CN1056421A - 用双链rna恢复损伤后免疫功能 - Google Patents
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Abstract
使用DSRNA选择性地重新激活人体细胞,组
织或器官内因损伤而减低了功能的天然防御系统。
描述了对获得性免疫缺陷状态的生物学上连续的各
临床阶段的特定治疗,以及对与TNF水平增加有关
之毒性作用的预防。
Description
本发明涉及用双链RNA来防止损伤后休克。
文献中已对休克或损伤后免疫学反应性的减弱作了充分的描述。使用多种免疫学检测手段,可以对外科手术或损伤后之不同类型免疫功能异常的特征作出鉴定(Meakins JL,Pietsch JB,Bubenick O,Kelley R,Rode H,Gordon J and MacLean LD,Delayed Hypersen-sitivity:Indicator of acquired failure of host defenses in sepsis and trauma,Ann Surg 1977,186:241-246.)依照损伤的严重性和病人的生理特征,免疫功能失调可于损伤后数小时内发生,并持续几天或几周。免疫系统的功能不能得以恢复,关系到发病率(败血症)和死亡率的增加(Tellado-Rodriguez,J and Christou,NV,Clinical Assessment of Host Defense,Surgical Clinics of North America Feb 88,68(1)41-55)例如,有报到指出,大手术后损伤的免疫学反应性,是创伤病人对机会性感染产生易感性的根本原因。(Faist E,Ertel W,Salmen B,Weiler A,Ressel C,Bolla K Heberer G,The immune-enhancing effect of perioperative thympoentin administration in elderly patients undergoing major surgery,Arch Surg Dec 1988,123:1449-1453.)这种易感性可在不同的并发症,如败血症,伤口延迟愈合、脓肿及成年人呼吸窘迫综合征(ARDS)中表现出来,有时称为多发性器官功能失调。
这种获得性免疫缺陷状态,是由多种刺激因素引起,如创伤、烧伤、外科手术、输血、放射治疗及某些化学治疗等。这种综合征表现为一种疾病状态,因而在相对短的时间内使得免疫系统不能发挥正常的功能。刺激与免疫失调之间的这一短时间间隔,暗示免疫缺陷是由细胞激活因子水平的改变所引起的(MacPhee M,Christou NV,Gordon J,Chartrand L,Rode H,Quantitative and qualitative study of the restoration by cytokines of mononuclear cell delivery to skin test sites in anergic surgical patients,Arch Surg Dec 1988,123:1470-1473.)。细胞激活因子(Cytokine)是细胞向血液内释放的,用以调节免疫系统其他组成细胞之活性的分子。细胞激活因子水平的改变,与可望观察到的免疫系统活性水平的改变相关。但对于免疫系统得以控制的机理所知甚少。目前确定的细胞激活因子间的相互作用是广泛的研究和探索主题。未来必将会鉴定出其他一些细胞激活因子。
免疫系统的某些个别细胞成分及其明显的功能特征正被确定,各种免疫活性及其功能的定量分析方法是已知的。刺激后的淋巴细胞的增殖速率、巨噬细胞的游动速率、吞噬速率、B淋巴细胞的抗体产生以及许多其他试验均可利用。其中,皮肤试验(迟发性超敏感性,或DTH)因其简便性和再现性而最常采用。本实验是将抗原经皮下注入并根据皮肤下层的硬化(肿胀)来检测细胞介导的免疫系统的反应。阳性皮肤试验表示,在对可察觉外源抗原反应中,具免疫能力的细胞宿主影响由各个别反应形成的一连串反应的总和。因此,DTH试验是整个免疫系统各成分的总体反应性。
在烧伤和创伤中,巨噬细胞可向损伤部位游动,并吞噬侵入伤口的细菌细胞,是免疫系统中特别重要的成分。因此,巨噬细胞代替皮肤在损伤期间作为对抗感染的第一条防线。可根据巨噬细胞对乳胶小滴(珠)的摄入来检测其吞噬速率,以分析巨噬细胞活性。
