CN110237270A - 自身免疫性疾病的治疗 - Google Patents
自身免疫性疾病的治疗 Download PDFInfo
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Abstract
本发明涉及自身免疫性疾病的治疗。具体地,本发明公开了可用于治疗导致毛发脱落如脱毛症的自身免疫性疾病或病症的组合物,其包含第一多核苷酸和第二多核苷酸,其中:a)所述第一多核苷酸包含编码自身抗原或其抗原性片段的序列,其中所述第一多核苷酸的至少约50%的CpG二核苷酸被甲基化;和b)所述第二多核苷酸包含编码促凋亡蛋白或其功能性促凋亡片段的序列,所述促凋亡蛋白选自BAK、BAX、BIM、死亡受体4、死亡受体5或FAS受体,其中所述第二多核苷酸的所述CpG二核苷酸的15%或更少被甲基化;用于皮内用于诱导针对所述自身抗原的致耐受性免疫应答。
Description
本发明是申请号为201480015896.9,申请日为2014年3月14日,发明名称为“自身免疫性疾病的治疗”的中国专利申请的分案申请。
相关申请
本申请要求2013年3月15日提交的美国专利申请No.61/800,354的权益;本申请的全部教导以引用的方式并入本文中。
序列表
本申请包含以电子方式作为ASCII文件提交的序列表,且其整体以引用的方式并入本文中。该ASCII复本名称为088025-0076_SL.txt,创建于2015年9月22日,其大小为1,119字节。
技术领域
主题技术总体上涉及用于治疗自身免疫性疾病或病症,特别是导致毛发脱落如脱毛症的自身免疫性疾病或病症的组合物和方法。
背景技术
脱毛症是毛发脱落的病症。脱毛症中的毛发的脱落不仅局限于头发,而且可发生于身体的任何部位。尽管通常不会危急生命,但由于其外观相关问题而伴随严重的精神损害,因此期望存在针对脱毛症的优异预防剂和治疗剂。另外,由于脱毛症通常伴随有毛发颜色的褪色,因此期望存在针对伴随毛发颜色褪色的脱毛症的预防剂和治疗剂。此外,由于脱毛症通常伴随诸如毛发变细或毛发变短的发质劣化,因此期望存在针对发质劣化伴随的脱毛症的预防剂和治疗剂。
就脱毛症的类型而言,存在斑秃症、雄激素性脱毛症、绝经后脱毛症、女性型脱毛症、皮脂溢性脱毛症、糠秕性脱毛症、老年性脱毛症、癌化疗药物诱发的脱毛症、辐射暴露引起的脱毛症、拔毛发癖、产后脱毛症等。
这些类型的脱毛症具有相同的毛发脱落症状,但基于不同的原因,因此疗法也各不相同。具体而言,基于雄性激素作用的雄激素性脱毛症和疑似免疫疾病的斑秃症是差异较大的疾病。另外,认为产后脱毛症、女性型脱毛症、皮脂溢性脱毛症、糠秕性脱毛症、老年性脱毛症、癌化疗药物诱发的脱毛症、辐射暴露引起的脱毛症具有各自不同的原因,有效的疗法几乎不存在。
斑秃症是在多数情况下无任何自觉症状或前驱症状等而突然产生硬币大小的环状至斑状的轮廓清晰的光秃区域,这些光秃区域随后在未自愈的情况下面积逐渐扩大而变得具有顽固性的脱毛症。斑秃症疑为自身免疫性疾病,但其病因尚未揭示,也还未知明确的治疗方法。
已知斑秃症与以下疾病相关:自身免疫性疾病,例如以桥本氏病(Hashimoto'sdisease)为代表的甲状腺疾病、白癜风、全身性红斑狼疮、类风湿性关节炎、或重症肌无力,或例如支气管哮喘、特应性皮炎、或变应性鼻炎的特应性疾病。
雄激素性脱毛症(AGA)是雄性激素作用于雄性激素敏感性毛囊而形成毫毛的脱毛症,其发生于约半数的男性以及10%-20%的女性中。据认为遗传倾向性是雄激素性脱毛症的重要因素;在男性雄激素性脱毛症中,额区和头顶的头发变细变短二变成毫毛,最终前额的发际线后退而头顶的头发消失。另一方面,在女性雄激素性脱毛症中,通常发际线不会改变,但整个头部,特别是头顶和额区的毛发变细。在男性雄激素性脱毛症中,非那雄胺(Finasteride)使得仅约1/4患者得到改善,并且由于禁忌对女性施用非那雄胺,因此非那雄胺不可用于女性的雄激素性脱毛症。
产后脱毛症是通过雌激素而维持生长期的毛发因分娩而突然进入静止期并且毛发脱落增加的脱毛症。产后脱毛症的毛发脱落通常从分娩后大约2个月开始并且持续到分娩后大约6个月;除非是晚育的情况,否在其通常在1年内恢复,因此在大多数情况下无需特殊治疗,但是也存在毛发无法自然恢复的情况。
女性型脱毛症被认为是由于雌性激素的雌激素的量相对于血流内的雄激素的量减少而产生的脱毛症。其多在绝经后发生,在该情况下也被称为绝经后脱毛症。女性型脱毛症可通过激素替代疗法而得以改善,但在大多情况下是顽固性的。
皮脂溢性脱毛症是由头皮皮脂分泌过量而引起的毛孔被堵塞从而引起毛孔周围或发根产生炎症、毛发掉落的脱毛症。皮脂溢性脱毛症可通过利用洗发去除皮脂而在某种程度上得以改善,但其容易复发并且表现出顽固性。
糠秕性脱毛症是头皮屑堵塞毛孔而引起炎症所导致的脱毛症。糠秕性脱毛症通常是由过度引起;通过减少洗发次数或使用洗涤能力弱的洗发剂来进行缓解,但其容易复发并且具有顽固性。
拔毛发癖是由于拔毛发障碍而导致的脱毛症。拔毛发癖是病理性焦虑所导致的症状,可通过行为疗法或心理疗法进行治疗。
老年性脱毛症是由于与性别无关的衰老而使得包括全部头发在内的全身体毛逐渐变薄的脱毛症。这被认为是大多数人群中由于衰老而表现出的自然现象,目前并非需要特别治疗的对象。然而,期望进行改善,因为随着平均寿命的延长,改善老年人生活质量的社会需求也在增加。
癌化疗药物诱发的脱毛症是作为癌化疗药物进行抗癌治疗的副作用的脱毛症。不仅包括头部的毛发,而且包括眉毛、睫毛、鼻毛、腋下毛和阴毛在内的所有区域的毛发脱落会给患者以沉重的打击,即便是在事先说明的情况下。由于这还妨碍实施癌化疗,因此对其具有高的治疗需求。类似地,辐射暴露伴随的脱毛症也是在通过抑制细胞分裂而选择性地杀死癌细胞方面、基于与癌化疗药物诱发的脱毛症相同机理而产生的脱毛症。因此,可治疗癌的化疗伴随的脱毛症的药物也可治疗辐射暴露伴随的脱毛症。
此外,已知诸如抗甲状腺药、抗凝血药、铊、精神药物或β-阻断剂的药物的副反应引起的脱毛症;真菌类引起的脱毛症;诸如垂体功能障碍、甲状腺机能减退或甲状腺机能亢进的内分泌紊乱引起的脱毛症;诸如营养失调、低白蛋白血症、恶病质、缺铁性贫血、缺锌症、高胱氨酸尿症或肝硬化的代谢紊乱引起的脱毛症;中毒性脱毛症;高热、分娩、大手术、体重急剧降低或严重疾病引起的脱毛症;等等,这些脱毛症可通过消除各自的病因原因而得以解决。
在这些类型的脱毛症中,女性型脱毛症、皮脂溢性脱毛症和糠秕性脱毛症可通过消除各自的病因在某种程度上得以解决,但它们容易复发并且具有顽固性。另外,尽管认为女性型脱毛症的病因与激素平衡有关,由于激素替代疗法的适应症为更年期障碍、骨质疏松症和高脂血症,而女性型脱毛症并非适应症;由于还存在激素替代疗法引起致癌的可能性,因此进行激素替代疗法的目的并不在于治疗女性型脱毛症。另外,就雄激素性脱毛症而言,尚无适当的疗法,并且就斑秃症而言,甚至对其病因也知之甚少。
