CN111936166A - 用于药物递送的免疫调节和免疫刺激多肽 - Google Patents
用于药物递送的免疫调节和免疫刺激多肽 Download PDFInfo
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Abstract
本发明涉及具有免疫调节和免疫刺激活性的经修饰的细菌多肽。更具体地,本发明涉及具有选自SEQ ID NO.1、SEQ ID NO.2、SEQ ID NO.3、SEQ ID NO.4和SEQ ID NO.5的氨基酸序列的经修饰的细菌多肽。所述经修饰的多肽为药物组合物的佐剂成分,用于引发针对所述药物组合物中存在的特定抗原的免疫应答。在一个优选的实施方案中,本发明提供了用于疫苗的药物组合物,其包含为任一种经修饰的多肽的佐剂成分,一种或多种抗原和可药用的赋形剂。
Description
技术领域
本发明总体上涉及作为免疫调节剂和免疫刺激剂的多肽。更具体地,本发明涉及具有免疫调节和免疫刺激活性的经修饰的细菌多肽。仍更具体地,本发明的经修饰的多肽为药物组合物的佐剂成分,用于引发针对所述药物组合物中存在的特定抗原的免疫应答。在一个优选的实施方案中,本发明提供了用于疫苗的药物组合物,所述用于疫苗的药物组合物包含佐剂成分,其为根据本发明的序列表的任一种经修饰的多肽,一种或多种抗原和可药用的赋形剂。
背景技术
在兽医和医学科学中,免疫调节为其中已经进行了广泛研究以设计出通过免疫系统的最佳调节来提高疾病抵抗力以及预防或防治宿主的免疫障碍的方法的领域。如今,人和动物的大多数传染病主要通过使用广谱抗生素和疫苗来治疗和防治。然而,由于抗性微生物菌株的快速出现,抗菌剂变得越来越无效。因此,迫切需要新的和改进的替代性治疗和预防策略以管理由于国际运输量的增加、全球化和饮食习惯改变而以惊人的速度爆发的几种疾病。免疫调节集中于通过精确调节来操纵免疫系统,以防治感染和其他不良健康影响,从而避免任何并发症,同时进行抑制或增强作用以使动物和人类健康受益。
免疫系统可通过疫苗接种进行特异性操纵,或可通过免疫调节进行非特异性操纵。
普遍认为疫苗接种是预防传染病的最有效和最划算的形式。尽管目前获得许可的大多数疫苗都是通过肠胃外途径施用,但是这种疫苗接种策略通常无法引发足够的粘膜免疫应答。因此,由粘膜病原体引起的疾病仍然是发展中国家的主要死亡原因之一。有充分的文献证明,口服免疫可在肠道粘膜以及全身产生强大的保护性免疫(1-5)。但是,抗原的口服给予面临两个主要问题,一个为胃肠道中存在的酶对抗原的降解,以及另一个为针对给予的抗原的免疫耐受性的诱导(6-8)。当前基于减毒病原体的口服疫苗通常能够规避这些困难,但另一方面存在重要的安全隐患(9)。安全的替代包括基于杀死的病原体或其亚基的口服疫苗的开发,但这面临着巨大的挑战,由于它们的免疫原性很差,并且通常需要多次剂量和使用有效的口服佐剂(10,11)。
两种细菌产品(来自霍乱孤菌(V.cholerae)的霍乱毒素(CT)和来自大肠杆菌(E.coli)的热不稳定肠毒素(LT))被用作小鼠模型中的口服佐剂(12)。由于肠毒性严重限制了这些化合物在人类中的实际使用,因此已经进行了修饰以降低这种作用。缺少A亚基的CT(CTB)的经修饰的版本目前被许可作为疫苗的一部分供人类使用(13),并且保留其佐剂特性的LT的双重突变体(dmLT)也正在临床试验中(14)。然而,这些分子均不能克服胃肠道中的抗原降解。解决这个问题的有趣的策略包括通过靶向肠的pH依赖性微粒(15),靶向M细胞(19)的可生物降解的纳米颗粒或微粒(16-18)抗原和蛋白酶抑制剂(20)来进行抗原递送。然而,仍然需要合适的佐剂和可口服给予的递送系统。
另外,并且如上所述,免疫系统也可通过免疫调节被非特异性地操纵。免疫调节剂可被定义为可刺激/抑制免疫系统先天免疫或适应性免疫或两者的任何生物或合成物质。免疫调节剂包括免疫刺激剂和免疫抑制剂。免疫刺激剂是能够增强宿主防御机制以提供针对感染的保护的物质。它们的作用方式包括通过免疫系统的细胞(包括淋巴细胞亚群、巨噬细胞、树突状细胞和自然杀伤细胞)增强抗感染免疫力。
树突状细胞(DC)代表具有产生细胞因子和趋化因子,捕获和加工抗原,迁移到次级淋巴器官以及激活幼稚(naive)T淋巴细胞的能力的岗哨样(sentinel-like)系统。它们可以存在于所有淋巴和大多数非淋巴组织(包括粘膜表面,如肺和肠)中,复杂的DC网络位于其中以感知潜在的有害暴露。
树突状细胞(DC)是免疫系统的主要门卫(gate-keeper),弥合了先天的和适应性免疫系统。在自身免疫和变应性疾病中,DC都能在炎症部位成熟为炎性DC,从而维持炎症部位处的免疫系统的连续激活。树突状细胞(DC)的成熟/激活是诱导适应性免疫应答的关键步骤。通过将DC暴露于免疫调节剂来调节和操纵DC功能是一种在许多临床状况下可产生治疗益处的方法。
发明内容
本发明提供了一种免疫调节多肽,其选自SEQ ID NO.1的来自肠道沙门氏菌(Salmonella enterica)的无信号肽的经修饰的大肠杆菌素(Ecotin),SEQ ID NO.2的来自铜绿假单胞菌(Pseudomonas aeruginosa)的无信号肽的经修饰的碱性蛋白酶抑制剂(aprin),SEQ ID NO.3的来自金黄色葡萄球菌(Staphylococcus aureus)的经修饰的葡萄球菌半胱氨酸蛋白酶(staphostatin)B,SEQ ID NO.4的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A,以及SEQ ID NO.5的来自幽门螺杆菌(Helicobacter pylori)的经修饰的丝氨酸羧肽酶Y抑制剂(Y inh.)。
