其组合。抗原可以是天然的或合成的,而且一般诱导对该抗原特异性的免疫应答。
术语“自身免疫性病症”一般指其中“自身”抗原遭受免疫***攻击的病症。该术语包括但不限于红斑狼疮(lupus erythematosus)、多发性硬化(multiple sclerosis)、I型糖尿病(type I diabetes mellitus)、肠易激综合征(irritablebowel syndrome)、克罗恩氏病(Chron’s disease)、类风湿性关节炎(rheumatoidarthritis)、感染性休克(septic shock)、普秃(alopecia universalis)、急性播散性脑脊髓炎(acute disseminated encephalomyelitis)、阿狄森氏病(Addison’sdisease)、强直性脊柱炎(ankylosing spondylitis)、抗磷脂抗体综合征(antiphospholipid antibody syndrome)、自身免疫性溶血性贫血(autoimmunehemolytic anemia)、自身免疫性肝炎(autoimmune hepatitis)、大疱性类天疱疮(Bullous pemphigoid)、查加斯病(chagas disease)、慢性阻塞性肺病(chronicobstructive pulmonary disease)、腹部疾病(coeliac disease)、皮肌炎(dermatomyositis)、子宫内膜异位症(endometriosis)、古德帕斯丘氏综合征(Goodpasture’s syndrome)、格雷夫斯氏病(Graves’disease)、格巴二氏综合征(Guillain-Barrésyndrome)、桥本氏病(Hashimoto’s disease)、化脓性汗腺炎(hidradenitis suppurativa)、特发性血小板减少性紫癜(idiopathicthrombocytopenic purpura)、间质性膀胱炎(interstitial cystitis)、硬斑病(morphea)、重症肌无力(myasthenia gravis)、发作性睡病(narcolepsy)、神经性肌强直(neuromyotonia)、天疱疮(pemphigus)、恶性贫血(pernicious anaemia)、多肌炎(polymyositis)、原发性胆汁性肝硬化(primary biliary cirrhosis)、精神***症(schizophrenia)、斯耶格伦氏综合征syndrome)、颞动脉炎(temporal arteritis)(巨细胞动脉炎(giant cell arteritis))、血管炎(vasculitis)、白癜风(vitiligo)、外阴痛(vulvodynia)和韦格纳氏肉芽肿病(Wegener’sgranulomatosis)、自身免疫性哮喘(autoimmune asthma)、感染性休克(septicshock)、银屑病(psoriasis)和疟疾(malaria)。
术语“癌症”一般包括但不限于由异常的或不受控制的细胞增殖和/或***引起的任何恶性生长或肿瘤。癌症可发生于人和/或动物中,而且可发生于任何和所有组织中。用本发明治疗具有癌症的患者可包括依照本发明的化合物、药物配制剂或疫苗的施用,使得异常的或不受控制的细胞增殖和/或***受到影响。
术语“载体”一般涵盖任何赋形剂、稀释剂、填充剂、盐、缓冲剂、稳定剂、增溶剂、油、脂、含脂的囊泡、微球体、脂质体封装、或本领域公知用于药物配制剂的其它物质。应当理解,载体、赋形剂、或稀释剂的特征会取决于用于特定应用的施用路径。含有这些物质的药学可接受配制剂的制备记载于例如《Remington’s Pharmaceutical Sciences》第18版(A.Gennaro编,Mack Publishing Co.,Easton,PA,1990)。
术语“药学可接受的”或“生理学可接受的”一般指不干扰依照本发明的化合物的效力和与生物学***(诸如细胞、细胞培养物、组织、或生物体)相容的物质。优选的是,所述生物学***是活的生物体,诸如脊椎动物。
术语“共施用”一般指在足够近的时间里施用至少两种不同物质以调控免疫应答。优选的是,共施用指同时施用至少两种不同物质。
术语“药学有效量”一般指足以实现期望生物学效应(诸如有益结果)的量。如此,“药学有效量”会取决于施用它的背景。药学有效量可以在一次或多次预防性或治疗性施用中施用。
术语“与...组合”一般指在治疗患者的过程中施用依照本发明的化合物和/或对治疗疾病或疾患有用的且不消除本发明化合物的TLR9拮抗剂效应的其它药剂。此类施用可以以任意次序进行,包括同时施用,以及相隔几秒钟至长达数天的时间上有间隔的次序。此类组合处理还可包括超过一次的依照本发明的化合物和/或独立的其它药剂的施用。依照本发明的化合物和其它药剂的施用可以是通过相同或不同的路径的。
术语“个体”和“受试者”一般指哺乳动物,诸如人。哺乳动物一般包括但不限于人、非人灵长类、大鼠、小鼠、猫、犬、马、牛(cattle)、奶牛(cows)、猪、绵羊和家兔。
术语“激酶抑制剂”一般指拮抗或抑制细胞中磷酸化依赖性细胞信号传导和/或生长途径的分子。激酶抑制剂可以是天然存在的或合成的,而且包括具有作为口服治疗剂施用的潜力的小分子。激酶抑制剂具有迅速且特异性抑制靶激酶分子活化的能力。蛋白质激酶是诱人的药物靶,部分因为它们调节极其多种信号传导和生长途径且包括许多不同蛋白质。因此,它们在牵涉激酶信号传导的疾病(包括癌症、心血管疾病、炎性病症、糖尿病、黄斑变性和神经学病症)的治疗中具有极大潜力。激酶抑制剂的例子包括sorafenibdasatinib、DasatinibTM、ZactimaTM、TykerbTM和STI571。
术语“线性合成”一般指在寡核苷酸的一端开始并线性进展至另一端的合成。线性合成容许将相同或不同(就所掺入的长度、碱基组成和/或化学修饰而言)的单体单元掺入寡核苷酸。
术语“哺乳动物”明确地意图包括温血的脊椎动物,包括但不限于人。
术语“经过修饰的核苷”一般是包括经过修饰的杂环碱基、经过修饰的糖模块、或其任意组合的核苷。在一些实施方案中,经过修饰的核苷是非天然嘧啶或嘌呤核苷,如本文所述。为了本发明,经过修饰的核苷、嘧啶或嘌呤类似物或非天然存在的嘧啶或嘌呤可互换使用,指包括非天然存在的碱基和/或非天然存在的糖模块的核苷。为了本发明,如果某碱基不是鸟嘌呤、胞嘧啶、腺嘌呤、胸腺嘧啶或尿嘧啶,那么认为该碱基是非天然的。
术语“调控”或“调控性”一般指变化,诸如响应的升高或TLR9介导的响应的定性差异。
术语“接头”一般指能借助共价或非共价键合经由糖、碱基、或主链附着至寡核苷酸的任何模块。接头可用于附着两个或更多个核苷,或者可附着至寡核苷酸的5’和/或3’末端核苷酸。在本发明的某些实施方案中,所述接头可以是非核苷酸接头。
术语“非核苷酸接头”一般指能借助共价或非共价键合附着至寡核苷酸的、核苷酸连接以外的化学模块。优选的是,所述非核苷酸接头的长度是约2埃至约200埃,而且可以是顺式或反式取向。
术语“核苷酸连接”一般指经由它们的糖(例如3’-3’、2’-3’、2’-5’、3’-5’)接合两个核苷的化学连接,其由相邻核苷间的磷原子和带电荷的或中性的基团(例如磷酸二酯、硫代磷酸酯或二硫代磷酸酯)组成。