如上所述,在所有的脱毛症类型中,难以治疗的脱毛症类型为斑秃症和雄激素性脱毛症,并且特别对于斑秃症而言,几乎不存在有效的治疗方法。此外,对于产后脱毛症、女性型脱毛症、糠秕性脱毛症、老年性脱毛症和癌化疗药物诱发的脱毛症而言,几乎无任何疗法。
需要开发治疗毛发脱落的治疗剂。
发明内容
发明概述
主题技术总体上涉及治疗毛发脱落或刺激毛发生长的组合物和方法。
发明详述
1.概述
主题技术总体上涉及治疗毛发脱落或刺激毛发生长的组合物和方法。
如本文所描述和例证,毛发脱落,例如斑秃症,是通常可归因于靶向毛囊的自身免疫性疾病的病症。通过递送促凋亡蛋白(例如,至炎症部位或毛发脱落部位),通过促凋亡蛋白诱导毛囊的致耐受性凋亡。因此,产生含自身抗原的雕亡小囊,其转而诱导对毛囊有特异性的调节反应。调节反应诱导对自身抗原的免疫耐受性,从而减少攻击毛囊细胞的异常自身免疫反应。
2.定义
除非另外明确指出,本申请中指定的各个范围内的数值的使用规定为近似值,如同在规定范围内的最小和最大值前均加上词“约”一样。高于和低于规定范围的细微变化可用于获得与所述范围内的值基本上相同的结果。范围的公开旨在作为包括介于所述最小值和最大值之间的每个值的连续范围以及可由此类值形成的任何范围。因此,技术人员将认识到许多此类比例、范围和比例范围可明确地由本文提出的数据和数字得到并且全部代表主题技术的各个实施方案。
正如本领域中的技术人员关于本公开将理解的那样,如本公开中所使用的,术语“自身抗原”意指并包括如同在自身免疫反应中,刺激自身抗体生成的内源性抗原,以及此类内源性抗原的一部分,或引起与完整内源性抗原相同的反应的经修饰内源性抗原。例如,在本公开的上下文中,碳酸酐酶II、嗜铬粒蛋白、胶原蛋白、CYP2D6(细胞色素P450、家族2、亚科Device 400、多肽6)、谷氨酸脱羧酶、分泌型谷氨酸脱羧酶55、hCDR1、HSP60、IA2、IGRP、胰岛素、髓鞘碱性蛋白、hNinein、Ro 60kDa、SOX-10(含基因10的SRY盒)、ZnT8等为自身抗原。还涵盖前述自身抗原中任一种的抗原片段。
术语“约”,如此处所使用,指值的+/-5%。
术语蛋白质的“功能片段”指为全长蛋白的一部分,并具有基本上相同的生物活性,或执行与全长蛋白基本上相同的功能(例如,执行相同酶促反应)的肽片段。例如,促凋亡蛋白的功能片段可促进细胞凋亡。
术语“高甲基化”(有时可缩写为“甲基化”)在关于DNA使用时,意指至少约30%(优选至少约35%、或至少约40%、或至少约45%、至少约50%、至少约55%、至少约60%、至少约65%、至少约70%)的CpG二核苷酸被甲基化。例如,其中所有CpG的60%至90%被甲基化的哺乳动物DNA是高甲基化的。
术语“低甲基化”(有时缩写为“未甲基化”)在关于DNA使用时,意指约15%或更少(优选约10%或更少、约7.5%或更少、约5%或更少、或约3%、或约1%或更少)的CpG二核苷酸被甲基化。例如,其中所有CpG的5%至15%被甲基化的细菌DNA是低甲基化的。
“甲基化”水平,在关于DNA使用时,指DNA分子的总CpG二核苷酸中的甲基化CpG二核苷酸的百分比。
术语“控制”意指“可操作地连接”,指核酸序列在另一核酸片段上的缔合,使得一个的功能受另一个的影响。例如,当启动子能够影响编码序列的表达时,则编码序列受启动子“控制”(即,编码序列受启动子的转录控制)。编码序列可在有义或反义方向上与调控序列可操作地连接。
3.编码促凋亡蛋白的多核苷酸
在一个方面,本发明提供一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的约30%至约60%的CpG二核苷酸被甲基化。
在另一个方面,本发明提供了一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平为约2倍至约4倍。
A.甲基化水平
脊椎动物中DNA甲基化通常在CpG位点发生。这种甲基化导致胞嘧啶转化为5-甲基胞嘧啶。Me-CpG的形成受到酶DNA甲基转移酶催化。在哺乳动物中所有CpG的60%至90%被甲基化。人类DNA的约80%-90%的CpG位点被甲基化。
细菌DNA与哺乳动物DNA相比含有低水平的甲基化CpG二核苷酸。哺乳动物免疫系统利用这种细菌DNA特征作为鉴别外源DNA和响应细菌性病原体的威胁的信号。
因此,本文所述的多核苷酸优选经高甲基化以避免在施用给哺乳动物受试者时被识别为细菌性病原体。例如,所述多核苷酸的至少约70%、至少约65%、至少约60%、至少约55%、至少约50%、至少约45%、至少约40%、至少约35%、至少约30%、约30%至约70%、约30%至约65%、约30%至约60%、约30%至约55%、约30%至约50%、约30%至约45%、约30%至约40%、约25%至约60%、约25%至约55%、约25%至约50%的CpG二核苷酸被甲基化。
或者,可通过将CpG二核苷酸总体甲基化水平与基线比较来测定多核苷酸的甲基化水平。合适的基线甲基化水平为来自于野生型细菌(例如,大肠杆菌(E.coli))的细菌DNA(例如,细菌基因组)的CpG二核苷酸平均甲基化水平。例如,所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平或附加体DNA例如来自于野生型大肠杆菌的质粒中CpG二核苷酸的平均甲基化水平可为至少约1.5倍、至少约2倍、至少约2.5倍、至少约3倍、至少约3.5倍、至少约4倍、至少约4.5倍、至少约5倍、至少约6倍、约1.5倍至约6倍、约2倍至约5倍,或约2倍至约4倍。野生型细菌菌株中CpG二核苷酸的平均甲基化水平通常已知或可确定。
本文所述的多核苷酸的甲基化水平,或野生型细菌的基线平均甲基化水平也可使用已知方法测定。例如,WO2011109529公开了检测DNA样品中DNA序列甲基化的普遍性的方法:还参见,Wu等,Statistical Quantification of Methylation Levels by Next-Generation Sequencing,PLoS ONE 6(6):e21034.doi:10.1371/journal.pone.0021034。
制备具有所需甲基化水平的多核苷酸的方法可通过多种方法实现。例如,PCT专利申请PCT/US12/56761公开了包含受组成型启动子控制的编码甲基化酶的工程化多核苷酸序列的细菌菌株,其中所述工程化多核苷酸稳定地并入所述细菌的染色体DNA中。这种细菌菌株可用于产生具有所需甲基化水平的多核苷酸。例如,可通过调节细菌宿主中甲基化酶的表达水平(例如,通过使用不同强度的启动子)来调节甲基化的水平。也可使用体外甲基化。参见例如,Wyngaert等,Genomic Imprinting:Methods and Protocols,第18章,InVitro Methylation of Predetermined Regions in Recombinant DNA Constructs243-250,DOI:10.1385/1-59259-211-2:243。