本文提供的实验证据表明,本发明的每种多肽已被证明都诱导树突状细胞(DC)的激活,因此是有价值的免疫调节剂。
因此,本发明还涉及一种药物组合物,其包含:(i)免疫调节多肽,其选自SEQ IDNO.1的来自肠道沙门氏菌的无信号肽的经修饰的大肠杆菌素,SEQ ID NO.2的来自铜绿假单胞菌的无信号肽的经修饰的碱性蛋白酶抑制剂,SEQ ID NO.3的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶B,SEQ ID NO.4的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A,和SEQ ID NO.5的来自幽门螺杆菌的经修饰的丝氨酸羧肽酶Y抑制剂,以及(ii)可药用的赋形剂。
实验证据表明,本发明的每种多肽已被证明可用作口服给予的抗原的佐剂。将所述多肽与抗原一起给予产生针对抗原的血清IgG和/或粘膜IgA。当多肽被递送时,Ag特异性CD4+和CD8+ T细胞也增加。
因此,本发明的一个目的是用于疫苗的免疫佐剂,优选通过口服途径给予,其中所述佐剂为选自以下的多肽:SEQ ID NO.1的来自肠道沙门氏菌的无信号肽的经修饰的大肠杆菌素,SEQ ID NO.2的来自铜绿假单胞菌的无信号肽的经修饰的碱性蛋白酶抑制剂,SEQID NO.3的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶B,SEQ ID NO.4的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A,和SEQ ID NO.5的来自幽门螺杆菌的经修饰的丝氨酸羧肽酶Y抑制剂。
本发明的进一步的目的是用于在整个宿主的粘膜表面上刺激保护性免疫的药物组合物。
本发明的另一个目的是用于诱导对任何抗原的保护性免疫应答的药物组合物,其中所述组合物包含至少一种抗原与选自以下的一种或多种多肽的组合:SEQ ID NO.1的来自肠道沙门氏菌的无信号肽的经修饰的大肠杆菌素,SEQ ID NO.2的来自铜绿假单胞菌的无信号肽的经修饰的碱性蛋白酶抑制剂,SEQ ID NO.3的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶B,SEQ ID NO.4的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A,和SEQ ID NO.5的来自幽门螺杆菌的经修饰的丝氨酸羧肽酶Y抑制剂。
根据另一个实施方案,本发明的组合物为针对任何特定抗原的疫苗的成分,其中特异性抗体或细胞应答将可用于对特定疾病的主动获得性免疫。
根据另一个实施方案,本发明的组合物为由任何需要或期望诱导特异性免疫应答的特异性抗原组成的疫苗或制剂的成分。
因此,本发明提供了一种疫苗或制剂,其包含至少一种抗原和选自以下的多肽:SEQ ID NO.1的来自肠道沙门氏菌的无信号肽的经修饰的大肠杆菌素,SEQ ID NO.2的来自铜绿假单胞菌的无信号肽的经修饰的碱性蛋白酶抑制剂,SEQ ID NO.3的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶B,SEQ ID NO.4的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A,和SEQ ID NO.5的来自幽门螺杆菌的经修饰的丝氨酸羧肽酶Y抑制剂,以及任选地药学上可接受的载体。
根据本发明的另一个目的,还提供了编码本发明的多肽的核苷酸序列。所述核酸序列选自SEQ ID NO.6-10,其中SEQ ID NO.6编码来自沙门氏菌的经修饰的大肠杆菌素(无信号肽);SEQ ID NO.7编码来自铜绿假单胞菌的经修饰的碱性蛋白酶抑制剂(无信号肽);SEQ ID NO.8编码来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶B;SEQ IDNO.9编码来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A;和SEQ ID NO.10编码来自幽门螺杆菌的经修饰的丝氨酸羧肽酶Y抑制剂。
根据本发明的另一个目的,提供了一种在受试者中刺激先天的免疫应答的方法,包括给予所述受试者有效量的包含一种或多种本发明的多肽的药物组合物。
根据本发明的另一个目的,提供了一种在受试者中增强针对抗原的免疫应答的方法,包括给予所述受试者有效量的包含一种或多种本发明的多肽的药物组合物或疫苗。
本发明的另一个目的是通过给予有需要的受试者至少一剂量的有效量的抗原和有效量的一种或多种本发明的多肽来诱导对抗原的保护性(有时称为适应性)免疫的方法。
特别地,本发明的另一个目的是通过给予有需要的受试者口服或肠胃外可接受的药物组合物中的至少一剂量的有效量的病原体衍生的抗原和有效量的多肽来诱导对病原体衍生的抗原的保护性(有时称为适应性)免疫的方法,所述多肽选自:SEQ ID NO.1的来自肠道沙门氏菌的无信号肽的经修饰的大肠杆菌素,SEQ ID NO.2的来自铜绿假单胞菌的无信号肽的经修饰的碱性蛋白酶抑制剂,SEQ ID NO.3的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶B,SEQ ID NO.4的来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A,和SEQ ID NO.5的来自幽门螺杆菌的经修饰的丝氨酸羧肽酶Y抑制剂。