术语“基于寡核苷酸的化合物”指自多个相连接的核苷单元形成的多核苷酸。核苷单元可以是病毒、细菌、细胞碎屑、siRNA或微小RNA的一部分,或者可以由病毒、细菌、细胞碎屑、siRNA或微小RNA的一部分构成。所述寡核苷酸还可以自现有的核酸来源获得,包括基因组或cDNA,但是优选是通过合成方法生成的。在优选的实施方案中,每个核苷单元包括杂环碱基和呋喃戊糖基、海藻糖、***糖、2’-脱氧-2’-取代的核苷、2’-脱氧-2’-取代的***糖、2’-O-取代的***糖或己糖基团。核苷残基可以通过多种已知的核苷间连接之每一种而彼此偶联。所述核苷间连接包括但不限于磷酸二酯(phosphodiester)、硫代磷酸酯(phosphorothioate)、二硫代磷酸酯(phosphorodithioate)、烃基膦酸酯(alkylphosphonate)、烃基硫代磷酸酯(alkylphosphonothioate)、磷酸三酯(phosphotriester)、亚氨基磷酸酯(phosphoramidite)、硅氧烷(siloxane)、碳酸酯(carbonate)、羰烷氧基(carboalkoxy)、氨基乙酸酯(acetamidate)、氨基甲酸酯(carbamate)、吗啉代(morpholino)、硼代(borano)、硫醚(thioether)、桥接氨基磷酸酯(bridgedphosphoramidate)、桥接亚甲基膦酸酯(bridged methylene phosphonate)、桥接硫代磷酸酯(bridged phosphorothioate)、和砜(sulfone)核苷间连接。术语“基于寡核苷酸”还涵盖具有一个或多个立体有择(stereospecific)核苷间连接(例如RP)-或(SP)-硫代磷酸酯、烃基膦酸酯、或磷酸三酯连接)的多核苷。如本文中所使用的,术语“寡核苷酸”和“二核苷酸”明确意图包括具有任何所述核苷间连接的多核苷和二核苷,无论所述连接是否包含磷酸根基团。在某些优选的实施方案中,这些核苷间连接可以是磷酸二酯、硫代磷酸酯或二硫代磷酸酯连接,或其组合。
术语“肽”一般指长度和组成足以影响生物学应答(例如抗体生成或细胞因子活性,无论该肽是否是半抗原)的多肽。术语“肽”可以包括经过修饰的氨基酸(无论是天然存在的还是非天然存在的),其中所述修饰包括但不限于磷酸化、糖基化、PEG化、脂化(lipidization)和甲基化。
术语“TLR9激动剂”一般指能够增强、诱导或调控由TLR9介导的免疫刺激的基于寡核苷酸的化合物。
术语“治疗”或“处理”一般指旨在获得有益的或期望的结果(其可以包括症状的缓和或者疾病进展的延迟或改善)的办法。
表1显示了依照本发明的某些TLR9激动剂。在此表中,除非指明,基于寡核苷酸的TLR9激动剂均为硫代磷酸酯(PS)连接。然而,本领域技术人员会认识到,可使用磷酸二酯(PO)连接或混用PS连接和PO连接。除非指明,所有核苷酸均为脱氧核糖核苷酸。
表1
化合物No.(SEQ ID NO:) | 序列和修饰 |
1(1) | 5’-TCG1TACG1TACG1-X-G1CATG1CATG1CT-5’ |
2(2) | 5’-TCTGTOCG2TTGT-X-TGTTG2COTGTCT-5’ |
3(3) | 5’-TCAGTOCG2TTAC-Z-CATTG2COTGACT-5’ |
4(4 & 170) | 5’-TCTGOTOCG2TAG-M-GATTG2COTOGTCT-5’ |
5(5) | 5’-TCG1TCG1TTT-L-M-L-TTTG1CTG1CT-5’ |
6(6) | 5’-TCG1TCG1TTT-L-X-L-TTTG1CTG1CT-5’ |
7(7) | 5’-TCG1AACG1TTCoG-Z-GoCTTG1CAAG1CT-5’ |
8(8 & 18) | 5’-TCG1TCG1TTL-Y-G1CTTG1CAAG1CT-5’ |
9(9) | 5’-TCTGTCG2TTCU-X-UCTTG2CTGTCT-5’ |
10(10) | 5’-TCG1TCG1TTTUU-X-UUTTTG1CTG1CT-5’ |
11(11) | 5’-TCG1TCG1TTU1Y-Z-YU1TTG1CTG1CT-5’ |
12(12) | 5’-TCG2TCG2TTU1Y-M-YU1TTG2CTG2CT-5’ |
13(13) | 5’-TAGTCG1TTCTC-X-CTCTTG1CTGAT-5’ |
14(14) | 5’-TCUTGTCG1TTC-X-CTTG1CTGTUCT-5’ |
15(15 & 171) | 5’-TCG1TCG1TTTTT-Y-TCTTG1CTGUCT-5’ |
16(16 & 172) | 5’-TCG1TCG1TTTTT-Y-TCTTG1CTGTCTTG1CT-5’ |
17(17 & 192) | 5’-TCTGTCG1TTCT-Y-TCTTG1CTGYYTTG1CT-5’ |
18(18 & 172) | 5’-TCG1AACG1TTCG1-Y-TCTTG1CTGTCTTG1CT-5’ |
19(19 & 193) | 5’-TCG1AACG1TTCG1-Y-TCTTG1CTGLLTTG1CT-5’ |
20(20 & 171) | 5’-TCG1AACG1TTCG1-Y-TCTTG1CTGUCT-5’ |
21(21 & 173) | 5’-TCG1AACG1TTCG1-Y-GACAG1CTGTCT-5’ |
22(22) | 5'-TCTGTCG1TTCT-m-TCTTG1CTGTCT-5' |
23(23) | 5'-CAGTCOG2TTCAG-M-GACTTG2OCTGAC-5' |
24(24 & 18) | 5'-CAGTCOG2TTCAG-Y-G1CTTG1CAAG1CT-5' |
25(25) | 5’-TCG1AACG1TTCG-Z-GCTTG1CAAG1CT-5' |
26(26 & 174) | 5’-TCG1TCG1TTTTT-Y-TCTTG1CTGUCT-5’ |
27(27) | 5’-TCG2TCOG2TTU1Y-X-YU1TTG2OCTG2CT-5’ |
28(28) | 5’-TCG1AACG1U1U1CG-X-GcU1U1G1CAAG1CT-5' |
29(29) | 5’-TCTGTCG1TTCT-L1-TCTTG1CTGTCT-5’ |
30(30 & 18) | 5’-CAGTCG2TTCAG-Y-G1CTTG1CAAG1CT-5' |
31(31) | 5’-CAGTCoG2TTCAG-Z-GACTTG2oCTGAC-5’ |
32(32 & 175) | 5’-TCTGTCG1TTCT-Y-TCTTG1CTGUCTTG1CT-5’ |
33(33) | 5’-TCG1AACG1U1U1CoG-M-GoCU1U1G1CAAG1CT-5’ |
34(34) | 5’-TCG1AACG1ToTCoG-m-GoCToTG1CAAG1CT-5’ |
35(35) | 5’-TCG1AACG1TTCG1-L1-G1CTTG1CAAG1CT-5’ |
36(36) | 5'-CAGTCG2TTCAG-X1-GACTTG2CTGAC-5' |
37(37) | 5'-CAGTCG2TTCAG-X2-GACTTG2CTGAC-5' |
38(38) | 5'-psCAGTCG2TTCAG-X-GACTTG2CTGACps-5' |
39(39 & 30) | 5’-TCG1AACG1TTCoG1-Y2-GACTTG2CTGAC-5' |
40(40 & 30) | 5’-TCG1AACG1TTCG-Y2-GACTTG2CTGAC-5' |
41(41 & 30) | 5’-TCG1AACG1TTCoG-Y2-GACTTG2CTGAC-5' |