B.促凋亡蛋白
促凋亡蛋白指能够通过凋亡直接或间接活化细胞死亡机制的蛋白质。
合适的促凋亡蛋白包括,例如Bax、Bak、Bim、Puma、Bad、Bik、Noxa、Bmf、Hrk、Bid、FAS、胱天蛋白酶突变体(经修饰的胱天蛋白酶)、存活素(survivin)突变体(经修饰的存活素蛋白)、死亡受体4(DR4)、死亡受体5(DR5)、FAS受体和肿瘤坏死因子受体。还涵盖这些促凋亡蛋白中任一种的功能片段。
已经表征了本文所述的示例性促凋亡蛋白。
Bcl-2家族的成员代表凋亡途径的一些定义最明确的调节因子。Bcl-2家族的一些成员,包括Bcl-2、Bcl-XL、Ced-9、Bcl-w等,促进细胞存活,而其它成员,包括Bax、Bcl-Xs、Bad、Bak、Bid、Bik和Bim,已经被证实会加强凋亡(Adams和Cory,1998)。Bcl-2家族成员的生物学功能包括二聚体形成(Oltvai等,J.Bcl-2heterodimerizes in vivo with aconserved homolog,Bax,that accelerates programmed cell death.Cell,74:609-619,1993.)、蛋白酶活化(Chinnaiyan等,a novel FAD D-homologous ICE/CED-3-likeprotease,is recruited to the CD95(Fas/APO-1)death-inducing signalingcomplex.Cell 1996;85:817-827)、线粒体膜去极化、活性氧中间体的生成(Hockenbery等,Bcl-2functions in an antioxidant pathway to prevent apoptosis.Cell,75:241-251,1993)、钙通量调节(Lam等,Evidence that Bcl-2represses apoptosis byregulating endoplasmic reticulum-associated Ca2+fluxes.Proc.Natl.Acad.Sci.USA,91:6569-6573,1994;Huiling等,Maintenance ofcalcium homeostasis in the endoplasmic reticulum by Bcl-2.J.Cell Biol.138:1219-1228,1997)和孔道形成。
在Bcl-2家族中,存在群集于两个保守区内的显着同源性:Bcl-2同源结构域1和2(BH1和BH2)(Oltvai等,1993;Boise等,bcl-x,a bcl-2-related gene that functions asa dominant regulator of apoptotic cell death.Cell.1993年8月27日;74(4):597-608;Kozopas等,MCL1,a gene expressed in programmed myeloid celldifferentiation,has sequence similarity to BCL2.Proc Natl Acad Sci USA.1993年4月15日;90(8):3516-20;Lin等,Characterization of A1,a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2.J.Immunol.1993年8月15日;151(4):1979-88)。Bax中不同于BH1和BH2的另一保守性结构域称为BH3并且介导细胞死亡和蛋白质结合功能。一个亚类的促凋亡蛋白仅含BH3结构域,意味着这种特定结构域可能在凋亡的促进中特别重要(Diaz等,Dimerization properties of humanBAD.Identification of a B H-3domain and analysis of its binding to mutantBCL-2and BCL-XL proteins.J Biol.Chem.1997年12月5日;272(49):30866-72)。
Bax,Bcl-2家族的21kDa死亡促进成员,首先被鉴定为与来自于不同细胞系的Bcl-2共同免疫沉淀的蛋白质(Oltvai等,1993)。响应于各种细胞毒性结果Bax的过表达加速细胞死亡。测定Bax蛋白质的氨基酸序列显示其与Bcl-2高度同源。Bax基因由6个外显子组成并且生成替代性转录产物,其主要形式编码1.0kb mRNA并且指定为Baxa。与Bcl-2和Bcl-2家族的几个其它成员一样,Bax蛋白具有高度保守区,BH1、BH2和BH3结构域,并且这些蛋白质序列的疏水分析表明在其C末端存在疏水性跨膜片段(Oltvai等,1993)。Bax广泛表达,无任何明显的组织特异性。
已经报道了Bax的剪接变体,Bax-α。
Bak在各种细胞类型中表达并且与酵母中的Bcl-2同源物Bcl-x2结合。Bak中的结构域被鉴定为对于细胞毒活性而言必需且足够并且与Bcl-x1结合。此外,在Bax和Bipl中已经鉴定了与该结构域相似的不同于BH1和BH2的序列。该结构域对于介导与Bcl-2家族成员相互作用的多种细胞死亡调节蛋白的功能至关重要。
Bad具有BH1和BH2结构域的关键氨基酸基序。Bad缺少负责其它家族成员的整合膜位置的经典C端信号锚序列。Bad选择性地与Bcl-XL以及Bcl-2二聚化,但不与Bax、Bcl-Xs-Mcl1、A1或本身二聚化。Bad逆转Bcl-XL而非Bcl-2的死亡阻遏活性。
Bik,Bcl-2家族的另一个成员,与细胞存活促进蛋白Bcl-2和Bcl-XL以及病毒存活促进蛋白、埃-巴二氏病毒(Epstein Barr virus)-BHRF1(Epstein Barr virus-BHRF1)和腺病毒E1B-19kDa相互作用。在瞬时转染测定中,Bik以类似于Bax和Bak,Bcl-2家族的其它促凋亡成员的方式促进细胞死亡。Bik的这种促凋亡活性可受Bcl-2、Bcl-XL、EBV-BHRF1和EIB-19kDa蛋白的共表达抑制,这表明Bik可为细胞和病毒抗凋亡蛋白的常见靶标。虽然Bik不含与Bcl-2家族特有的BH1和BH2保守性结构域的明显同源性,但是与Bax和Bak共有一个9个氨基酸的结构域(BH3),这对于这些蛋白质的死亡促进活性可能是关键决定因素。