所述抗原可由肽、蛋白质、多糖或生物体或无生命生物体的任何分子或化学部分成分或所述生物体的提取物组成,宿主可诱导针对所述抗原的免疫应答。替代地,所述抗原可由含有表位的物质组成,所述表位由宿主先前已经针对其建立引起过敏表现的过敏免疫应答的物质(过敏原)共有。
根据一个优选的实施方案,所述抗原选自病原体衍生的抗原、肿瘤细胞抗原、自身抗原和过敏原。病原体衍生的抗原可来自细菌、病毒、寄生虫或真菌。
根据一个优选的实施方案,所述病原体衍生的抗原选自病毒抗原、细菌抗原、寄生抗原和真菌抗原。
根据另一个实施方案,所述抗原为病毒抗原,其选自包括但不限于以下病毒的组:痘病毒科(Poxviridae)、疱疹病毒科(Herpesviridae)、单纯疱疹病毒1型(Herpes Simplexvirus 1)、单纯疱疹病毒2型(Herpes Simplex virus 2)、腺病毒科(Adenoviridae)、乳多空病毒科(Papovaviridae)、肠道病毒科(Enteroviridae)、小RNA病毒科(Picornaviridae)、乳头瘤病毒科(Papillomaviridae)、细小病毒科(Parvoviridae)、呼肠孤病毒科(Reoviridae)、逆转录病毒科(retroviridae)、流感病毒、副流感病毒、腮腺炎(mumps)、麻疹(measles)、呼吸道合胞体病毒、风疹(rubella)、虫媒病毒科(Arboviridae)、弹状病毒科(Rhabdoviridae)、沙粒病毒科(Arenaviridae)、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒、非甲型/非乙型肝炎病毒、鼻病毒科(Rhinoviridae)、冠状病毒科(Coronaviridae)、轮状病毒科(Rotaviridae)、牛痘病毒。
根据另一个实施方案,所述抗原为细菌抗原,其选自包括但不限于以下细菌的组:化脓性链球菌(Streptococcus pyogenes)、肺炎链球菌(Streptococcus pneumoniae)、淋病奈瑟菌(Neisseria gonorrheae)、脑膜炎奈瑟球菌(Neisseria meningitidis)、白喉棒状杆菌(Corynebacterium diphtheriae)、肉毒梭菌(Clostridium botulinum)、产气荚膜梭菌(Clostridium perfringens)、破伤风梭菌(Clostridium tetani)、流感杆菌(Hemophilus influenzae)、肺炎克雷伯氏菌(Klebsiella pheumoniae)、臭鼻克雷伯氏菌(Klebsiella ozaenae)鼻硬结克雷白氏杆菌(Klebsiella rhinoscleromatis)、金黄色葡萄球菌(Staphylococcus aureus)、霍乱弧菌(Vibrio cholerae)、大肠杆菌(Escherichiacoli)、铜绿假单胞菌(Pseudomonas aeruginosa)、胎儿弯曲杆菌(弧菌)(Campylobacter(Vibrio)fetus)、嗜水气单胞菌(Aeromonas hydrophila)、蜡样芽胞杆菌(Bacilluscereus)、迟钝爱德华氏菌(Edwardsiella tarda)、小肠结肠炎耶尔森氏菌(Yersiniaenterocolitica)、鼠疫耶尔森氏菌(Yersinia pestis)、假结核耶尔森氏菌(Yersiniapseudotuberculosis)、痢疾志贺氏菌(Shigella dysenteriae)、氟氏志贺氏菌(Shigellaflexneri)、宋内氏志贺氏菌(Shigella sonnei)、鼠伤寒沙门菌(Salmonellatyphimurium)、苍白密螺旋体(Treponema pallidum)、极细密螺旋体(Treponemapertenue)、斑点病密螺旋体(Treponema carateneum)、奋森氏螺旋体(Borreliavincentii)、布氏疏螺旋体(Borrelia burgdorferi)、出血性黄疸钩端螺旋体(Leptospiraicterohemorrhagiae)、结核分枝杆菌(Mycobacterium tuberculosis)、土拉弗朗西斯菌(Francisella tularensis)、流产布鲁氏菌(Brucella abortus)、猪布鲁氏菌(Brucellasuis)、羊布鲁氏菌(Brucella melitensis)、支原体属种(Mycoplasma spp.)、普氏立克次氏体(Rickettsia prowazeki)、恙虫病立克次体(Rickettsia tsutsugamushi)、衣原体属种(Chlamydia spp)、单核细胞增生李斯特氏菌(Listeria monocytogenes)。
根据另一个实施方案,所述抗原为原生动物的抗原,其选自包括但不限于以下原生动物的组:溶组织内阿米巴(Entomoeba histolytica)、口腔滴虫(Trichomonas tenas)、人毛滴虫(Trichomonas hominis)、阴道毛滴虫(Trichomonas vaginalis)、冈比亚锥虫(Trypanosoma gambiense)、罗得西亚锥虫(Trypanosoma rhodesiense)、克鲁斯锥虫(Trypanosoma cruzi)、杜氏利什曼原虫(Leishamania donovani)、热带利什曼原虫(Leishamania tropica)、巴西利什曼原虫(Leishmania braziliensis)、肺囊虫性肺炎(Pneumocystis pneumonia)、间日疟原虫(Plasmodium vivax)、恶性疟原虫(Plasmodiumfalciparum)和三日疟原虫(Plasmodium malaria)。