42(42 & 176) | 5’-TCG1AACG1TTCoG-Y2-CTTG2CTGACUTG1CT-5' |
43(43 & 17) | 5'-CAGTCG2TTCAG-Y2-TCTTG1CTGTCT-5' |
44(44 & 177) | 5’-TCG1AACG1TTCoG-Y2-CTTG2CTGApmCTTG1CT-5' |
45(45 & 178) | 5’-TCG1AACG1TTCG1-Y3-TGTTG1CTGTCTTG1CT-5' |
46(46) | 5’-TCAGTCG1TTAC-X-CATTG1CTGACT-5' |
47(47) | 5’-TCTGTCG1TTTT-X-TTTTG1CTGTCT-5' |
48(48) | 5’-TCAGTCG1TTACY1-X3-Y1CATTG1CTGACT-5' |
49(49) | 5’-TCTGTCG1TTTTY1-X3-Y1TTTTG1CTGTCT-5’ |
50(50 & 18) | 5’-TCG1TCG1TTY3-Y-G1CTTG1CAAG1CT-5' |
51(51) | 5’-TCG1TCG1TTdUY-Z-YdUTTG1CTG1CT-5’ |
52(52) | 5’-TCG1TCG1TTdUY-X-YdUTTG1CTG1CT-5’ |
53(53) | 5’-TCG1TCG1TTdUY-M-YdUTTG1CTG1CT-5’ |
54(54) | 5’-TCG1TCG1TTdUY-m-YdUTTG1CTG1CT-5’ |
55(55) | 5’-TCG2TCG2TTdUY-Z-YdUTTG2CTG2CT-5’ |
56(56) | 5’-TCG2TCG2TTdUY-X-YdUTTG2CTG2CT-5’ |
57(57) | 5’-TCG2TCG2TTdUY-M-YdUTTG2CTG2CT-5’ |
58(58) | 5’-TCG2TCG2TTdUY-m-YdUTTG2CTG2CT-5’ |
59(59) | 5’-TCG1TCG1ACG1AT-Z-TAG1CAG1CTG1CT-5’ |
60(60) | 5’-TCAGTCG2TTAC-X-CATTG2CTGACT-5’ |
61(61) | 5’-TCG1ATCG1ATCG1-X-G1CTAG1CTAG1CT-5' |
62(62) | 5’-TCG1AACG1TTCG1-Z-G1CTTG1CAAG1CT-5' |
63(63) | 5’-TCG1AACG1TTCG-Z-GCTTG1CAAG1CT-5' |
64(64 & 173) | 5’-TCG1AACG1TTCG1-Y-GACAG1CTGTCT-5’ |
65(65 & 179) | 5’-TAGTCG1TTTTT-X-TTTTTG1CGTAT-5’ |
66(66) | 5’-TCGTCGTTCTT-X-TTCTTGCTGCT-5’ |
67(67) | 5’-TGGTCG2TTCTT-X-TTCTTG2CTGGT-5’ |
68(68) | 5’-TAGTCG2TTCTC-X-CTCTTG2CTGAT-5’ |
69(69 & 180) | 5’-TCG1TCG1TTTTT-Y-TCTTG1CTGTCT-5’ |
70(70 & 174) | 5’-TCG1TCG1TTTTT-Y-TCTTG1CTGUCT-5’ |
71(71 & 181) | 5’-TCG1TCG1TTTTT-Y-TCTTG1CTGTCTTCCT-5’ |
72(72) | 5’-TCTTGTCG1TTC-X-CTTG1CTGTTCT-5' |
73(73) | 5’-TCTTGTCG1TTC-X-CTTG1CTGTTCT-5' |
74(74) | 5’-TCTGTCG3TTCT-X-TCTTG3CTGTCT-5' |
75(75) | 5’-TCG3AACG3TTCG3-X-G3CTTG3CAAG3CT-5' |
76(76 & 175) | 5’-TCG1TCG1TTTTT-X-TCTTG1CTGUCTTG1CT-5’ |
77(77 & 192) | 5’-TCG1TCG1TTTTT-X-TCTTG1CTGYYTTG1CT-5’ |
78(78 & 193) | 5’-TCG1TCG1TTTTT-X-TCTTG1CTGLLTTG1CT-5’ |
79(79 & 193) | 5’-TCTGTCG1TTCT-Y-TCTTG1CTGLLTTG1CT-5’ |
80(80 & 171) | 5’-TCG1AACG1TTCG1-L-TCTTG1CTGUCT-5’ |
81(81) | 5’-CAGTCG2TTCAG-X-GACTTG2CTGAC-5’ |
82(82 & 182) | 5’-CAGTCG2TTCAG-Z-GACTTG2CTTAC-5’ |
83(83 & 182) | 5’-CAGTCG2TTCAG-M-GACTTG2CTTAC-5’ |
84(84 & 182) | 5’-CAGTCG2TTCAG-m-GACTTG2CTTAC-5’ |
85(85 & 183) | 5’-CAGTCoG2TTCAG-X-GACTTG2CoTTAC-5’ |
86(86 & 183) | 5’-CAGTCoG2TTCAG-M-GACTTG2CoTTAC-5’ |
87(87 & 183) | 5’-CAGTCoG2TTCAG-m-GACTTG2CoTTAC-5’ |
88(88 & 18) | 5’-CAGTCoG2TTCAG-Y-G1CTTG1CAAG1CT-5’ |
89(89) | 5’-TCG1AACG1ToTCoG1-m-G1oCToTG1CAAG1CT-5' |
90(90) | 5’-TCG1AACG1oTTCG1-Z-G1CTToG1CAAG1CT-5' |
91(91) | 5’-TCG1AACG1oToToCoG-Z-GoCoToToG1CAAG1CT-5' |
92(92) | 5’-TCG1AACoG1TTCG1-X-G1CTTG1oCAAG1CT-5’ |
93(93) | 5’-TCG1AACG1dUdUCG1-X-G1CdUdUG1CAAG1CT-5’ |
94(94) | 5’-TCG1AACG1dUdUCoG-X-GoCdUdUG1CAAG1CT-5’ |
95(95) | 5’-TCG1AACG1dUdUCoG-Z-GoCdUdUG1CAAG1CT-5’ |
96(96) | 5’-TCG1AACG1dUdUCoG-m-GoCdUdUG1CAAG1CT-5’ |
97(97) | 5’-TCG1AACG1dUdUCG-X-GCdUdUG1CAAG1CT-5’ |
98(98) | 5’-TCG1AACG1TTCG1-L2-G1CTTG1CAAG1CT-5’ |
99(99 & 184) | 5’-TCG1TCG1TTCT-L3-TCTTG1CTGG1CT-5’ |
100(100 & 185) | 5’-TCTG1TCG1TTCG1-L3-M-L3-G1CTTG1CTGTCT-5’ |
101(101) | 5’-TCG1GTCG1TTCG1-L3-m-L3-G1CTTG1CTGG1CT-5’ |
102(102) | 5’-TCTGTCG1TTCT-L2-TCTTG1CTGTCT-5’ |
103(103) | 5’-TCTGTCG1TTCT-L3-TCTTG1CTGTCT-5’ |
104(104) | 5’-TCTGTCG1TTCT-L3-M-L3-TCTTG1CTGTCT-5’ |