PUMA(p53上调的凋亡调控因子)是通过p53活化的靶标。基因编码在p53活化之后在细胞内诱导的两种含BH3结构域的蛋白质(PUMA-α和PUMA-β)。PUMA-α和PUMA-β显示出相似的活性;其与Bcl-2结合,定位于线粒体以诱导细胞色素c释放,并活化对程序性细胞死亡的快速诱导。对PUMA表达的反义抑制诱导了对p53的凋亡反应,并且PUMA很可能在通过细胞色素c/Apaf-1-依赖途径介导p53诱导的细胞死亡中起作用。参见例如,Nakano等,MolCell.2001 Mar;7(3):683-94。
BH3-only蛋白Bim是线粒体上诱导Bax/Bak-寡聚的促凋亡蛋白。参见例如,Gogada等,BIM,经由转录因子E2F1依赖性机制上调的促凋亡蛋白,在癌症中起促存活分子的作用(a proapoptotic protein,upregulated via transcription factor E2F1-dependentmechanism,functions as a prosurvival molecule in cancer),doi:10.1074/jbc.M112.386102jbc.M112.386102。
p53对内源性凋亡途径的活化常常需要转录促凋亡Bcl-2蛋白Noxa、Puma或二者。已经报道微粒物质诱导的细胞死亡和肺部炎症需要Noxa。
Bmf是通过与失巢凋亡活化的肌球蛋白V肌动蛋白运动复合物的相互作用调节的促凋亡BH3-only蛋白。
BH3-only家族成员HRK(也称为DP5)牵涉于凋亡调节中。发现Hrk基因表达限于中枢和周围神经系统的细胞和组织。
BH3相互作用结构域死亡激动剂或BID基因是Bcl-2蛋白家族的促凋亡成员。响应于凋亡信号,BID与另一Bcl-2家族蛋白Bax相互作用,导致Bax插入细胞器膜,主要是线粒体外膜中。据信Bax与线粒体电压依赖性阴离子通道VDAC相互作用,并且诱导其打开。或者,越来越多的证据表明活化Bax和/或Bak在外膜中形成寡聚空隙MAC。这导致细胞色素c和其它促凋亡因子(例如SMAC/DIABLO)从线粒体释放,常常称为线粒体外膜透化,导致胱天蛋白酶活化。这将BID定义为Bax的直接活化剂,为仅含BH3结构域的一些促凋亡Bcl-2蛋白共有的作用。
Fas配体(FasL或CD95L)是属于肿瘤坏死因子(TNF)家族的II型跨膜蛋白。其与其受体的结合诱导凋亡。Fas配体/受体相互作用在免疫系统的调节和癌症的进展中起重要作用。
FAS受体(FasR),也称为雕亡抗原1(APO-1或APT)、分化群95(CD95)或肿瘤坏死因子受体超家族成员6(TNFRSF6)是人类中由TNFRSF6基因编码的蛋白质。Fas受体是细胞表面上导致程序性细胞死亡(凋亡)的死亡受体。其为两种凋亡途径之一,另一种为线粒体途径。FasR位于人类中的染色体10和小鼠中的染色体19上。在大多数哺乳动物中找到了进化相关的相似序列(直向同源物)。
胱天蛋白酶,或半胱氨酸-天冬氨酸蛋白酶或半胱氨酸依赖性天冬氨酸定向蛋白酶是在凋亡(程序性细胞死亡)、坏死和炎症中发挥不可或缺的作用的半胱氨酸蛋白酶家族。已经在人体中鉴定出12种胱天蛋白酶。存在两类凋亡性胱天蛋白酶:起始(顶端)胱天蛋白酶和效应(处决者)胱天蛋白酶。起始胱天蛋白酶(例如,CASP2、CASP8、CASP9和CASP10)裂解效应胱天蛋白酶的非活性前体形式,从而将其活化。效应胱天蛋白酶(例如,CASP3、CASP6、CASP7)转而裂解细胞内的其它蛋白质底物,以触发凋亡过程。这种级联反应的引发受胱天蛋白酶抑制剂调节。在白癫风和由NALP1变体引起的相关自身免疫性疾病的一些情况下过表达的CASP4和CASP5在MeSH中目前未分类为起始型或效应型,因为它们是和CASP1相一致的牵涉T细胞成熟的炎性酶。本文还考虑到了保持促凋亡活性的胱天蛋白酶突变体。
存活素,也称为含杆状病毒凋亡抑制因子重复序列5或BIRC5,是人类中由BIRC5基因编码的蛋白质。NCBI参考序列:NG_029069.1。存活素是凋亡抑制因子(IAP)家族的成员。存活素蛋白起抑制胱天蛋白酶活化的作用,从而导致对凋亡或程序性细胞死亡的负调节。本文还考虑到了消除抗凋亡活性的存活素突变体。
死亡受体4(DR4)是某些细胞表面上结合称为TRAIL的另一种蛋白质,可杀伤一些癌细胞的蛋白质。癌细胞上死亡受体4的量或活性增加可杀伤更多细胞。也称为DR4、TRAIL受体1、TRAIL-R1和肿瘤坏死因子受体超家族成员10A。
肿瘤坏死因子受体超家族成员10b也称为:DR5、CD262、KILLER、TRICK2、TRICKB、ZTNFR9、TRAILR2、TRICK2A、TRICK2B、TRAIL-R2、KILLER/DR5。所述蛋白质是TNF受体超家族的成员,并且含有细胞内死亡结构域。这种受体可通过肿瘤坏死因子相关的凋亡,包括配体(TNFSF10/TRAIL/APO-2L)活化,并且转导凋亡信号。小鼠具有同源基因tnfrsf10b,在阐明该基因在人类中的功能中已必不可少。对FADD缺陷小鼠的研究表明FADD,含有衔接蛋白的死亡结构域,对于该蛋白质介导的凋亡而言需要。
肿瘤坏死因子受体(TNFR)或死亡受体,是结合肿瘤坏死因子(TNF)的三聚细胞因子受体。受体与衔接蛋白(例如,TRADD、TRAF、RIP)协作,这在确定反应结果(例如凋亡、炎症)中很重要。
也可使用本文所述促凋亡蛋白的促凋亡片段。促凋亡蛋白的促凋亡片段包含促凋亡蛋白的一部分,但不含全长序列,同时保持促凋亡活性。
促凋亡蛋白或其片段可以是具有促凋亡活性的自然存在的蛋白质,或自然存在的蛋白质的活性变体。
如本文所使用,“活性变体”指保持促凋亡活性的变体肽。活性变体在氨基酸序列上与参考促凋亡蛋白不同,但是保持促凋亡活性。促凋亡蛋白或其片段的活性变体包括自然存在的变体(例如,等位基因形式)和未知自然存在的变体。
一般而言,促凋亡片段可含有促凋亡蛋白的功能结构域。
通常,差异是有限的,使得参考多肽和活性变体的序列总体上非常相似并且,在许多区域相同。促凋亡蛋白或其片段的活性变体和参考促凋亡蛋白或其片段在氨基酸序列上的区别可在于一个或多个氨基酸取代、添加、缺失、截短、融合或其任何组合。优选地,氨基酸取代为保守性取代。保守性氨基酸取代指第一氨基酸被具有与第一氨基酸相似的化学和/或物理性质(例如,电荷、结构、极性、疏水性/亲水性)的第二氨基酸置换。保守性取代包括以下类别中一个氨基酸被另一个置换:赖氨酸(K)、精氨酸(R)和组氨酸(H);天冬氨酸(D)和谷氨酸(E);天冬酰胺(N)、谷氨酰胺(Q)、丝氨酸(S)、苏氨酸(T)、酪氨酸、(Y)、K、R、H、D和E;丙氨酸(A)、缬氨酸(V)、亮氨酸(L)、异亮氨酸(I)、脯氨酸(P)、苯丙氨酸(F)、色氨酸(W)、甲硫氨酸(M)、半胱氨酸(C)和甘氨酸(G);F、W和Y;C、S和T。
促凋亡蛋白或其片段的活性变体可使用适合方法制备,例如通过直接合成、诱变(例如,定点诱变、扫描诱变)和重组DNA技术的其它方法。可使用合适的凋亡测定鉴定和/或选择活性变体。