根据另一个实施方案,所述抗原为蠕虫的抗原,其选自包括但不限于以下蠕虫的组:蛲虫(Enterobius vermicularis)、毛首鞭虫(Trichuris trichiura)、蛔虫(Ascarislumbricoides)、旋毛虫(Trichinella spiralis)、粪类圆线虫(Strongyloidesstercoralis)、日本血吸虫(Schistosoma japonicum)、曼森氏裂体吸虫(Schistosomamansoni)、埃及裂体吸虫(Schistosoma haematobium)和钩虫(hookworm)。
根据另一个实施方案,所述抗原为真菌抗原,其选自包括但不限于以下真菌的组:粗球孢子菌(Coccidioides immitis)、烟曲霉(Aspergillus fumigatus)、白假丝酵母(Candida albicans)、皮炎芽生菌(Blastomyces dermatitidis)、新型隐球菌(Cryptococcus neoformans)和荚膜组织胞浆菌(Histoplasma capsulatum)。
根据另一个实施方案,所述抗原为肿瘤衍生的抗原,其选自包括例如但不限于以下抗原的组;AFP(α-胎甲球蛋白)、ETA(上皮肿瘤抗原)、CEA(癌胚抗原)、MAGE(黑素瘤相关抗原)、MUC-1、ras的异常产物、p53、TPBG(滋养层糖蛋白)、CEA(结直肠癌),未成熟层粘连蛋白受体(RCC)、TAG-72(前列腺癌)、HPV E6、E7(宫颈癌)、BING-4(黑色素瘤)、钙激活的氯离子通道2(肺癌)、细胞周期素B1(多种)、9D7(RCC)、Ep-CAM(乳腺癌)、EphA3(多种)、Her2/神经鞘(多种)、端粒酶(多种)、间皮素(胰腺导管癌)、SAP-1(结直肠癌)、存活(多种)、BAGE家族(多种)、CAGE家族(多种)、GAGE家族(多种)、MAGE家族(多种)、SAGE家族(多种)、XAGE家族(多种)、NY-ESO-1/LAGE-1(多种)、PRAME(多种)、SSX-2(黑色素瘤,多种)、黑色素A/MART-1(黑色素瘤)、Gp100/pmel17(黑色素瘤)、酪氨酸酶(黑色素瘤)、TRP-1/2(黑色素瘤)、疟原虫多肽(P.polypeptide)(黑色素瘤)、MC1R(黑色素瘤)、前列腺特异性抗原(PSA,前列腺)、β-连环蛋白(黑色素瘤,前列腺,HCC)、BRCA1/2(乳腺癌,卵巢癌)、CDK4(多种)、CML66(CML)、纤连蛋白(多种)、MART-2(黑色素瘤)、p53(多种)、Ras(多种)、TGF-βRII(结直肠癌)、MUC1(导管癌,RCC)、Ig、TCR(B,T白血病,淋巴瘤,骨髓瘤)。
根据另一个实施方案,所述抗原为保护性抗原。保护性抗原为宿主的获得性免疫应答特异性靶向,并且能够在宿主中诱导针对感染性和非感染性疾病的保护。用于不同疾病的保护性抗原的实例为以下抗原,但不限于此:Lef;LF;PA;PA63;PA63-LAMP1;PA83;Pag;PagA;TPA-PA63;TPA-PA63-LAMP1;UQ-PA63;BoNT/A;BoNT/A1;BoNT/B;BoNT/C(Hc50);BotA;FHc;来自破伤风梭菌(Clostridium tetani)的片段C;TTC;破伤风类毒素(Tetanustoxoid);Tox;白喉类毒素(Diphteria toxoid);spaA;Hly;p60;Ag85B;Ag85A;Ag85A;Ag85B;Apa;bfrA;DnaK;ESAT-6;EsxA(ESAT-6);EsxB;FbpA(Ag85A);FbpB;FbpD;HBHA;KatG;Mpt63;MPT64;MPT83;Mtb72F;PE20;PepA;PPE14;PPE18;PPE31;PstS1;PstS3;Rv1806;Rv1807;Rv2660c;ClfA;can;efb;FnbA;isdB;MecA;BipA;BPS;Rib;Sip;结合蛋白Eag;胶原蛋白结合,辅助纤毛亚基Cne;Fbp;Fnz;HAP;Sfs;CbpA;ClpP;GltX;Gnd;LplA;phpA-79;PiaA;Ply;PsaA;PspA;psrP;SrtA;emm1;FbaA;FBP54;Sfb;Sib35;APP7_1016;ApxIA;apxIA;ApxIIA;apxIIA;CP;脂多糖;AroA;AsaP1;brkA;Cpn60;CyaA;FhaB;Prn;PtxA;PtxB;PtxC;PtxD;PtxE;S1;DbpA;OspA;OspB;OspC;AsnC;L7/L12;P39;BAB1_0278;BCSP31;Bfr;Bp26;cob;DnaK;Gap;IalB;L7/L12;Omp16;Omp19;Omp25;Omp31;ORF;P39;RplL;SodC;SurA;Tig;FliC;LolC/E;LPS;PotF;CadF;来自空肠弯曲菌(C.jejuni)的CjaA;来自空肠弯曲菌RM1221的CjaA;来自空肠弯曲菌81-176的FlaA;来自空肠弯曲菌NCTC 