105(105) | 5’-TCTGTCG1TTCT-L3-m-L3-TCTTG1CTGTCT-5’ |
106(106) | 5'-CAGTCG3TTCAG-X-GACTTG3CTGAC-5' |
107(107) | 5'-TCTGTCG3TTCT-X-TCTTG3CTGTCT-5' |
108(108) | 5'-TCTGTCG1TTCT-X1-TCTTG1CTGTCT-5' |
109(109) | 5'-TCTGTCG1TTCT-X2-TCTTG1CTGTCT-5' |
110(110) | 5'-TCTGTCG1TTCT-Z-TCTTG1CTGTCT-5' |
111(111) | 5'-TCTGTCG1TTCT-M-TCTTG1CTGTCT-5' |
112(112) | 5'-TCTGTCG1TTCT-m-TCTTG1CTGTCT-5' |
113(113) | 5'-TCG1AACG1TTCG1-Z-G1CTTG1CAAG1CT-5' |
114(114) | 5'-TCG1AACG1TTCG1-M-G1CTTG1CAAG1CT-5' |
115(115) | 5'-TCG1AACG1TTCG1-m-G1CTTG1CAAG1CT-5' |
116(116) | 5'-TCG1AACG1TTCG1-X2-G1CTTG1CAAG1CT-5' |
117(117) | 5'-TCG1AACG1TTCG1-X1-G1CTTG1CAAG1CT-5' |
118(118) | 5'-Y1CAGTCG2TTCAG-X-GACTTG2CTGACY1-5' |
119(119) | 5'-YCAGTCG2TTCAG-X-GACTTG2CTGACY-5' |
120(120) | 5'-poCAGTCG2TTCAG-X-GACTTG2CTGACpo-5' |
121(121 & 22) | 5'-CAGTCG2TTCAG-Y2-TCTTG1CTGTCT-5' |
122(122 & 186) | 5’-TCG1AACG1TTCoG-Y2-CTTG2CTGACTTG1CT-5' |
123(123) | 5’-TCAGTCG1TTAC-X-CATTG1CTGACT-5' |
124(124) | 5’-TCTGTCG1TTAG-X-GATTG1CTGTCT-5' |
125(125) | 5’-TCTGTCG1TTTT-X-TTTTG1CTGTCT-5' |
126(126) | 5’-TCTGTCG1TTGT-X-TGTTG1CTGTCT-5' |
127(127 & 186) | 5’-TCG1AACG1TTCoG-Y2-CTTG2CTGACTTG1CT-5' |
128(128) | 5’-TCG1AACG1oTTCG1-Z-G1CTToG1CAAG1CT-5' |
129(129) | 5'-TCG1AACG1TTCG1-X2-G1CTTG1CAAG1CT-5' |
130(130 & 177) | 5’-TCG1AACG1TTCoG-Y2-CTTG2CTGApmCTTG1CT-5' |
131(131 & 187) | 5’-TCG1AACG1TTCoG-Y2-CTTG2CTGApmCpmTTG1CT-5' |
132(132 & 180) | 5’-TCG1TCG1TTTTT-Y3-TCTTG1CTGTCT-5’ |
133(133 & 181) | 5’-TCG1TCG1TTTTT-Y3-TCTTG1CTGTCTTCCT-5’ |
134(134) | 5’-TCG2TCG2TTdUY3-X3-Y3dUTTG2CTG2CT-5’ |
135(135) | 5’-TCG1AACG1oTTCG1-X3-G1CTToG1CAAG1CT-5' |
136(136 & 194) | 5’-TCTGTCG1TTAC-Y3-CATTG1CTGYYTTG1CT-5’ |
137(137 & 195) | 5’-TCTGTCG1TTGT-Y3-TGTTG1CTGYYTTG1CT-5’ |
138(138 & 194) | 5’-TCAGTCG1TTCT-Y3-CATTG1CTGYYTTG1CT-5’ |
139(139 & 188) | 5’-TCG1AACG1TTCG1-Y3-CATTG1CTGTCTTG1CT |
140(140 & 178) | 5’-TCG1AACG1TTCG1-Y3-TGTTG1CTGTCTTG1CT |
141(141 & 189) | 5’-TCTGTCG1TTAC-Y3-TGTTG1CTGUCTTG1CT-5’ |
142(142 & 190) | 5’-TCTGTCG1TTGT-Y3-AGTTG1CTGUCTTG1CT-5’ |
143(143 & 191) | 5’-TCAGTCG1TTAG-Y3-CATTG1CTGUCTTG1CT-5’ |
144(144) | 5’-TCAGTCG1TTAC-X-CATTG1CTGACT-5' |
145(145) | 5’-TCTGTCG1TTAG-X-GATTG1CTGTCT-5' |
146(146) | 5’-TCTGTCG1TTTT-X-TTTTG1CTGTCT-5' |
147(147) | 5’-TCTGTCG1TTGT-X-TGTTG1CTGTCT-5' |
148(148) | 5'-Y1CAGTCG2TTCAG-X-GACTTG2CTGACY1-5' |
149(149) | 5’-TCAGTCG1TTACY1-X3-Y1CATTG1CTGACT-5' |
150(150) | 5’-TCTGTCG1TTAGY1-X3-Y1GATTG1CTGTCT-5' |
151(151) | 5’-TCTGTCG1TTTTY1-X3-Y1TTTTG1CTGTCT-5' |
152(152) | 5’-TCTGTCG1TTGTY1-X3-Y1TGTTG1CTGTCT-5' |
153(153) | 5’-TCG1AACG1oTTCG1-Z-G1CTToG1CAAG1CT-5' |
154(154) | 5'-TCG1AACG1TTCG1-X2-G1CTTG1CAAG1CT-5' |
155(155) | 5'-TCG1TACG1TACG1-X1-G1CATG1CATG1CT-5' |
156(156) | 5'-TCG1TACG1TACG1-X3-G1CATG1CATG1CT-5' |
157(157) | 5'-TCG1TACG1TACG1-X-G1CATG1CATG1CT-5' |
158(158 & 29) | 5'-CAGTCG2TTCAG-Y2-TCTTG1CTGTCT-5' |
159(159 & 179) | 5’-TAGTCG1TTTTT-X-TTTTTG1CGTAT-5’ |
160(160) | 5’-TCTGTCG1TTCT-Z-TCTTG1CTGTCT-5' |
161(161) | 5’-TCTGTCG1TTCT-M-TCTTG1CTGTCT-5' |
162(162) | 5’-TCTGTCG1TTCT-L2-TCTTG1CTGTCT-5’ |
163(163) | 5’-TCG1AACG1oTTCG1-Z-G1CTToG1CAAG1CT-5' |
164(164) | 5'-TCG1AACG1TTCG1-X2-G1CTTG1CAAG1CT-5' |
165(165) | 5’-TCG1AACG1TTCG1-m-G1CTTG1CAAG1CT-5' |