还考虑到了包含促凋亡蛋白或其片段的融合蛋白。融合蛋白可涵盖包含作为第一部分经由共价键(例如,肽键)与在自然界中发现时在促凋亡蛋白中不存在的第二部分(融合伴侣)连接的促凋亡蛋白、其片段或其变体的多肽。融合蛋白可使用适合方法制备,例如通过直接合成、重组DNA技术等。
本发明还涉及编码促凋亡蛋白、其片段或其变体的核酸。
C.自身抗原
任选地,本文所述的组合物可包含自身抗原。自身抗原可由相同多核苷酸或由第二多核苷酸编码。优选地,自身抗原存在于皮肤或毛囊中。
4.多核苷酸的递送
作为带负电、高分子量分子,多核苷酸难以自发通过磷脂细胞膜。因此使用各种载体以便允许基因转移,一方面包括病毒载体,另一方面包括天然或合成化学和/或生物化学载体。
病毒载体(逆转录病毒、腺病毒、腺相关病毒等)尤其对于通过膜非常有效,但是呈现许多风险,例如病原性、重组、复制、免疫原性等。化学和/或生物化学载体使得能够避免这些风险。它们是,例如,通过与DNA形成沉淀物起作用的阳离子(磷酸钙、DEAE-葡聚糖等),然后所述沉淀物可被细胞“吞噬”。它们也可以是其中并入了DNA并且与质膜融合的脂质体。合成基因转移载体通常为复合DNA可与之形成带表面正电荷的颗粒的阳离子脂质或聚合物。这些颗粒能够与细胞膜的负电荷相互作用,然后穿过后者。此类载体的实例可包括双十八烷基酰胺基甘氨酰精胺(DOGS,TransfectamTM)或N-[1-(2,3-二油烯基氧基)丙基]-N,N,N-三甲基氯化铵(DOTMA,LipofectinTM)。还已研发了嵌合蛋白:其由使DNA浓缩、连接到与膜受体结合并且通过胞吞作用在细胞内产生复合物的配体上的聚阳离子部分组成。因此理论上可能“靶向”组织或某些细胞群以便提高转移基因的体内生物利用率。
病毒载体可呈重组病毒的形式递送至宿主细胞。可通过任何适合程序,例如通过将重组病毒载体转染至包装细胞系内,将重组病毒载体包装至病毒外壳或衣壳中。任何合适的包装细胞系均可用于生成重组病毒。逆转录病毒的适合包装系包括PA317细胞、ψ-2细胞、CRE细胞、CRIP细胞、E-86-GP细胞和293GP细胞的衍生物。293系细胞可用于腺病毒和腺相关病毒。神经母细胞瘤细胞可用于单纯疱疹病毒,例如1型单纯疱疹病毒。有时,可能需要辅助病毒(其提供缺失蛋白以生成新的病毒体)以生成本文所述的重组病毒。
也可使用非病毒基核酸递送系统递送编码促凋亡蛋白或其片段的核酸分子。例如,在美国专利No.6,413,942、6,214,804、5,580,859、5,589,466、5,763,270和5,693,622中已经描述了将核酸递送至靶细胞的方法。
如美国专利No.5,580,859、5,549,127、5,264,618、5,703,055中所述,在递送给受试者或细胞之前将本文所述的核酸分子包装在脂质体中。对脂质体作为递送核酸的载体的用途的评述,参见Hug和Sleight(1991)Biochim.Biophys.Acta.1097:1-17;Straubinger等(1983)在Methods of Enzymology中第101卷,第512-27页;de Lima等(2003)CurrentMedicinal Chemistry,第10卷(14):1221-31。代表性脂质体包括但不限于阳离子脂质体,任选涂有聚乙二醇(PEG)以减少血清蛋白的非特异性结合并延长循环时间。参见Koning等,1999;Nam等,1999;和Kirpotin等,1997。也可使用温度敏感型脂质体,例如如美国专利No.6,200,598中公开的THERMOSOMESTM。在美国专利No.5,851,818中已经描述了载体-脂质体复合物的用途。脂质体可通过本领域中已知的各种技术中的任一种制备。参见例如Betageri等,1993;Gregoriadis,1993;Janoff,1999;Lasic和Martin,1995;Nabel,1997;和美国专利No.4,235,871、4,551,482、6,197,333和6,132,766。
也可以与Papahadjopoulos等(1975)Biochem.Biophys.Acta.394:483-491所述相似的螺旋形脂质复合物递送核酸。还参见美国专利No.4,663,161和4,871,488。例如,质粒载体也可与Lipofectamine2000复合。Wang等(2005)Mol.Therapy 12(2):314-320。
采用微粒载体例如金和钨的基因枪递送系统也可用于递送核酸(例如,重组病毒载体和非病毒载体)。颗粒被载体包裹并且通常在低压下,使用来自于“基因枪”的弹药排放(gun powder discharge)加速至高速。参见例如,美国专利No.4,945,050、5,036,006、5,100,792、5,179,022、5,371,015和5,478,744。
可使用各种其它方法递送本文所述的核酸。此类方法包括DEAE葡聚糖介导的转染、磷酸钙沉淀、聚赖氨酸或聚鸟氨酸介导的转染,或使用其它不溶性无机盐例如磷酸锶、硅酸铝(包括膨润土和高岭土)、氧化铬、硅酸镁、滑石等沉淀。其它有用的转染方法包括电穿孔、声孔作用、原生质体融合、类肽递送或显微注射。参见例如,Sambrook等(1989)Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratories,NewYork,对转化目标细胞的技术的讨论;和Felgner,P.L.(1990)Advanced Drug DeliveryReviews 5:163-87,对用于基因转移的递送系统的评述。在美国专利No.6,132,419、6,451,002、6,418,341、6,233,483、美国专利公布No.2002/0146831和国际公布No.WO 00/45823中描述了使用电穿孔递送DNA的示例性方法。
5.药物组合物和治疗方法
主题技术的一个方面描述了治疗毛发脱落的方法,本文所述多核苷酸在疗法中的用途,及本文所述多核苷酸在制备疗法用药剂中的用途。术语治疗包括在无症状时的预防性治疗,以及减轻疾病或疾病症状的治疗。
主题技术提供包含本文所述多核苷酸的药物组合物。任选地,可提供用于递送核酸的递送系统(例如,脂质体)。递送系统可与核酸一起共同配制成药物组合物,或单独供给(例如,于试剂盒的单独容器中)。如果单独提供,则可在施用之前将递送系统与核酸混合。