11168的FlaA;FlaC;FspA1;FspA2;Peb1A;PorA;MOMP;PmpE/F-2;PmpG-1;RplF;Tarp;TC0439粘附因子;TC0512外膜蛋白,假定的;TC0757假设蛋白;TC0767假设蛋白;TC0768假设蛋白;ompA;CAB049假定青霉素结合蛋白;CAB613假定肽酶;DnaK;DnaX;GatA;GatB;GatC;OmlA;Omp1;Pomp90A;CopN;FabD;HSP-60;LcrE;PknD;Ssb;MOMP;OmpA;HspB;P1;esa1;et18;eta6;fliC;C0393;C3389;C4424;CS1;Eae;ECSE_P3-0034;EltB;FimH;FyuA;Hma;IreA;IroN;Iss;IutA;StxB2;Tir;FopA;FopB;GroEL;IglC1;IglC2;LpnA;LPS;TUL4;WbtI;D15;Hap;Hpd;HtrA;NucA;Omp26;OmpP1;OmpP2;OmpP5;P145;P4;Pal;Tbp2;gapA;过氧化氢酶;GltA;Hsp60;HspA;HspB;NAP;oipA;UreB;VacA;ligB;ompL1;TM-1;P97;ExbB;GNA1030;GNA1162;GNA1220;GNA1870;GNA1946;GNA2001;GNA2091;GNA2132;GNA33;GNA992(hsf);gp120;LctP;LpdA;LPS;NadA;NspA;MC58;P1;TBP2;TbpA;OmpA;ompH;ompH;OprF;OprI;PcrV;pilA;OmpA;OmpB;SpaP;DnaJ;GroEL;HslU;IroN;SopB;TviB;GuaB;IpaB;IpaC;IpaD;Spa32;GlpQ;TmpB;Tp92;OmpU;CtxB;TcpA;TcpF;LcrV;Cafl;HpmB;HtpG;Irp7;LcrV;LolA;Pla;Psn;V抗原;YapF;YdeN;YerA;YopD;YopE;YopH;YopO;YPMT1.84(F1荚膜抗原);YPO0420;YPO0612;YscF;pYV0055;融合蛋白(NCBI蛋白质GI6018112);来自BRSV的G;gB;gIV;UL44;UL49;US6;US7;Env/Rex/Tax;F基因;E2;VP1;VP2;E0;Gp55;E2;18H6合成E蛋白;E蛋白;来自登革热(Dengue)1的E蛋白;来自登革热3的E蛋白;来自登革热4的E蛋白;M蛋白;NS1;PrM;来自登革热1的prM;来自登革热2的prM;来自登革热3的prM;VP1;EBOV NP;来自雷斯顿埃博拉病毒(ebolavirus)的GP;来自苏丹埃博拉病毒的GP;来自扎伊尔埃博拉病毒的GP;NP;SGP;来自雷斯顿埃博拉病毒的VP24;来自扎伊尔埃博拉病毒的VP24;来自雷斯顿埃博拉病毒的VP30;来自扎伊尔埃博拉病毒的VP30;来自雷斯顿埃博拉病毒的VP35;来自扎伊尔埃博拉病毒的VP35;来自雷斯顿埃博拉病毒的VP40;来自扎伊尔埃博拉病毒的VP40;ZGP;来自FeLV-A/格拉斯哥的env;来自FRA菌株的Env;Gag;1D;2A;3C;3D;FMDV A12基因组;P1;VP1;gB;UL27;ANDVsSgp1;G1;G1和G2;Gc;HTNVsSgp1;M区段;N蛋白[托普格拉夫病毒];PUUVsSgp1;来自多布拉瓦-贝尔格莱德病毒的S核衣壳蛋白;SNVsSgp1;G糖蛋白;HAVgp2;HBVgp2前S1/前S2/S;乙型肝炎表面抗原;大S蛋白;前S2中表面蛋白;PreS2+S(中蛋白);来自鸭乙型肝炎病毒的S蛋白;小包膜抗原;小S蛋白;p27;来自HSV-1KOS的gB;来自HSV-1的ICP27;来自HSV-2的ICP27;来自HSV-1的UL27;来自HSV-2的UL27;来自HSV-1的UL44;来自HSV-2的UL44;US4;US5;US6;US7;US8;G糖蛋白;N核衣壳蛋白;VP1;糖蛋白B;pp65;Env;来自进化枝(clade)B的env;来自HIV 2的env;来自HIV-1分离株037克隆08的env;来自HIV-1分离株715的env;来自HIV-1菌株96ZM651的env;来自HIV-1菌株976克隆17的env;来自HIV-1菌株Ba-L的env;来自SHIV-89.6的env;来自SHIV89.6P的env;来自SIV的env;Env Gp160;env MN分离株;来自HXB2的包膜多蛋白;来自进化枝A的gag;来自HIV 1的Gag;来自HIV 2的gag;来自HIV B亚型的gag;来自HIV-1载体pNL4-3的gag;来自HXB2的gag;来自SHIV-89.6的gag;来自SIV-mnd 2的Gag蛋白;gag-pol;gag-pol SIV;gpl20;来自MN的gp120;gp120印度C亚型;gp41;Nef;来自HIV 2的nef;来自HIV 1的pol;来自SHIV-89.6的pol;来自HIV1的rev;来自SHIV-89.6的rev;Tat;来自HIV 