烧伤后免疫力低下是已知的事实。对创伤特别敏感的宿主防御网络之一,是细胞介导的免疫性。虽然细胞介导的免疫性是有许多细胞类型参与的十分复杂的过程,但通过对所注入之抗原的迟发性超敏性皮肤反应,可简便又可靠地估计出该免疫学反应的总体状态,热损伤后,皮肤试验的反应性小,即是说,在注入抗原后,48小时硬化(肿胀)的面积比通常情况下小些。那些在皮肤试验中显示反应性继后增加,即表现出细胞介导的免疫性部分恢复的病人可以有较好的预后(Hiebert JM,McGough M,Rodeheaver G,Tobiasen J,Edgerton MT,Edlich RF,The influence of catabolism on immunocompetence in burned patients,Surgery Aug 1979 86(2):242-247.)。另外,免疫功能(如根据皮肤试验反应性检测的)的恢复速度可与存活率有关(Kagan RJ,Bratescu A,Jonasson O,Matsuda T,Teodorescu M,The relationship between the percentage of circulating B cells,corticosteroid levels,and other immunologic parameters in thermally injured patients,J Trauma 1989 Feb;29(2):208-13.)
热损伤病人免疫功能的其他表征也受到抑制。这些表征包括T细胞数(Calvano SE,deRiesthal HF,Marano MA,Antonacci AC,The decrease in peripheral blood.CD4+T cells following thermal injury in humans can be accounted for by a concomitant decrease in suppressor-inducer CD4+,T cells as assessed using anti-CD45R,Clin Immunol Immunopathol 1988 May;47(2):164-73.)、HLA-DR抗原(Gibbons RA,Martinez OM,Lim RC,Horn JK,Garovoy MR,Reduction in HLA-DR,HLA-DQ and HLA-DP ex-pression by Leu-M3+cells from the peripheral blood of patients with thermal injury,Clin Exp Immunol 1989 Mar,75(3):371-5)、B细胞数(Kagan RJ,Bratescu A,onasson O,Matsuda T,Teodorescu.M,The relationship between the percentage of circulating B cells,corticosteroid levels,and other immunologic parameters in thermally injured patients,J Trauma 1989 Feb;29(2):208-13.)、白细胞功能(Tchervenkov JI,Latter DA,Psychogios J.Christou NV,Altered leukocyte delivery to specific and nonspecific inflammatory skin lesions following burn injury,J Trauma 1988 May;28(5):582-8.)、补体功能(Bjornson AB,Bjornson HS,Lincoln NA,Altemeier WA,Relative role of burn injury,wound colonization and wound infection in induction of alterations of complement function in a guinea pig model of burn injury,J.Trauma 1984 24:106-115)、抑制淋巴细胞增殖反应(Singh II,Herdon DN,Stein MD,Kinetics of lymphoprolife-rativ responses following scald injury in a rat burn model,Clin Immuno and Immunopath 1986 40:476-484.)、移植物抗宿主反应(Shelby J,Merrell SW,In vivo monitoring of postburn immune response,J.Trauma 1987 27:213-216.)及嗜异趋化性(Davis JM,Gallin JI,Abnormal rabbit heterophil chemotaxis following thermal injury,Arch Surg 1988 June 123:752-755.)。对热损伤后的免疫学后遗症已有详述(Winkelstein A,What arethe immunological alterations induced by burn injury?J.Trauma 1984 sept 24(9):572-583,What is the relationship between the status of a patient′s host defense mechanisms,his metabolic response and his ability to respond to injury?J.Trauma 1984 Sept 24(9):S84-S100.)另外,对热损伤后某些细胞活素水平的改变也作过定性分析(Antonacci AC,How do immuno-modulators affect host defense in the burn patient?J.Trauma 1984 Sept 24(9):S101-S118.)。