本文公开的多核苷酸通常配制于适合体内施用的组合物中。此类组合物通常包括可接受用于配制并向受试者施用试剂的载体。此类可接受的载体在本领域中众所周知并且包括,例如水溶液如水或生理缓冲盐水或其它溶剂或媒介物如乙二醇、甘油,油如橄榄油或可注射有机酯。可接受的载体可含有起作用(例如)以稳定或增加偶联物的吸收的生理上可接受的化合物。此类生理上可接受的化合物包括,例如碳水化合物(例如葡萄糖、蔗糖或葡聚糖)、抗氧化剂(例如抗坏血酸或谷胱甘肽)、螯合剂、低分子量蛋白质或其它稳定剂或赋形剂。本领域中的技术人员将了解,包括生理上可接受的化合物在内的可接受的载体的选择取决于例如治疗剂的理化特征和组合物的施用途径,施用途径可为例如口服或肠胃外(例如静脉内),和通过注射、插管,或本领域中已知的其它此类方法。药物组合物可含有第二试剂例如诊断试剂、营养物质、毒素或治疗剂,例如癌化疗剂。
本文所述的多核苷酸可并入封装材料中,例如并入水包油乳液、微乳液、微胶粒、混合微胶粒、脂质体、微球或其它聚合物基质中(参见例如,Gregoriadis,LiposomeTechnology,第1卷(CRC Press,Boca Raton,Fla.1984);Fraley等,Trends Biochem.Sci.,6:77(1981))。例如由磷脂或其它脂质组成的脂质体是制备和施用相对简单的无毒、生理上可接受且可代谢的载体。“隐形(Stealth)”脂质体(参见例如,美国专利No.5,882,679、5,395,619和5,225,212)是对制备用于本发明方法的组合物特别有用的此类封装材料的实例,并且类似地可使用其它“隐藏性”脂质体,例如延长治疗剂在循环中保持的时间的脂质体。例如,阳离子脂质体也可经特异性受体或配体修饰(Morishita等,J.Clin.Invest.,91:2580-2585(1993),其通过引用并入本文)。另外,可使用(例如)腺病毒-聚赖氨酸DNA复合物将多核苷酸引入细胞内(参见例如,Michael等,J.Biol.Chem.268:6866-6869(1993))。
在一个方面,在主题技术提供一种治疗斑秃症的方法,其包括:向有需要的受试者施用有效量的多核苷酸,其中所述多核苷酸包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的约30%至约60%的CpG二核苷酸被甲基化。
在另一个方面,主题技术提供一种治疗斑秃症的方法,其包括:向有需要的受试者施用有效量的多核苷酸,其中所述多核苷酸包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平为约2倍至约4倍。
受试者可以是有变应性疾病或自身免疫性疾病史或共存变应性疾病或自身免疫性疾病的脱毛症受试者。
斑秃症可为正常斑秃症、全秃、普秃或匐行性脱毛症。
本文所述的组合物也可用于治疗白发、毫毛形成,或抑制脂溢性头皮或头皮屑出现的试剂。
在一个方面,主题技术提供一种刺激毛干从毛囊中生长的方法,其包括:向有需要的受试者施用有效量的多核苷酸,其中所述多核苷酸包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的约30%至约60%的CpG二核苷酸被甲基化。
在一个方面,主题技术提供一种刺激毛干从毛囊中生长的方法,其包括:向有需要的受试者施用有效量的多核苷酸,其中所述多核苷酸包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平为约2倍至约4倍。
在一个方面,主题技术提供一种治疗毛发脱落的方法,其中所述毛发脱落可归因于自身免疫性疾病,所述方法包括:向有需要的受试者施用有效量的多核苷酸,其中所述多核苷酸包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的约30%至约60%的CpG二核苷酸被甲基化。
在一个方面,主题技术提供一种刺激毛干从毛囊中生长的方法,其包括:向有需要的受试者施用有效量的多核苷酸,其中所述多核苷酸包含编码促凋亡蛋白或其功能片段的序列,并且其中所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平为约2倍至约4倍。
在许多情况下,毛发脱落可归因于自身免疫性病症。可导致毛发脱落的示例性自身免疫性疾病包括,例如慢性盘状红斑狼疮、局限性硬皮病、天疱疮、类天疱疮、妊娠疱疹、线状IgA大疱性皮肤病、获得性大疱性表皮松解、白癫风、萨顿氏痣、自身免疫性甲状腺疾病、全身性红斑狼疮、类风湿性关节炎或重症肌无力。
雄激素性脱毛症也可导致毛发脱落。雄激素性脱毛症可以是在男性中或是在女性中的雄激素性脱毛症。
可向有需要的受试者施用有效量。“有效量”或“治疗有效量”是在施用条件下足以达到所需治疗或预防效果的量,例如足以减少/改善疾病症状的量。
含有本文所述的多核苷酸的组合物的施用途径将部分取决于分子的化学结构。例如,多肽和多核苷酸当口服施用时并非特别有用,因为它们可在消化道内降解。然而,本文公开了或在本领域中另外已知化学修饰多肽(例如)以致使其不易受内源蛋白酶降解影响或通过消化道更多吸收的方法(参见例如,Blondelle等,同上,1995;Ecker和Crook,同上,1995)。另外,多肽可使用D-氨基酸制备,或可含有基于为模拟结构域的结构的有机分子的拟肽,或基于类肽(例如插烯类肽)的一个或多个结构域。
可通过各种途径,包括例如口服或肠胃外,例如静脉内、肌肉内、皮下、眶内、囊内、腹膜内、直肠内、脑池内或分别使用(例如)皮肤贴片或经皮离子电渗疗法通过皮肤被动或易化吸收,向个体施用如本文所公开的组合物。此外,可通过注射、插管、口服或局部施用所述组合物,其中后者可为被动式,例如通过直接涂敷药膏,或为主动式,例如使用鼻喷雾剂或吸入剂,在这种情况下所述组合物的一个组分为适当推进剂。也可向病况部位,例如向正发生或可能发生毛发脱落的头皮施用药物组合物。
优选施用途径包括皮下、皮内或经皮中的至少一种。可向毛发脱落部位,例如额区或头顶施用所述组合物。
在实践本发明方法中要施用的多核苷酸的总量可作为单剂量,作为药丸或在相对较短的时间段内通过输注施用给受试者,或可使用分级治疗方案施用,其中在长时间段内施用多个剂量。技术人员将了解所述组合物在受试者中治疗病理状况的量取决于许多因素,包括受试者的年龄和总体健康状况以及施用途径和要施用的治疗次数。考虑到这些因素,技术人员将在必要时调节特定剂量。一般而言,最初使用I期和II期临床试验确定所述组合物的配方及施用途径和频率。
在各个实施方案中,当所述方法包括施用一种或一种以上免疫抑制剂时,所述一种或一种以上免疫抑制剂可同时、单独或依次施用。