166(166) | 5’-TCG1AACG1ToTCoG-m-GoCToTG1CAAG1CT-5' |
167(167) | 5’-TCG1AACG1dUdUCoG-M-GCodUdUG1CAAG1CT-5’ |
168(168) | 5’-TCG1TCG1ACG1AT-X-TAG1CAG1CTG1CT-5’ |
169(169) | 5’-TCG1ATCG1ATCG1-X-G1CTAG1CTAG1CT-5' |
G1=7-脱氮-dG;G2=AraG;G3=7-脱氮-araG;A/G/C/U=2’-O-甲基核糖核苷酸;dU=U1=2’-脱氧-U;o=磷酸二酯连接;po=5’-单磷酸酯;ps=5’硫代磷酸酯连接;pm=甲基膦酸酯(非离子连接);L=1,5-戊二醇接头;L=1,2-双脱氧核糖;L1=三甘醇接头;L2=四甘醇接头;L3=六甘醇接头;M=顺式,顺式-1,3,5-环己三醇接头;m=顺式,反式-1,3,5-环己三醇接头;X=甘油接头;X1=1,2,4-丁三醇接头;X2=1,3,5-三(2-羟乙基)氰尿酸接头;X3=异丁三醇接头;Y=1,3-丙二醇接头;Y1=1,2-乙二醇接头;Y2=1,4-丁二醇接头;Y3=1,5-戊二醇接头;Z=1,3,5-戊三醇接头。
如实施例2中所述,在表达TLR9的HEK293细胞中对表1例示的TLR9激动剂测试了免疫刺激活性。图3A、3B、3C、3D、和3E所示结果证明了对3’-3’连接的寡核苷酸的特定化学修饰会改变它们在施用的18小时后被TLR9介导的NF-kB激活谱。更一般地,这些数据证明了对3’-3’连接的寡核苷酸的特定化学修饰可用于提高或降低NF-kB激活。
如实施例3中所述,在针对IL-12、IL-10、IL-8、IL-6、IFN-α、IP-10、MIP-1α、MIP-1β、IL-1Rα、IL-2R、和MCP-1的人PBMC测定法中对表1例示的TLR9激动剂测试了免疫刺激活性。图4A-4FF所示结果证明了对3’-3’连接的寡核苷酸的特定化学修饰会改变它们在人PBMC中的TLR9介导的IL-12、IL-10、IL-8、IL-6、IFN-α、IP-10、MIP-1α、MIP-1β、IL-1Rα、IL-2R、和/或MCP-1激活谱。更一般地,这些数据证明了对3’-3’连接的寡核苷酸的特定化学修饰可用于提高或降低IL-12、IL-10、IL-8、IL-6、IFN-α、IP-10、MIP-1α、MIP-1β、IL-1Rα、IL-2R、和MCP-1激活。
如实施例3中所述,在针对IL-12、IL-6、IFN-α、IP-10、MIP-1α、MIP-1β、和TNFα的人pDC测定法中对表1例示的TLR9激动剂测试了免疫刺激活性。图5A和5B所示结果证明了对3’-3’连接的寡核苷酸的特定化学修饰会改变它们在人pDC中的TLR9介导的免疫激活谱。更一般地,这些数据证明了对3’-3’连接的寡核苷酸的特定化学修饰可用于提高或降低IL-12、IL-6、IFN-α、IP-10、MIP-1α、MIP-1β、和TNFα激活。
如实施例4中所述,在人B细胞增殖测定法中对表1例示的TLR9激动剂测试了免疫刺激活性。图6A、6B、6C、6D、6E和6F所示结果证明了对3’-3’连接的寡核苷酸的特定化学修饰会改变它们被TLR9介导的B细胞增殖活性,而且这种激活谱根据化学修饰的不同而可以是剂量依赖性的。更一般地,这些数据证明了对3’-3’连接的寡核苷酸的特定化学修饰可用于调节B细胞增殖。
如实施例5中所述,在C57Bl/6和BALB/c小鼠中对表1例示的TLR9激动剂测试了体内免疫刺激活性。图7A、7B、7D、7E和8F所示结果证明了对3’-3’连接的寡核苷酸的特定化学修饰会改变它们在小鼠模型中的体内TLR9介导的免疫激活谱。更一般地,这些数据证明了对3’-3’连接的寡核苷酸的特定化学修饰能改变体内细胞因子和/或趋化因子浓度,这会在许多疾病中找到应用。
如上文所描述的,在第一个方面,本发明提供了TLR9的基于寡核苷酸的合成激动剂。基于对碱基、糖、连接或接头的某些化学修饰,TLR9的激动剂在与其它TLR9激动剂分子结合和/或成双(duplex)时可拥有升高的稳定性,同时保留可及的5’-末端。
在一些实施方案中,所述非核苷酸接头可以包括但不限于表2所列那些。
表2:代表性的非核苷酸接头
表2:续
表2:续
表2:续
表2:续
表2:续
在第二个方面,本发明提供了药物配制剂,其包含依照本发明的基于寡核苷酸的TLR9激动剂(“化合物”)和药学可接受载体。
药学可接受载体或稀释剂中所包括的活性化合物的量足以给患者投递药学有效量而不会在所处理的患者中引起严重的毒性作用。药学可接受衍生物的有效剂量范围可基于要投递的亲本化合物的重量或通过本领域技术人员知道的其它手段来计算。如果衍生物自身展现出活性,那么有效剂量可如上所述使用衍生物的重量或通过本领域技术人员知道的其它手段来估算。
在第三个方面,本发明提供了疫苗。依照这个方面的疫苗包含依照本发明的药物配制剂,且进一步包含抗原。抗原指引发特异性免疫应答的分子。此类抗原包括但不限于蛋白质、肽、核酸、碳水化合物及其任何复合物或组合。任何此类抗原可任选是与免疫原性蛋白质或肽相连接的,诸如匙孔血蓝蛋白(KLH)、霍乱毒素B亚基、或任何其它免疫原性载体蛋白。
依照本发明的疫苗可进一步包括众多已知佐剂中的任何佐剂,包括但不限于弗氏完全佐剂、匙孔血蓝蛋白(KLH)、单磷酰基脂质A(MPL)、明矾、和皂苷,包括QS-21、咪喹莫特(imiquimod)、R848、TLR激动剂或其组合。
在第四个方面,本发明提供了用于在个体中产生TLR9介导的免疫应答的方法,此类方法包括对个体施用依照本发明的化合物、药物配制剂或疫苗。在一些实施方案中,个体是哺乳动物。在优选的实施方案中,对需要免疫刺激的个体施用化合物、药物配制剂或疫苗。
在依照本发明这个方面的方法中,依照本发明的化合物、药物配制剂组合物或疫苗的施用可通过任何合适路径来进行,包括但不限于胃肠外、口服、肿瘤内、舌下、透皮、表面局部(topical)、鼻内、气溶胶、眼内、气管内、直肠内、粘膜、***、通过基因枪、皮肤贴片或以滴眼液或漱口水的形式。化合物、药物配制剂或疫苗的施用可使用已知规程以有效减轻疾病的症状或替代标志物的剂量和时间段来进行。在***性施用时,优选以足够剂量施用化合物、药物配制剂或疫苗以使依照本发明的化合物的血液水平达到约0.0001微摩尔至约10微摩尔。对于局部施用,比这低得多的浓度可以是有效的,而且可耐受高得多的浓度而没有毒性作用。优选的是,依照本发明的化合物的总剂量的范围为约0.001mg每名患者每天至约200mg每kg体重每天。可能希望对个体同时地或顺序地施用治疗有效量的一种或多种本发明治疗用组合物作为单次处理事件。
在某些优选的实施方案中,与其它药剂组合地施用或共施用依照本发明的化合物、药物配制剂或疫苗,所述其它药剂包括但不限于抗体、细胞毒剂、变应原、抗生素、反义寡核苷酸、siRNA、适体、核酶、靶向疗法、激酶抑制剂、肽、蛋白质、基因疗法载体、DNA疫苗、和/或佐剂(用以增强免疫应答的特异性或强度)。
依照本发明这个方面的方法对于人或动物疾病的预防性或治疗性处理是有用的。例如,所述方法对于儿科和兽医疫苗应用是有用的。所述方法对于免疫***的模型研究也是有用的。
在第五个方面,本发明提供了治疗性处理患有疾病或病症的患者的方法,此类方法包括对患者施用依照本发明的化合物、药物配制剂或疫苗。在各种实施方案中,要治疗的疾病或病症是癌症、自身免疫性病症、传染病、气道炎症、炎性病症、***反应、哮喘或由病原体或变应原引起的疾病。病原体包括例如细菌、寄生物、真菌、病毒、类病毒、和朊病毒。施用如关于本发明第四个方面所述的进行。