已试验过许多免疫调节药物在恢复后天性免疫功能失常方面的治疗效果。作为有潜力的治疗剂,已鉴定了布洛芬和干扰素Ⅱ(ShelbyJ,Hisatake G,Effect of ibuprofen and interleukin 2 on transfusion-induced suppression of cell-mediated immunity,Arch Surg 1988 Nov 123:1397-1399.)、重组人粒细胞菌落刺激因子(rhGCSF)(Mooney DP,Gamelli RL,O′Reilly M,Herbert JC,Recombinant human granulocyte colony-stimulating factor and Pseudomonas burn wound sepsis,Arch Surg 1988 Sept 123:1353-1357.)、前列腺素E(Waymack JP,Yurt RW,Effect of prostag-landin E on immune function in multiple animal models,Arch Surg 1988 Nov 123:1429-1432)、RU41740(Biostin)(Chris-tou NV,Zakaluzny I,Marshall JC,Nohr CW,The effect of the immunomodulator RU 41740(Biostim) on the specific and nons-pecific immunosupression induced by thermal injury or protein deprivation,Arch Surg 1988 Feb 123:207-211.)、左旋咪唑(Mea-kins JL,Christou NV,Shizgal HM,MacLean LD,Therapeuticapproaches to anergy in surgical patients,Ann Surg 1979 Sept 190(3):286296.)和胸腺生成素(Faist E,Ertel W,Salmen B,Weiler A,Ressel C,Bolla K,Heberer G,The immune-enhancing effect of perioperative thymopentin administration in elderly patients undergoing major surgery,Arch Surg 1988 Dec 123:1449-1453.)。已在动物试验和早期临床试用中对这些药物作了研究,以确定它们是否有效,初步研究结果表明,它们对有限数目的个体是有效的,而且除非在损伤前给药,否则一般都没有效果。这样就限制了这些有潜力治疗剂的临床实用性。
本发明描述了使用双链RNA(dsRNA)治疗休克(如经损害皮肤试验或其他机制证实的)。dsRNA可按下述程序的适当剂量给药。
下面描述的是一个典型实验。用锁孔 虫兰蛋白(KLH)0.5mg加入0.1ml完全弗氏佐剂(DFA)中致敏三十只雄性Sprague-Dawley大鼠(380-430g)。两周后(定为0天)进行复活DTH皮肤试验。为此目的所作皮肤试验的方法学,已在文献中由Rodriguez和Christou(附于申请中)以及Bates等人(Bates,SE Suen JY,Tranum BL,Immunological skin tesing and interpre-tation;A plea for uniformity,Cancer 1979 June 43:2306-2314.)作了深入的介绍。也可使用检测免疫功能失常的其他方法。将动物分成三组,组1(N=10)作为对照组。第1天所有动物经Rompine(4mg/kg)和Ketamine(175mg/kg)腹腔内(IP)注射麻醉;组2(N=10)和组3(N=10),在背部25%体表面积(BSA)上造成全皮层浸没烧伤。所有动物均经腹腔注射15ml普通生理盐水而复甦。在第1、3、7和13天,对第2和3组动物皮下注射10(8)菌落形成单位的金黄色葡萄球菌。在第1到第5天,对第3组动物经尾静脉注射15mg/Kg dsRNA(Ampligen )。第3、7和13天用0.25mgKLH(在0.1mlCFA中)作复活皮肤试验:用卡尺测量皮肤反应区的大小。第14天在二氧化碳小室内杀死动物。