2的tat;来自SHIV-89.6的tat;来自SHIV-89.6的vif;来自SHIV-89.6的vpr;来自SHIV-89.6的vpu;来自人类的钙网蛋白;E6;E7;L1;L2;F蛋白;G蛋白;M膜蛋白;N蛋白;S1;VP2;VP2-VP4-VP3;G糖蛋白;ORF;VP2;来自甲型流感病毒的HA,来自甲型流感病毒的NA,来自甲型流感病毒(A/鸡/河南/12/2004(H5N1))的NP;来自甲型流感病毒的NP,来自乙型流感病毒的NP;包膜蛋白;M蛋白;NS1;NS3;NS5;PreM;PrM;GPC;LASVsSgp1核蛋白;LASVsSgp2糖蛋白;NP;GP;来自维多利亚湖马尔堡病毒穆索科株的GP;来自扎伊尔埃博拉病毒的GP;NP;来自维多利亚湖马尔堡病毒的NP;来自扎伊尔埃博拉病毒的NP;NP马尔堡病毒-Ravn;SGP;VP35;MDV040;MDV095;F融合蛋白;H血凝素蛋白;M基质蛋白;N核衣壳蛋白;P磷蛋白;HN;gM;gN;IE1;F融合蛋白;来自D26菌株的F蛋白;HN血凝素-神经氨酸酶;F融合蛋白;G糖蛋白;VP4;ORF2;来自CH-1a的GP5;来自YA1的GP5;ORF7;泛素;GB;GI;GII;GIII;Gp50;IE180;UL44;US6;VP60;env;gag;VP22;RVFVsMgp1 M蛋白;RVFVsSgp2 N蛋白;RPVgp5 F;RPVgp6 H;VP2;VP4;VP6;VP7;S蛋白;env;来自辛德毕斯病毒的E2;TBEVgp1多蛋白;A27L;A33R;A34R;A36R;A4L;B5R;D8L;H5R;L1R;ORF67;ORF68;A21L;H3L;来自猴痘病毒扎依尔-96-I-16的L1R;26SmRNA;C-E3-E2-E1-6K;E1糖蛋白;E2包膜蛋白;糖蛋白;核衣壳;E蛋白;PrM;26S;6K;E1;E2;E(包膜糖蛋白);NS1(非结构蛋白1);11C5;12D3;21B4;RAP-1;CP15/60;CP23;gam56;Gam82;3-1E;3-1E;GX3262;MIC2;Rho;TA4;CEL-170/4;Gal/GalNAc凝集素;GEh29;SREHP;CWP2;CP半胱氨酸蛋白酶;Gp46;M2;P4;WD;A2;β-微管蛋白;BT1;F1-ATP合酶;GRP-78;HASPB1;Hsp70;KMP-11;MspC;NH;ORFF;P1;H1;HASPB1;LIPO-A;P36/LACK;SMT;Cpa;Cpb;Gp63;H2B;KMP-11;LACK;LmSTI1;PSA-2;SP;SW3.1;TSA;MIC10;NcDG1;NcDG2;NcMAG1;NcMIC1;NcPDI;NcSAG1;NcSRS2;ABRA;来自(伯氏疟原虫(P.berghei)、夏氏疟原虫(P.chabaudi)、恶性疟原虫(P.falciparum)3D7或诺氏疟原虫(P.knowlesi))的AMA-1;来自伯氏疟原虫ANKA菌株ANKA的CS;来自恶性疟原虫的CS;来自约氏疟原虫(P.yoelii)17XNL菌株的CS;来自诺氏疟原虫的CSP;eba-175;EMP1;GLURP;HEP17;来自约氏疟原虫的HSP60;Hsp90;Kβ;LSA-3;来自恶性疟原虫的MSP-1;来自伯氏疟原虫的MSP1;来自诺氏疟原虫的MSP1;来自间日疟原虫(P.vivax)的MSP1;来自约氏疟原虫17XNL菌株的MSP1;MSP3;MSP4/5;MSP8;PF10_0155烯醇化酶;pfCelTOS;Pvs25;RESA;SERA-5;SSP2;来自诺氏疟原虫的SSP2;来自恶性疟原虫的TRAP;SAG1;FABP;Il12a;副肌球蛋白;Sj23;TPI;钙蛋白酶;GPX;Sm23;SOD;Spag-1;TA17050裂殖子-梨浆虫表面抗原Tams1;P67;GRA1;GRA4;hsp70;MIC13;MIC3;MIC8;Rop2;ROP8;SAG1;SAG2;MAPP15;TSA;无鞭毛体表面蛋白-2;ASP-2;来自Tulahuen菌株的ASP-2;来自Y菌株的ASP-2;ASP1;CRP-10;克鲁兹蛋白酶(Cruzipain);G2;Par1;蛋白G4;Tc00.1047053434931.10;来自克鲁斯锥虫的Tc24;TS;来自Y菌株的TS;TSA-1;AMN1;ELI-Ag1;GEL1;PEP1;PLB;Pmp1;Para;TcrP;URE;Angpt1;Cd276;Cd86;Fas;Flt3;Il18;Il25;Il33;LPS脂多糖;Phl p 12(梯牧草(Phleum pratense);Phl p I过敏原[梯牧草];Phl p7蛋白[梯牧草];Tbx21;Tnfrsfl3b;Tnfrsf9;COL2A1;胶原蛋白II型;来自麻风分枝杆菌(M.leprae)的hsp65;ACPP;AFP;来自人类的AFP;ANTXR1;Ccl21a;Cd40lg;Cd80;Cd86;CEA;CEACAM3;CTAG1B;CTLA4;E2A;Eng;EPCAM;ERBB2;Fap;Fasl;FASLG;Flt3;Fosl1;来自破伤风毒素的片段C;GAST;GM-CSF;gp100;gp75;GPC3;GRP;H2-K1;热休克蛋白;hsp70;HuD;IgGFc;Il18;免疫球蛋白;KDR;KLK3;MAGE-1;MAGEA3;Mcam;MLANA;MUC1;Muc1;PAP;Pdgfrb;Pmel17;前列腺特异性抗原;前列腺干细胞抗原;前列腺特异性膜抗原;PSCA;SCFV;SCGB2A2;SILV;SLC5A5;Steap1;来自乙型肝炎的表面抗原;存活素(Survivin);TERT;TNFRSF18;TPBG;TRP-1;TRP-2;Trp2;Trp53;酪氨酸酶;来自小鼠的酪氨酸酶;TYRP1;泛素;VEGFA;WT1;BAX;Gad65;IgG Fc;来自豚鼠的MBP;Mog;来自人类的IRBP;蓖麻毒素A链。
根据另一个实施方案,所述抗原包括引起疾病(诸如上面列出的那些,但不限于)的源自热灭活/福尔马林灭活的整个生物体或生物体的提取物的抗原物质。