在第六个方面,本发明提供了用于预防疾病或病症的方法,此类方法包括对患者施用依照本发明的化合物、药物配制剂或疫苗。在各种实施方案中,要预防的疾病或病症是癌症、自身免疫性病症、气道炎症、炎性病症、传染病、***反应、哮喘或由病原体引起的疾病。病原体包括但不限于细菌、寄生物、真菌、病毒、类病毒、和朊病毒。施用如关于本发明第四个方面所述的进行。
在任何依照本发明的方法中,可以与对预防或治疗疾病或疾患有用的且不消除依照本发明的化合物、药物配制剂或疫苗的免疫刺激效应的任何其它药剂组合地施用或共施用依照本发明的化合物、药物配制剂或疫苗。在任何依照本发明的方法中,对预防或治疗疾病或疾患有用的药剂包括但不限于疫苗、抗原、抗体、细胞毒剂、变应原、抗生素、反义寡核苷酸、TLR激动剂、激酶抑制剂、肽、蛋白质、基因疗法载体、DNA疫苗和/或佐剂(用以增强免疫应答的特异性或强度)、或共刺激分子诸如细胞因子、趋化因子、蛋白质配体、反式激活因子、肽和包含经修饰氨基酸的肽。例如,在癌症的预防和/或治疗中,涵盖可以与化疗化合物或单克隆抗体组合地施用或共施用依照本发明的化合物、药物配制剂或疫苗。
优选的化疗剂包括但不限于吉西他滨(Gemcitabine)甲氨喋呤(methotrexate)、长春新碱(vincristine)、阿霉素(adriamycin)、顺铂(cisplatin)、不含糖的氯乙基亚硝基脲类(non-sugar containing chloroethylnitrosoureas)、5-氟尿嘧啶(5-fluorouracil)、丝裂霉素C(mitomycin C)、博来霉素(bleomycin)、多柔比星(doxorubicin)、达卡巴嗪(dacarbazine)、fragyline、MeglamineGLA、戊柔比星(valrubicin)、卡莫司汀(carmustaine)和poliferposan、MMI270、BAY 12-9566、RAS法尼基转移酶抑制剂(famesyl transferase inhibitor)、法尼基转移酶抑制剂(famesyl transferase inhibitor)、MMP、MTA/LY231514、LY264618/Lometexol、Glamolec、CI-994、TNP-470、和美新(Hycamtin)/托泊替康(Topotecan)、PKC412、伐司朴达(Valspodar)/PSC833、米托蒽醌(Mitroxantrone)、Metaret/苏拉明(Suramin)、巴马司他(Batimastat)、E7070、BCH-4556、CS-682、9-AC、AG3340、AG3433、Incel/VX-710、VX-853、ZD0101、ISI641、ODN 698、TA2516/Marmistat、BB2516/Marmistat、CDP 845、D2163、PD183805、DX8951f、Lemonal DP 2202、FK 317、甲磺酸伊马替尼(imatinib mesylate)/Picibanil/OK-432、AD 32/戊柔比星(Valrubicin)、/锶衍生物、Temodal/替莫唑胺(Temozolomide)、Evacet/脂质体多柔比星、Yewtaxan/帕利他塞(Placlitaxel)、帕利他塞(Paclitaxel)、希罗达(Xeload)/卡培他滨(Capecitabine)、氟铁龙(Furtulon)/去氧氟尿苷(Doxfluridine)、Cyclopax/口服帕利他塞、口服类紫杉醇(Taxoid)、SPU-077/顺铂(Cisplatin)、HMR 1275/Flavopiridol、CP-358(774)/EGFR、CP-609(754)/RAS癌基因抑制剂、BMS-182751/口服铂、UFTTM(替加氟(Tegafur)/尿嘧啶(Uracil))、左旋咪唑(Levamisole)、恩尿嘧啶(Eniluracil)/776C85/5FU增强剂、Campto/左旋咪唑(Levamisole)、伊立替康(Irinotecan)、Tumodex/Ralitrexed、克拉克屈滨(Cladribine)、Paxex/帕利他塞(Paclitaxel)、/脂质体多柔比星、Caelyx/脂质体多柔比星、/氟达拉滨(Fludarabine)、Pharmarubicin/表柔比星(Epirubicin)、ZD1839、LU 79553/Bis-Naphtalimide、LU 103793/多拉司他汀(Dolastain)、Caetyx/脂质体多柔比星、吉西他滨(Gemcitabine)、ZD 0473/YM 116、罗丁种子(lodine seeds)、CDK4和CDK2抑制剂、PARP抑制剂、D4809/Dexifosamide、异环磷酰胺(Ifosamide)、替尼泊苷(Teniposide)、卡铂(Carboplatin)、Plantinol/顺铂(cisplatin)、Vepeside/依托泊苷(Etoposide)、ZD9331、多西他塞(Docetaxel)、鸟嘌呤阿糖胞苷的前体药物(prodrugof guanine arabinoside)、紫杉烷类似物(Taxane Analog)、亚硝基脲类(nitrosoureas)、烷化剂类(alkylating agents)诸如美法仑(melphelan)和环磷酰胺(cyclopho sphamide)、氨鲁米特(Aminoglutethimide)、天东酰胺酶(Asparaginase)、白消安(Busulfan)、卡铂(Carboplatin)、氯丁酸氮芥(Chlorombucil)、盐酸阿糖胞苷(Cytarabine HCl)、放线菌素D(Dactinomycin)、盐酸柔红霉素(Daunorubicin HCl)、雌莫司汀磷酸钠(Estramustine phosphatesodium)、依托泊苷(Etoposide)(VP16-213)、氟尿苷(Floxuridine)、氟尿嘧啶(Fluorouracil)(5-FU)、氟他胺(Flutamide)、羟脲(Hydroxyurea)(羟基尿素(hydroxycarbamide))、异环磷酰胺(Ifosfamide)、干扰素α-2a、α-2b)、醋酸亮丙瑞林(Leuprolide acetate)(LHRH释放因子类似物)、洛莫司汀(Lomustine)(CCNU)、盐酸双氯乙基甲胺(Mechlorethamine HCl)(氮芥(nitrogen mustard))、巯嘌呤(Mercaptopurine)、美司钠(Mesna)、米托坦(Mitotane)(o.p’-DDD)、盐酸米托蒽醌(Mitoxantrone HCl)、奥曲肽(Octreotide)、普卡霉素(Plicamycin)、盐酸丙卡巴肼(Procarbazine HCl)、链侳星(Streptozocin)、柠檬酸他莫昔芬(Tamoxifen citrate)、硫鸟嘌呤(Thioguanine)、塞替派(Thiotepa)、硫酸长春碱(Vinblastine sulfate)、安吖啶(Amsacrine)(m-AMSA)、阿扎胞苷(Azacitidine)、红细胞生成素(Erthropoietin)、六甲蜜胺(Hexamethylmelamine)(HMM)、白介素2、米托胍腙(Mitoguazone)(甲基-GAG;甲基乙二醛双-脒基腙;MGBG)、喷司他丁(Pentostatin)(2’-脱氧助间型霉素(2’deoxycoformycin))、司莫司汀(Semustine)(甲基-CCNU)、替尼泊苷(Teniposide)(VM-26)和硫酸长春地辛(Vindesine sulfate)。优选的单克隆抗体包括但不限于(Glaxo-Welicome)、(IDEC/Genentech/Hoffman la Roche)、(Wyeth)、(Millennium)、(IDEC and Schering AG)、(Corixa/GSK)、(Imclone/BMS)、(Genentech)(Genentech/Hoffman la Roche)、(OSI Pharmaceuticals/Genentech)。