第3、7和13天时,使用差异分析法(ANOVA,表1)来比较各组动物的平均皮肤反应(以厘米表示)(Karmy-Jones,R,Hinson D,Henriques HF,Einck L,Fakhry SM,DePalma RG,Restoration of delayed hypersensitivity by an immune modulator following thermal injury,1989 Oct Surgical Forum)。结果显示第3、7和13天时,各组动物之间的皮肤反应有显著差异(P<0.0001,ANOVA);第2组动物较对照组明显降低。
这些结果表明,在损伤后前5天内,采用静脉内注射dsRNA,可使25%BSA热损伤后由抑制的DTH反应所显示的免疫反应可得到恢复,(参见下列图1)。
迟发型超敏性皮肤反应
0天 | 3天 | 7天 | 13天 | |
组1(对照) | 1.31(±.26) | 1.54(±.21) | 1.26(±.15) | 1.31(±.20) |
组2(烧伤) | 1.29(±.17) | 0.90(±.20) | 0.83(±.17) | 0.83(±.10) |
组3(烧伤 + dsRNA) | 1.32(±.12) | 1.46(±.25) | 1.37(±.14) | 1.49(±.10) |
表1.皮肤试验数据,烧伤前和烧伤后第3、7及13天时硬结大小用平均数±SD(厘米数)表示。
另外两个实验组中,只有烧伤组相似于烧伤+葡萄球菌组,而低剂量dsRNA(5mg/Kg)组介于烧伤组和高剂量dsRNA(15mg/Kg)组中间。此为免疫反应对dsRNA剂量依赖性的指征(参见图1)。
在该类型实验中,25%全皮层热损伤可出现高死亡率。如所预料的,在只有烧伤组有两只动物死亡,烧伤+葡萄球菌感染组有三只动物死亡(图解显示见图3)。但在低剂量(5mg/Kg)dsRNA组则只有一只动物死亡,且未烧伤的对照组和高剂量dsRNA组(上述组3,15mg/Kg)没有死亡者。这些数据表明,dsRNA因可恢复损伤动物的免疫功能,故按施用剂量的多少动物死亡率相应降低(参见图2)。
除了能够恢复细胞介导的免疫功能(如由皮肤试验和改良预后情况所证明的)外,dsRNA还可引发巨噬细胞活性的明显改变。在一典型实验中,分别由未治疗(对照用)、只有25%体表烧伤组或25%体表烧伤并于热损伤后连续5天静脉内输注dsRNA组大鼠收集腹腔内巨噬细胞,收集至损伤后14天并检测其活性。众所周知,巨噬细胞的功能在于吞噬它们所遭遇到的细菌及其他外来物质。我们利用了一个模拟活性的试验,从而可以对巨噬细胞的活性水平进行准确的定量估计。将分离出的巨噬细胞与乳胶小粒混合,以攻击巨噬细胞使吞噬之。对这种攻击起反应的巨噬细胞的比例即代表了免疫系统中巨噬细胞成分的定量活性水平。进入巨噬细胞内的乳胶小粒数很容易由荧光显微镜检测出。下述实验中,可将得自未治疗大鼠的巨噬细胞均分为三个活性范围:无反应(0个小珠)、中等反应(1-5个小珠)和全活性(>5个小珠)(参见图解显示巨噬细胞活性的附图4)。烧伤本身可引起巨噬细胞活性的中度偏移,即无反应巨噬细胞减少,而中等活性和全活性细胞增加。烧伤后dsRNA治疗可导致巨噬细胞活性显著偏移。在接触到dsRNA后,有75%以上的巨噬细胞为全活性细胞(参见图3)。
这些实验清楚地证明,热损伤后应用dsRNA可提高存活率并恢复免疫功能。巨噬细胞系统和细胞介导的免疫系统可代表受到热损伤之病人抗感染的主要防御机制。而几乎所有存活甦醒烧伤病人的死亡都是因细菌感染造成的。
已证明可提高巨噬细胞活性的一种淋巴活素称为肿瘤坏死因子(TNF)。为证明dsRNA引发TNF合成或释放之可能性的实验表明,dsRNA确实导致大鼠体内TNF水平的增加(参见图5)。给一组4只大鼠输注dsRNA(15mg/Kg),在不到2小时时间内,其中有2只动物明显地诱导了TNF水平增加(Meager A,Leung H,Wooley J,Review Article;Assays for tumour necrosis factor and related cytokines.J.Immuno Methods 1989 116:1-17)(参见图4)。
尽管对TNF的诱导与巨噬细胞活性及抗病毒活性的确有关,但此种诱导本身未必是优点。TNF水平与败血症休克的并发症有关(Schirmer WJ,schirmer JM,Fry DE,Recombinant Human Tumor Necrosis Factor produces hemodynamic changes characteristic of sepsis and endotoxemia,Arch surg 1989 April 124:445-448)。有关研究人员认为,与败血症休克相关的死亡率是TNF释放的直接结果。可使用模拟败血症休克生理学的动物模型加以证明。经大鼠(或其他动物)静脉内注射得自革兰氏阴性菌的纯化的脂多糖(LPS),可使动物出现相同于败血症休克的复合症状,并引发一连串征候,其最终导致动物死亡。一项经典实验中,在注射LPS之前输入抗TNF抗体,可避免与内毒素有关的死亡(Beutler B,Milsark IW,Cerami AC,Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin,Science 1985,229:869-871)。按下述方法试验dsRNA对与败血症相关的复合症状的治疗效果。