在各个实施方案中,所述一种或一种以上免疫抑制剂可选自皮质类固醇、糖皮质激素、环磷酰胺、6-巯基嘌呤(6-MP)、硫唑嘌呤(AZA)、甲氨蝶呤环孢霉素、吗替麦考酚酯(MMF)、霉酚酸(MPA)、他克莫司(tacrolimus)(FK506)、西罗莫司(sirolimus)([SRL]雷帕霉素(rapamycin))、依维莫司(everolimus)(Certican)、咪唑立宾(mizoribine)、来氟米特(leflunomide)、脱氧精胍菌素(deoxyspergualin)、布喹那(brequinar)、偶氮二甲酰胺(azodicarbonamide)、维生素D类似物(例如MC1288和双吲哚马来酰亚胺VIII)、抗淋巴细胞球蛋白、抗胸腺细胞球蛋白(ATG)、抗CD3单克隆抗体(莫罗单抗-CD3(Muromonab-CD3),Orthoclone OKT3)、抗白细胞介素(IL)-2受体(抗CD25)抗体(达利珠单抗(Daclizumab)、赛尼哌(Zenapax)、巴利昔单抗(basiliximab)、舒莱(Simulect))、抗CD52抗体(阿仑单抗(Alemtuzumab)、Campath-1H))、抗CD20抗体(利妥昔单抗(Rituximab)、美罗华(Rituxan))、抗肿瘤坏死因子(TNF)试剂(英夫利昔单抗(Infliximab)、瑞米凯德(Remicade)、阿达木单抗(Adalimumab)、修美乐(Humira))、LFA-1抑制剂(依法利珠单抗(Efalizumab)、瑞体肤(Raptiva))等。
在一个方面,主题技术提供一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,其中所述多核苷酸的约30%至约60%的CpG二核苷酸被甲基化,从而用于治疗斑秃症。
在一个方面,主题技术提供一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,其中所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平为约2倍至约4倍,从而用于治疗斑秃症。
在一个方面,主题技术提供一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,其中所述多核苷酸的约30%至约60%的CpG二核苷酸被甲基化,从而用于刺激毛干从毛囊中生长。
在一个方面,主题技术提供一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,其中所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平为约2倍至约4倍,从而用于刺激毛干从毛囊中生长。
在一个方面,主题技术提供一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,其中所述多核苷酸的约30%至约60%的CpG二核苷酸被甲基化,从而用于治疗毛发脱落,其中所述毛发脱落可归因于自身免疫性疾病。
在一个方面,主题技术提供一种多核苷酸,其包含编码促凋亡蛋白或其功能片段的序列,其中所述多核苷酸的CpG二核苷酸的甲基化水平相较于野生型大肠杆菌(E.coli)基因组中CpG二核苷酸的平均甲基化水平为约2倍至约4倍,从而用于治疗毛发脱落,其中所述毛发脱落可归因于自身免疫性疾病。
以下实施例提供了对主题技术的进一步说明并非旨在限制主题技术的范围。
具体实施方式
实施例
实施例1.DNA疫苗用于治疗斑秃症的用途
制备编码促凋亡蛋白的质粒DNA构建体。促凋亡蛋白选自:Bax、Bak、Bim、Puma、Bad、Bik、Noxa、Bmf、Hrk、Bid、FAS、胱天蛋白酶突变体或存活素突变体。从使CpG二核苷酸高甲基化的细菌菌株和未使CpG二核苷酸高甲基化(即,低甲基化)的细菌菌株中分离质粒。在高甲基化DNA构建体的情况下,控制编码促凋亡蛋白的基因/cDNA的转录的启动子未通过CpG高甲基化灭活,例如SV40启动子。在非高甲基化构建体的情况下,所述启动子可为任何诱导型或组成型启动子,例如CMV或LTR启动子。
然后例如使用C3H/HeJ小鼠模型将每种质粒DNA构建体或不同比例的两种构建体的不同组合递送至皮肤以治疗斑秃症。在健康(即,有毛)皮肤皮内递送DNA,或直接递送至显示毛发脱落的患病区域。DNA量的范围可从每次治疗1μg至200μg或更多,并且每周递送治疗直至观察到毛发生长。或者,DNA可在包装至促进细胞转染的纳米或微观粒子中后经皮递送。
另外,质粒DNA构建体还可编码毛囊内存在的自身抗原。在这种情况下可在无毛囊的皮肤或促进毛囊形成的干细胞内注射DNA。
应理解,虽然已经连同其详述一起描述了主题技术,但是前面的描述旨在说明而非限制主题技术的范围。主题技术的其它方面、优点和修改在以下提出的权利要求的范围之内。根据说明书中引用的参考文献的教学,说明书得到最透彻的理解。说明书中的实施方案提供了对本发明实施方案的说明而不得解释为限制本发明的范围。技术人员易于认识到本发明涵盖许多其它实施方案。本公开中引用的所有出版物、专利和序列通过引用整体并入。就通过引用并入的材料同本说明书矛盾或不一致来说,本说明书将代替任何此类材料。本文中任何参考文献的引用并不是承认此类参考文献先于本发明。
本领域中的技术人员将认识到,或仅仅使用常规实验就能够确定本文所述本发明特定实施方案的许多等效方案。此类等效方案旨在为以下实施方案所涵盖。
附录:序列
1.编码人BAX的核苷酸序列(SEQ ID NO:1)
序列表
<110> 洛马林达大学
<120> 自身免疫性疾病的治疗
<130> PCT/US2014/029685
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 579
<212> DNA
<213> 人类
<400> 1
atggacgggt ccggggagca gcccagaggc ggggggccca ccagctctga gcagatcatg 60
aagacagggg cccttttgct tcagggtttc atccaggatc gagcagggcg aatggggggg 120
gaggcacccg agctggccct ggacccggtg cctcaggatg cgtccaccaa gaagctgagc 180
gagtgtctca agcgcatcgg ggacgaactg gacagtaaca tggagctgca gaggatgatt 240
gccgccgtgg acacagactc cccccgagag gtctttttcc gagtggcagc tgacatgttt 300
tctgacggca acttcaactg gggccgggtt gtcgcccttt tctactttgc cagcaaactg 360
gtgctcaagg ccctgtgcac caaggtgccg gaactgatca gaaccatcat gggctggaca 420
ttggacttcc tccgggagcg gctgttgggc tggatccaag accagggtgg ttgggacggc 480
ctcctctcct actttgggac gcccacgtgg cagaccgtga ccatctttgt ggcgggagtg 540