或者,对预防或治疗疾病或疾患有用的药剂可包括编码抗原或变应原的DNA载体。在这些实施方案中,依照本发明的化合物、药物配制剂或疫苗能作为佐剂起多方面作用和/或产生直接的免疫调控效应。
以下实施例旨在进一步例示本发明的某些优选实施方案,并非意图以任何方式限制本发明的范围。
实施例1:含有免疫刺激模块的基于寡核苷酸的化合物的合成
依照本发明的化学实体是使用自动化DNA合成仪(OligoPilot II,AKTA,(Amersham)和/或Expedite 8909(Applied Biosystem))遵循图1和2中所概述的线性合成或平行合成规程以1μmol至0.1mM规模合成的。
5’-DMT dA、dG、dC和T亚氨基磷酸酯购自Proligo(Boulder,CO)。5’-DMT7-脱氮-dG和araG亚氨基磷酸酯得自Chemgenes(Wilmington,MA)。DiDMT-甘油接头固体支持物得自Chemgenes。1-(2’-脱氧-β-D-呋喃核糖基)-2-氧-7-脱氮-8-甲基-嘌呤酰亚胺(amidite)得自Glen Research(Sterling,VA),2’-O-甲基核糖核苷酰亚胺得自Promega(Obispo,CA)。所有依照本发明的化合物都是经硫代磷酸酯主链修饰的。
通过31P和1H NMR光谱来表征所有核苷亚氨基磷酸酯。使用供应商推荐的正常偶联循环在特定位点掺入经修饰的核苷。合成后,使用浓缩的氢氧化铵将化合物脱保护,并通过反相HPLC、脱三苯甲基化(detritylation)、继以透析来纯化。将钠盐形式的纯化的化合物冻干备用。通过CGE和MALDI-TOFMS测试纯度。LAL测试测出内毒素水平低于1.0EU/mg。
实施例2:细胞培养条件和试剂
表达小鼠TLR9的HEK293细胞或HEK293XL细胞(Invivogen,San Diego,CA)在5%CO2温箱中的48孔板中培养,每孔250μl DMEM且补充有10%热灭活FBS。在80%汇合时,在培养基中存在4μl/ml Lipofectamine(Invitrogen,Carlsbad,CA)的情况中用400ng/ml SEAP(分泌型人胚胎碱性磷酸酶)报道质粒(pNifty2-Seap)(Invivogen)瞬时转染培养物。在无血清培养基中分开稀释质粒DNA和Lipofectamine并在室温温育5分钟。温育后,将稀释的DNA和Lipofectamine混合并将混合物在室温温育20分钟。25μl含有100ng质粒DNA和1μl Lipofectamine的DNA/Lipofectamine混合物等分试样添加至细胞培养板的每个孔,并继续培养4小时。
表1例示的化合物在表达小鼠TLR9的HEK293细胞中对细胞因子的诱导
转染后,培养基更换为新鲜培养基,将表1例示的化合物以0、0.1、0.3、1.0、3.0、或10.0μg/ml的浓度添加至培养物,并将培养物继续培养18小时。在化合物处理结束时,使用SEAP(分泌型人胚胎碱性磷酸酶)测定法依照制造商的方案(Invivogen)测定NF-κB水平。简言之,自每种处理取出30μl培养物上清,并与对硝基苯基磷酸酯底物一起温育,所生成的黄色用读板仪在405nm测量(Putta MR等,Nucleic Acids Res.,2006,34:3231-8)。
实施例3:表1例示的化合物在人PBMC、pDC、和小鼠脾细胞中对细胞因子的诱导
分离人PBMC
通过Ficoll密度梯度离心法(Histopaque-1077,Sigma)自新鲜采集的健康志愿者血液分离外周血单个核细胞(PBMC)(CBR Laboratories,Boston,MA)。
分离人pDC
使用BDCA4细胞分离试剂盒(Miltenyi Biotec)依照制造商的说明书通过正选择自新鲜获得的健康人志愿者血液PBMC分离人类浆细胞样树突细胞(pDC)。
分离小鼠脾细胞
将5x106个细胞/ml的人PBMC分配入48孔板中。将1x106个细胞/ml的人pDC分配入96孔板中。将溶于DPBS(pH 7.4;Mediatech)的表1例示化合物以0、0.1、0.3、1.0、3.0、或10.0μg/ml的剂量添加至细胞培养物。然后将细胞在37°C温育24小时,收集上清液进行Luminex Multiplex或ELISA测定。在某些实验中,通过夹心ELISA测量IFN-α、IL-6、和/或IL-12水平。所需要的试剂(包括细胞因子抗体和标准品)购自PharMingen。
细胞因子Luminex Multiplex
在某些实验中,通过Luminex Multiplex测定法测量培养物上清液中的IL-1Rα、IL-6、IL-10、IL-12、IFN-α、IFN-γ、MIP-1α、MIP-β、MCP-1、和IL-12p40p70水平,其使用Biosource人多种细胞因子测定试剂盒在Luminex100仪器上实施,并使用由Applied Cytometry Systems(Sacramento,CA)提供的StarStation软件分析数据。
对人免疫细胞的激活
自新鲜获得的健康人血液PBMC分离人类浆细胞样树突细胞(pDC),并与50μg/ml TLR9激动剂或对照一起温育24小时。将细胞用荧光偶联的抗体(CD 123、CD80、CD86)染色,并在FC500MPL细胞计上收集数据。使用FlowJo软件分析CD123+细胞上的CD80和CD86荧光强度均值,并表示为相对于PBS对照的倍数变化。
自新鲜获得的健康人血液PBMC分离人髓样树突细胞(mDC),并与50μg/ml TLR9激动剂或对照一起温育24小时。将细胞用荧光偶联的抗体(CD11c、CD80、CD40)染色,并在FC500MPL细胞计上收集数据。使用FlowJo软件分析CD11c+细胞上的CD80和CD40荧光强度均值,并表示为相对于PBS对照的倍数变化。
实施例4:在存在表1例示的化合物的情况中的人B细胞增殖测定法
使用CD 19细胞分离试剂盒(Miltenyi Biotec,Auburn,CA)依照制造商的说明书通过正选择自PBMC分离人B细胞。
用于该测定法的培养基组成如下:RPMI 1640培养基,补充有1.5mM谷氨酰胺、1mM丙酮酸钠,0.1mM非必需氨基酸,50μM 2-巯基乙醇,100IU/ml青霉素-链霉素混合物和10%热灭活的胎牛血清。
用不同浓度的表1例示性化合物一式三份地在96孔平底板中刺激总共0.5X 106个B细胞/ml(即1X 105/200μl/孔)总共68小时。68小时后,在每孔中,用20μl RPMI 1640培养基(无血清)中的0.75μCi[3H]-胸苷(1Ci=37GBq;PerkinElmer Life Sciences)脉冲细胞,在6-8小时后收获。然后使用细胞收集器收获平板并使用标准液体闪烁技术测定放射性掺入。在有些情况中,将相应的[3H]-T(cpm)换算成增殖指数并如此报告。