在一经典实验中,给大鼠输注LPS(0.5mg/Kg)。如所预料的,在12小时内100%大鼠因败血症休克综合征死亡,而在注射LPS之前30分钟已单用dsRNA(15mg/Kg)治疗的大鼠则存活36小时以上。48小时后,约50%经dsRNA治疗的动物仍然存活,然后再杀死之。检测结果显示,在注射过LPS的大鼠中,明显地诱导了TNF水平(参见图5)。
这种诱导作用与败血症休克综合征及死亡相关。原先所作的这种实验证实TNF是与已观察到的死亡率有直接关联的淋巴活素(Schir-mer WJ,Schirmer JM,Fry DE,Recombinant Human Tumor Necrosis Factor produces hemodynamic changes characteristic of sepsis and endotoxemia,Arch surg 1989 April.)
由对dsRNA治疗的动物提高存活率及败血症相关死亡率与TNF水平间的相互关系的研究,一个全然未曾预料的结果是,注射LPS后用dsRNA治疗的大鼠不仅存活,而且显示同样明显的TNF诱导作用。注射LPS后,dsRNA可保护动物免于遭受其毒性作用,或者在临床上抑制败血症的发展。
已研究了许多与Ampligen相似的错配dsRNA高分子,错配dsRNA由细胞外体液中迅速清除,并因而观察到毒性的显著降低,可能是因有可随时接近核酸酶的错配物的存在,随之而产生很快的降解作用而致。
已描述了各种干扰素、干扰素诱导剂及dsRNA的已知活性(参见Handbook of Experimental Pharmacology on Interferons,ed.by P.E.Came and W.A.Carter,1984,Published by Springer-Verlag,New York and Heibelbery,533-555页,描述了dsRNA的某些已知性质)
本发明是基于dsRNA另一个新的和未曾预见的性质,包括但不只限于错配的dsRNA在内,例如Ampligen。
本发明提供了dsRNA在治疗休克或损伤中的应用方法。
如通过免疫皮肤反应所表明的,休克和损伤的一个重要症状是正常免疫状态受到抑制。而经dsRNA治疗可成功地恢复。
因此,本发明包括用dsRNA使免疫功能由无力反应状态恢复到正常状态(如经免疫反应试验测知的)。
dsRNA作为细胞活素或生物学激活剂的实用性是已知的(Greene JJ,Ts′o POP,Double-stranded RNA and its analogs:The prospects and the promise of the first nucleic acid therapeutic agent,In:Clinical,Applications of Interferons and Their Inducers,2nd ed.,Stringfellow DA,ed.,New York:Marcel Dekker,Inc.,pp245-268,Greene JJ,Ts′o POP,Strayer DR,Carter WA,Therapeutic applications of double-stranded RNAs,In:Interferons and Their Applications,Came PE and Carter WA,eds.,Berlin:Springer,1984,pp535-555.)。已检验了许多种dsRNA,并发现它们可引发相似的生物学效应。如A.G.Johnson评述了polyI∶C和polyA∶U的免疫调节性质,并发现它们的作用是相同的(Johnson AG,Immunomodulating effects of synthetic polyribonucleotides J Biol Resp Modif 4:481-3,1985.).Chapekar等人比较了各种dsRNA的杀细胞能力[poly I:C,poly A:U,polyICLC和rIn,(C12U)n],发现它们是相似的(Chapekar MS,Glazer RI,Potentiation of the cytocidal effect of human immune interferon by different synthetic double-stranded RNAs in the refractory human colon carcinoma cell line BE,Cancer Res 1986 Apr;46(4 Pt 1):1698-702.)。