另外,本发明提供的实验数据表明,大肠杆菌素多肽是针对小鼠沙门氏菌感染的良好抗原。
对于本领域技术人员显而易见的是,本发明可用于任何特异性抗原,其中特异性中和抗体应答或特异性细胞免疫应答可用于消除与该抗原相关的生理或疾病状态。
附图说明
图1描绘了在实施例1中用于获得最终表达载体的pET-22b(+)载体(Novagen)的圆形图谱。所述pET-22b(+)载体携带有用于潜在周质定位的N端pelB信号序列,加上任选的C端序列。独特的位点显示在圆形图谱上。所述序列由pBR322习惯编号,因此T7表达区域在圆形图谱上是反向的。
图2A-2B显示了SDS-PAGE(2A)的照片,其中纯化的多肽用考马斯蓝染色;以及蛋白质免疫印迹(2B)的照片,其中单克隆抗体抗His-Tag用于确定蛋白质的同一性。泳道对应于:M:分子量标记物;1:经修饰的大肠杆菌素;2:经修饰的碱性蛋白酶抑制剂;3:经修饰的葡萄球菌半胱氨酸蛋白酶A;4:经修饰的葡萄球菌半胱氨酸蛋白酶B;和5:经修饰的Y抑制剂。
图3A-3B显示了树突状细胞(DC)的培养上清液中促炎细胞因子的产生。将BALB/c小鼠骨髓来源的DC与单独的OVA或OVA加不同浓度的表1的每种多肽(1、10或50μg/ml)一起孵育,并通过ELISA评估培养上清液中促炎细胞因子的产生。IL-6(3A)和TNF-α(3B)的产生以pg/ml表示。
图4说明了在BMDC的培养上清液中促炎细胞因子的产生。将来自C3H/HeJ小鼠的BMDC与不同浓度的表1的每种多肽(25、50或100μg/ml)一起孵育,并通过ELISA评估培养上清液中促炎细胞因子的产生。IL-6的产生以pg/ml表示。
图5A-5B显示了树突状细胞(DC)的培养上清液中促炎细胞因子的产生。将C57BL/6小鼠骨髓来源的DC与不同浓度的表1的每种多肽(10、50或100μg/ml)一起孵育,并通过ELISA评估培养上清液中促炎细胞因子的产生。TNF-α(5A)和IL-6(5B)的产生以pg/ml表示。
图6显示了通过流式细胞术测量的由特异性CD4+ T细胞产生的IFN-γ。将来自BALB/c小鼠的BMDC与培养基(RPMI)、单独的OVA或OVA加不同浓度的表1的每种多肽一起孵育,然后洗涤,并与来自DO11.10转基因小鼠的脾细胞共培养。细胞用布雷菲德菌素A(brefeldin A)处理。之后,收获细胞并用特异性抗体抗CD4染色,固定,透化并用抗IFN-γAb细胞内染色。结果表示为产生IFN-γ的CD4+ T细胞的百分比。
图7A-7D显示了在经修饰的大肠杆菌素、碱性蛋白酶抑制剂、葡萄球菌半胱氨酸蛋白酶A或葡萄球菌半胱氨酸蛋白酶B多肽与作为Ag的CTB口服共给药后诱导的Ag特异性抗体应答。在第0、7和14天免疫BALB/c小鼠。第二次免疫后第7天,通过ELISA评估粪便和血清中的特异性抗体应答(抗CT IgA和IgG)。结果表示为Vmax(平均值±SD)(毫单位/分钟)。
图8A-8D显示了在经修饰的大肠杆菌素、碱性蛋白酶抑制剂、葡萄球菌半胱氨酸蛋白酶A或葡萄球菌半胱氨酸蛋白酶B多肽与作为Ag的CTB口服共给药后诱导的Ag特异性抗体应答。在第0、7和14天免疫BALB/c小鼠。第三次免疫后第7天,通过ELISA评估粪便和血清中的特异性抗体应答(抗CT IgA和IgG)。结果表示为Vmax(平均值±SD)(毫单位/分钟)。
图9显示了与本发明的经修饰的多肽口服共给药后诱导的Ag特异性抗体应答。通过ELISA在不同时间点评估了抗大肠杆菌素IgG、抗碱性蛋白酶抑制剂IgG、抗葡萄球菌半胱氨酸蛋白酶A IgG、抗葡萄球菌半胱氨酸蛋白酶B IgG和抗Y抑制剂IgG的特异性抗体应答。结果表示为在450nm处的光密度。
图10A-10B显示了用TT加表1的每种多肽免疫的小鼠中对TT的延迟型超敏(DTH)应答。将TT注射到一个脚垫中,并将盐水注射到对侧脚垫中,作为阴性对照。在48h(10A)和72h(10B)之后测量两个脚垫的厚度,并绘制TT和注射的食盐水之间的增量。
图11显示了CD4+ T细胞的体内增殖。将来自DO11.10的CD4+ T细胞用CFSE标记并转移至WT BALB/c小鼠。口服给予小鼠盐水、OVA或OVA加表1的每种多肽。三天后,获得脾脏并通过流式细胞术分析细胞悬浮液的CFSE稀释度。数据表示为CD4+ CFSE+增殖性T细胞的百分比(平均值±SD)。
图12A-12D说明了CD8+ T细胞的体内增殖。将来自OT1小鼠的脾细胞用CFSE标记并转移至WT C57BL/6小鼠。口服给予小鼠盐水、OVA或OVA加表1的每种多肽。三天后,获得脾脏和MLN并通过流式细胞术分析细胞悬浮液的CFSE稀释度。结果显示为点图和代表性直方图(图12A和图12B)和柱状图(图12C-12D)。数据表示为CD8+ CFSE+增殖性T细胞的百分比。
图13A-13B说明了派尔集合淋巴结(Peyer’s Patches,PPs)(13A)和肠系膜淋巴结(MLN)(13B)细胞内Ag对蛋白水解的易感性降低。胃内给予小鼠(n=3/组)OVADQ加i)缓冲液,ii)经修饰的大肠杆菌素,iii)经修饰的碱性蛋白酶抑制剂或iv)经修饰的Y抑制剂一次。通过在荧光计中检测荧光来确定Ag状态。荧光增加与Ag降解成正比。结果表示为平均荧光强度(任意单位=a.u.)±SEM。
图14说明了经修饰的大肠杆菌素、碱性蛋白酶抑制剂、葡萄球菌半胱氨酸蛋白酶A、葡萄球菌半胱氨酸蛋白酶B和Y抑制剂多肽保护Ag免受肠提取物消化。抑制剂混合物和BSA分别为阳性和阴性对照。加入底物酪蛋白BODIPY FL,并在荧光板读数器中测量荧光强度。结果显示为平均蛋白水解活性%±SEM。★★★P<0.001相对BSA组。