实施例5:用TLR9激动剂化合物处理的小鼠模型中的体内细胞因子分泌
5-6周龄的C57BL/6小鼠BALB/c小鼠得自Taconic Farms(Germantown,NY)并依照Idera Pharmaceutical的IACUC批准的动物方案来饲养。给小鼠(n=3)皮下(s.c)注射表1的各ge免疫调控化合物0.25或1.0mg/kg(单剂)。施用免疫调控化合物的2小时后通过眶后取血来收集血清,并通过夹心ELISA或Luminex多重测定法测定IL-12、IL-10、IL-6、IP-10、KC、MCP1、MIG、MIP-1α和TNF-α浓度。结果显示于图7A、7B、7C、7D、7E和8F,并证明了体内施用含有免疫调控化合物的新的化学组合物产生独特的细胞因子和趋化因子谱。所有试剂(包括细胞因子和趋化因子抗体和标准品)都购自PharMingen(SanDiego,CA)。
等同方案
虽然出于澄清和理解的目的已经较为详细地描述了上述发明,但是本领域技术人员在阅读本公开内容后会领会,可以对形式和细节做各种改变而不背离本发明和所附权利要求的真正范围。
Claims (9)
1.一种免疫调控化合物,其选自下组:
5’-TCG2TCG2TTU1Y-M-YU1TTG2CTG2CT-5’
[5'-SEQ ID NO:12-3'-M-3'-SEQ ID NO:12-5'];
5’-TCG1AACG1TTCoG-Z-GoCTTG1CAAG1CT-5’
[5'-SEQ ID NO:7-3'-Z-3'-SEQ ID NO:7-5'];
5’-TCG1AACG1TTCG1-Y-TCTTG1CTGTCTTG1CT-5’
[5'-SEQ ID NO:18-3'-Y-3'-SEQ ID NO:172-5'];
5’-TCG1AACG1TTCG1-Y-TCTTG1CTGUCT-5’
[5'-SEQ ID NO:20-3'-Y-3'-SEQ ID NO:171-5'];
5’-TCG1AACG1ToTCoG-m-GoCToTG1CAAG1CT-5’
[5'-SEQ ID NO:34-3'-m-3'-SEQ ID NO:-34-5'];
5’-TCG1AACG1TTCoG-Y2-GACTTG2CTGAC-5'
[5'-SEQ ID NO:41-3'-Y2-3'-SEQ ID NO:30-5'];
5’-TCG1AACG1TTCG1-Y3-TGTTG1CTGTCTTG1CT-5'
[5'-SEQ ID NO:45-3'-Y3-3'-SEQ ID NO:178-5'];和
5'-CAGTCG2TTCAG-Y2-TCTTG1CTGTCT-5'
[5'-SEQ ID NO:43-Y2-SEQ ID NO:17-5'],
其中G1=7-脱氮-dG;G2=AraG;G/G/U=2’-O-甲基核糖核苷酸;o=磷酸二酯连接;m=顺式,反式-1,3,5-环己三醇接头;Y=1,3-丙二醇接头;Y2=1,4-丁二醇接头;Y3=1,5-戊二醇接头;Z=1,3,5-戊三醇接头。
2.一种组合物,其包含依照权利要求1的免疫调控化合物和生理学可接受的载体。
3.权利要求1的免疫调控化合物在制备药物中的用途,所述药物用于在个体中产生免疫应答的方法,所述方法包括对个体施用药学有效量的依照权利要求1的化合物。
4.权利要求1的免疫调控化合物在制备药物中的用途,所述药物用于治疗性处理患有受益于免疫应答调控的疾病或病症的个体的方法,所述方法包括对个体施用药学有效量的依照权利要求1的化合物。
5.依照权利要求4的用途,其中所述疾病或病症是癌症、自身免疫性病症、气道炎症、炎性病症、传染病、皮肤病症、***反应、哮喘或由病原体或变应原引起的疾病。
6.依照权利要求4的用途,进一步包括施用一种或多种化疗化合物、靶向治疗剂、疫苗、抗原、抗体、细胞毒剂、变应原、抗生素、反义寡核苷酸、TLR激动剂、激酶抑制剂、肽、蛋白质、DNA疫苗、佐剂、共刺激分子或其组合。
7.权利要求1的免疫调控化合物在制备药物中的用途,所述药物用于预防性处理患有受益于免疫应答调控的疾病或病症的个体的方法,所述方法包括对个体施用药学有效量的依照权利要求1的化合物。
8.依照权利要求7的用途,其中所述疾病或病症是个体中的癌症、自身免疫性病症、气道炎症、炎性病症、传染病、皮肤病症、***反应、哮喘或由病原体或变应原引起的疾病。
9.依照权利要求7的用途,进一步包括施用一种或多种化疗化合物、靶向治疗剂、疫苗、抗原、抗体、细胞毒剂、变应原、抗生素、反义寡核苷酸、TLR激动剂、激酶抑制剂、肽、蛋白质、DNA疫苗、佐剂、共刺激分子或其组合。
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Cited By (1)
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CN110201156A (zh) * | 2013-05-30 | 2019-09-06 | 莫洛根股份公司 | 用于癌症治疗的预测性生物标记物 |
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RU2010107207A (ru) | 2011-09-10 |
US8361986B2 (en) | 2013-01-29 |
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CN105177014A (zh) | 2015-12-23 |
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EP2821488A3 (en) | 2015-04-29 |
EP2650369B1 (en) | 2015-04-29 |
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EP2821488B1 (en) | 2016-07-27 |
WO2009018431A2 (en) | 2009-02-05 |
RU2468819C2 (ru) | 2012-12-10 |
EP2821488A2 (en) | 2015-01-07 |
JP2014205691A (ja) | 2014-10-30 |
JP2010535242A (ja) | 2010-11-18 |
EP2173912A2 (en) | 2010-04-14 |
IN2010KN00195A (zh) | 2015-08-28 |
WO2009018431A3 (en) | 2009-12-30 |
ES2539353T3 (es) | 2015-06-30 |
EP2650369A1 (en) | 2013-10-16 |
US20110311518A1 (en) | 2011-12-22 |
HK1216430A1 (zh) | 2016-11-11 |
CN102864151B (zh) | 2015-07-08 |
JP5816720B2 (ja) | 2015-11-18 |
US20090053206A1 (en) | 2009-02-26 |
CA2693266A1 (en) | 2009-02-05 |
AU2008282172A1 (en) | 2009-02-05 |
CN101878311A (zh) | 2010-11-03 |
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