已用作治疗剂的dsRNA及同系物包括poly I:C、polyICLC、polyICL-CM葡聚糖、rIn,(C12U)n(即Ampligen )poly A:U、poly G:C和poly I:D巯基多聚胞苷酸。
dsRNA可以是错配的dsRNA。“匹配dsRNA”是指配对链间的氢键连接(碱基堆积)是相对完整的,即每29个连续的碱基残基中被破坏者平均少于1个碱基对。据此,“错配dsRNA”的含义也就可以理解了。
dsRNA可以是含有一定比例尿嘧啶碱基或胍碱基的聚次黄苷酸与聚胞苷酸的复合物,其中所述可以是5个中有1个至30个中有1个这样的碱基[polyI,poly(C4-29XU或G)]。
dsRNA可以是通式rIn,(C12U)n。dsRNA的其他的适当例子,如下所述。
也可以将非均聚体RNA中的腺苷残基修改成次黄苷以产生错配dsRNA,如产生次黄苷:尿苷错配物。
本发明的医药组合物包括dsRNA与医药上可接受的载体或稀释剂配制的组合物。
本发明精心配制的医药组合物包括含适当的医药载体,适于胃肠道外给药的医药组合物。
因此,可根据需要,按照已知的制药技术,用无菌水或无热原水作稀释剂,也可任意采用其生理上可接受的盐。制成肠道外溶液剂,悬浮剂和分散剂。
作为dsRNA治疗的重要受体之一,在某些临床状态下,宜于使用胶粒或脂质体可使药物特别指向巨噬细胞,这样即可避免全身性免疫激活作用。由于巨噬细胞的吞噬活性,脂质体中的dsRNA将主要进入巨噬细胞,而不是作为一种总体免疫激活剂存在,这样对于器官移植病人来说,这种传输机将适于调节免疫系统中巨噬细胞成分的免疫活性,从而使细胞介导的免疫性及器官排斥作用受到抑制。然而,因dsRNA有针对性(脂质体指向)的激活免疫系统中的巨噬细胞成分,故不仅可阻止细菌或病毒感染,同时又不会刺激细胞介导的免疫性。
应该明确的是,在以适当速率和方式给药时,以任何剂量单位存在的活性成分的绝对量不应是过量的:但另一方面,还应通过使用小剂量足以达到预期的给药速度。给药速度将依据所期望的精确药理学作用而定。
dsRNA给药量最好是当体内dsRNA水平平衡后每毫升体液为0.01mg,但给药后循环体液立即高达每毫升1000mg。这时所说的体液是指在器官内循环及浸没组织的血液、淋巴液等。至于推测的病人体液体积是临床医生知道的,而且也可以从已出版的有关图表中查到。
本发明描述了选择性地重新激活人体细胞、组织和器官内因损伤后降低了功能的天然防御系统的机制。因为受到感染的巨大挑战和威胁,免疫系统对于生命存活攸关重要,所以这种治疗可以改善受损伤病人的预后。
本发明中描述的dsRNA治疗适用于各种损伤后的休克,所说的损伤包括(但不只限于)创伤、烧伤、外科手术、输血、放射治疗及某些化学治疗。文献中已描述过dsRNA在治疗与放射疗法有关之免疫抑制中的实用价值[即放射保护作用(Neta R,Role of cyto-kines in radioprotection,Pharmac.Ther.1988 39:261-266.)]。
附图说明:
图1.图解显示烧伤前和烧伤后第3.7和13天时,检测25%体表烧伤后用dsRNA(15mg/Kg)治疗,免疫功能的恢复程度,结果用硬结直径的厘米数表示。
图2 图解显示25%全皮层体表烧伤后使用dsRNA导致死亡率降低。
图3.图解显示,根据分离出的腹膜巨噬细胞吞噬涂布抗原玻璃小珠的能力测得的Ampligen治疗后巨噬细胞活性的增加
图4.图解显示输注dsRNA后对TNF的诱导作用。其中数值用TNF功能(抗病毒活性)的实验室单位表示
图5.图解显示与败血症休克综合征和100%死亡率相关的TNF水平(用实验室单位表示)
Claims (7)
1、在制备用于治疗病人,防止损伤后休克医药物中dsRNA的用途。
2、根据权利要求1的用途,其中休克是因败血症引起的。
3、根据权利要求1的用途,其中损伤是烧伤。
4、根据权利要求1的用途,其中休克或损伤伴有组织坏死因子释放。
5、根据权利要求1的用途,其中休克或损伤导致获得性免疫功能失常。
6、根据权利要求5的用途,其中免疫功能失常包括单核细胞或巨噬细胞活性不足。
7、根据权利要求5的用途,其中损伤是创伤、烧伤、外科手术,输血、放射治疗或化学治疗。
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WO2009030254A1 (en) | 2007-09-04 | 2009-03-12 | Curevac Gmbh | Complexes of rna and cationic peptides for transfection and for immunostimulation |
SG188104A1 (en) | 2008-01-31 | 2013-03-28 | Curevac Gmbh | Nucleic acids comprising formula (nuglxmgnnv)a and derivatives thereof as an immunostimulating agents /adjuvants |