ctcaccgcct cgctcaccat ctggaagaag atgggctga 579
Claims (14)
1.一种药物组合物,其包含第一多核苷酸和第二多核苷酸,其中:
a)所述第一多核苷酸包含编码自身抗原或其抗原性片段的序列,其中所述第一多核苷酸的至少约50%的CpG二核苷酸被甲基化;和
b)所述第二多核苷酸包含编码促凋亡蛋白或其功能性促凋亡片段的序列,所述促凋亡蛋白选自BAK、BAX、BIM、死亡受体4、死亡受体5或FAS受体,其中所述第二多核苷酸的所述CpG二核苷酸的15%或更少被甲基化;
用于皮内用于诱导针对所述自身抗原的致耐受性免疫应答。
2.如权利要求1所述的药物组合物,其中所述自身抗原是谷氨酸脱羧酶,分泌形式的谷氨酸脱羧酶或其自身抗原性片段。
3.如权利要求1所述的药物组合物,其中所述的第二多核苷酸包含编码BAX或其功能性促凋亡片段的序列。
4.如权利要求3所述的药物组合物,其中所述BAX是由SEQ ID NO:1所示的多核苷酸编码。
5.如权利要求1至4中任一项所述的药物组合物,其中所述自身抗原与自身免疫疾病相关。
6.如权利要求5所述的药物组合物,其中所述自身免疫疾病选自下列所组成的群组:慢性盘状红斑狼疮、局限性硬皮病、天疱疮、类天疱疮、妊娠疱疹、线状IgA大疱性皮肤病、获得性大疱性表皮松解症、萨顿氏痣、自身免疫性甲状腺疾病、类风湿性关节炎、全身性红斑狼疮、桥本氏病、白癫风、重症肌无力、支气管哮喘、特应性皮炎或变应性鼻炎。
7.如权利要求5所述的药物组合物,其中所述药物组合物用于向所述自身免疫疾病的部位给药。
8.一种组合物在制备用于诱导针对自身免疫疾病的自身抗原的致耐受性免疫应答的药物中的用途,其中所述组合物包含:
a)第一多核苷酸,其包含编码自身抗原或其抗原性片段的序列,其中所述第一多核苷酸的至少50%的CpG二核苷酸被甲基化;和
b)第二多核苷酸,其包含编码促凋亡蛋白或其功能性促凋亡片段的序列,所述促凋亡蛋白选自BAK、BAX、BIM、死亡受体4、死亡受体5或FAS受体,其中所述第二多核苷酸的所述CpG二核苷酸的15%或更少被甲基化。
9.如权利要求8所述的用途,其中所述自身抗原是谷氨酸脱羧酶,分泌形式的谷氨酸脱羧酶或其自身抗原性片段。
10.如权利要求8所述的用途,其中所述第二多核苷酸包含编码BAX或其功能性促凋亡片段的序列。
11.如权利要求10所述的用途,其中所述BAX是由SEQ ID NO:1所示的多核苷酸编码。
12.如权利要求8至11中任一项所述的用途,其中所述组合物是皮内施用的。
13.如权利要求8至11中任一项所述的用途,其中将所述组合物施用于所述自身免疫疾病的部位。
14.如权利要求8至11中任一项所述的用途,其中所述自身免疫疾病选自下列所组成的群组:慢性盘状红斑狼疮、局限性硬皮病、天疱疮、类天疱疮、妊娠疱疹、线状IgA大疱性皮肤病、获得性大疱性表皮松解症、萨顿氏痣、自身免疫性甲状腺疾病、类风湿性关节炎、全身性红斑狼疮、桥本氏病、白癫风、重症肌无力、支气管哮喘、特应性皮炎或变应性鼻炎。
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AU2009223148B2 (en) * | 2008-03-12 | 2013-03-14 | Loma Linda University | DNA vaccines and methods for the prevention of transplantation rejection |
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2014
- 2014-03-14 CN CN201480015896.9A patent/CN105451777A/zh active Pending
- 2014-03-14 WO PCT/US2014/029685 patent/WO2014145042A1/en active Application Filing
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- 2014-03-14 AU AU2014233428A patent/AU2014233428B2/en active Active
- 2014-03-14 ES ES14764420T patent/ES2825078T3/es active Active
- 2014-03-14 JP JP2016503195A patent/JP6499155B2/ja active Active
- 2014-03-14 CA CA2902565A patent/CA2902565C/en active Active
- 2014-03-14 DK DK14764420.7T patent/DK2968606T3/da active
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2016
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CN105451777A (zh) * | 2013-03-15 | 2016-03-30 | 洛马林达大学 | 自身免疫性疾病的治疗 |
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AU2014233428B2 (en) | 2019-09-19 |
CA2902565A1 (en) | 2014-09-18 |
DK2968606T3 (da) | 2020-10-26 |
HK1220127A1 (zh) | 2017-04-28 |
JP2016516725A (ja) | 2016-06-09 |
EP2968606A1 (en) | 2016-01-20 |
EP2968606A4 (en) | 2016-10-12 |
WO2014145042A1 (en) | 2014-09-18 |
JP2021091742A (ja) | 2021-06-17 |
EP2968606B1 (en) | 2020-10-07 |
AU2014233428A1 (en) | 2015-09-17 |
AU2019219835A1 (en) | 2019-09-12 |
CA2902565C (en) | 2022-11-29 |
JP2019077715A (ja) | 2019-05-23 |
CN105451777A (zh) | 2016-03-30 |
JP6499155B2 (ja) | 2019-04-10 |
AU2019219835B2 (en) | 2021-10-07 |
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