WO2010037408A1 (en) | 2008-09-30 | 2010-04-08 | Curevac Gmbh | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
US20110053829A1 (en) | 2009-09-03 | 2011-03-03 | Curevac Gmbh | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
ES2558106T3 (es) | 2010-07-30 | 2016-02-02 | Curevac Ag | Formación de complejos de ácidos nucleicos con componentes catiónicos disulfuro-reticulados para la transfección e inmunoestimulación |
WO2013113326A1 (en) | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Pharmaceutical composition comprising a polymeric carrier cargo complex and at least one protein or peptide antigen |
BR112016003361A2 (pt) | 2013-08-21 | 2017-11-21 | Curevac Ag | vacina do vírus sincicial respiratório (rsv) |
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DE2046506A1 (en) * | 1970-09-21 | 1972-03-23 | Brendel, Walter, Prof. Dr.; Seinfeld, Hugo; 8000 München | Xenologous nucleic acids as immunosupressors - for extending the survival time of transplantates |
CA1326450C (en) * | 1985-08-26 | 1994-01-25 | William A. Carter | Modulation of aids virus-related events by double stranded rnas (dsrnas) |
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AU1820388A (en) * | 1987-07-17 | 1989-01-19 | Hem Research, Inc. | Double stranded rna correction of aberrant metabolic pathways associated with uncontrolled tumor cell and virus growth cycles |
AU1820588A (en) * | 1987-07-17 | 1989-01-19 | Hem Research, Inc. | Double-stranded rna correction of abnormalities in circulating immune complexes and monocyte function |
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WO1991005560A1 (en) | 1991-05-02 |
AU6740590A (en) | 1991-05-16 |
EP0495919A1 (en) | 1992-07-29 |
TW206154B (zh) | 1993-05-21 |
HU9201197D0 (en) | 1992-08-28 |
ATE147630T1 (de) | 1997-02-15 |
AU6751294A (en) | 1994-12-08 |
IE903622A1 (en) | 1991-04-24 |
EP0495919B1 (en) | 1997-01-15 |
DE69029738D1 (de) | 1997-02-27 |
DE69029738T2 (de) | 1997-08-14 |
NZ235636A (en) | 1997-02-24 |
HUT65404A (en) | 1994-06-28 |
EP0495919A4 (en) | 1993-03-03 |
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