图15说明了经修饰的大肠杆菌素、碱性蛋白酶抑制剂、葡萄球菌半胱氨酸蛋白酶A、葡萄球菌半胱氨酸蛋白酶B和Y抑制剂多肽保护Ag免受胃提取物消化。抑制剂混合物和BSA分别为阳性和阴性对照。加入底物酪蛋白BODIPY FL,并在荧光板读数器中测量荧光强度。结果显示为平均蛋白水解活性%±SEM。★★P<0.01,★★★P<0.001相对BSA组。
图16说明了经修饰的大肠杆菌素、碱性蛋白酶抑制剂、葡萄球菌半胱氨酸蛋白酶A、葡萄球菌半胱氨酸蛋白酶B和Y抑制剂多肽保护Ag免受胰酶消化。抑制剂混合物和BSA分别为阳性和阴性对照。加入底物酪蛋白BODIPY FL,并在荧光板读数器中测量荧光强度。结果显示为平均蛋白水解活性%±SEM。★P<0.05,★★P<0.01,★★★P<0.001相对BSA组。
图17A-17B显示了由大肠杆菌素多肽诱导的针对沙门氏菌感染的保护。结果表示为BALB/c小鼠的脾脏(17A)和肝脏(17B)中每克组织的CFU量,所述小鼠在第0、15和30天经胃内用生理溶液(SF)、大肠杆菌素(100μg)、大肠杆菌素(100μg)+CT(10μg)、大肠杆菌素(100μg)+U-Omp19(150μg),或腹膜内用大肠杆菌素(20μg)加弗氏不完全佐剂FIA-(100μL)进行免疫。
具体实施方式
本申请公开了显示免疫调节和免疫刺激特性的经修饰的多肽。所述经修饰的多肽为细菌来源的重组多肽。
如本文所用,术语“免疫调节(immunomodulating)”“免疫调节(immunomodulation)”是指通过抑制(免疫抑制剂)或增强(免疫刺激剂)改变免疫应答的试剂。免疫调节剂可定义为可刺激/抑制免疫系统先天的或适应性的或两者的任何生物或合成物质。
本发明人已经证明,本发明的经修饰的多肽可诱导树突状细胞(DC)的激活。因此,根据一个特定的实施方案,将本发明的多肽配制在药物组合物中以调节免疫应答。
根据另一个实施方案,本发明的经修饰的多肽为药物组合物的佐剂成分,用于引发针对所述药物组合物中存在的特定抗原的免疫应答。
如本文所用,术语“佐剂”是指掺入抗原(Ag)或与抗原(Ag)同时给予,诱导针对所述抗原的更有效免疫应答的物质。它们可以若干种方式用于增强针对Ag的免疫应答:它们可增强针对弱Ag的免疫应答的强度(magnitude);增加免疫应答的速度和持续时间,调节抗体(Ab)亲和力;同种型或亚类分布;刺激和调节细胞免疫应答;促进诱导局部免疫应答(例如粘膜)的诱导;减少必需的Ag量并降低疫苗成本;或者它们能有助于避免组合疫苗中存在的Ag能力(21)。
佐剂介导的免疫应答的增强可通过本领域已知的任何方法进行评估,包括但不限于以下一种或多种:(i)与单独用抗原免疫应答产生的抗体相比,用佐剂/抗原组合免疫应答产生的抗体数量增加;(ii)识别抗原或佐剂的T细胞的数量或激活状态增加;(iii)一种或多种细胞因子的水平增加;以及(iv)活体激发后的体内保护。
与单独用抗原激发的受试者相比,当用抗原和佐剂激发受试者时,如果抗原特异性免疫反应性的任何可测量参数(例如,抗体效价或T细胞产生)增加至少10%,则认为免疫应答增强。在本发明的某些实施方案中,如果抗原特异性免疫反应性的任何可测量参数增加至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少90%、至少95%、至少100%、至少125%、至少150%、至少175%、至少200%、至少225%、至少250%、至少275%、至少300%、至少350%、至少400%、至少450%、至少500%或至少1000%,则免疫应答增强。
如果在给予本发明的多肽而不给予抗原的受试者中,免疫反应性的任何可测量参数(例如细胞因子产生)增加至少10%,则认为非特异性免疫应答增强。在本发明的某些实施方案中,如果在给予本发明的多肽而不给予抗原的受试者中,免疫反应性的任何可测量参数增加至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少90%、至少95%、至少100%、至少125%、至少150%、至少175%、至少200%、至少225%、至少250%、至少275%、至少300%、至少350%、至少400%、至少450%、至少500%或至少1000%,则免疫应答增强。
如本发明所用,术语“抗原”为能够引发免疫应答并产生针对其的(特异性)抗体或细胞应答的物质或分子。
如本文所用,“免疫原”为可由免疫系统的成分(诸如抗体或淋巴细胞)特异性识别的抗原或任何物质。因此,免疫原能够诱导免疫应答,抗体或细胞免疫应答。
因此,出于本发明的目的,术语“免疫原”和“抗原”具有相同的含义,并且被定义为在免疫活性生物体中可诱导针对其的抗体或细胞免疫应答的任何物质。因此,两个术语在本文中可互换使用,即在本申请中,抗原被认为是免疫原的同义词。
根据一个优选的实施方案,所述抗原选自病原体衍生的抗原、肿瘤细胞抗原、自身抗原和过敏原。病原体衍生的抗原可来自细菌、病毒、寄生虫或真菌。
根据一个优选的实施方案,所述病原体衍生的抗原选自病毒抗原、细菌抗原、寄生抗原或真菌抗原。
如本文所用,自身抗原为被识别为非自身的但亲本生物体的健康免疫系统耐受的内源性抗原。
如本文所用,过敏原为能够诱导过敏反应的抗原的类型。
在另外的实施方案中,本发明涉及一种疫苗组合物,其包含a)一种或多种本文所述的多肽,b)抗原,以及c)药学上可接受的载体或稀释剂,其中a)和b)的组合的量可有效引发免疫应答。
疫苗为用作预防或治疗性给予以赋予针对特定疾病的免疫力的任何药学上可接受的制剂。
如本文所用,“疫苗组合物”为提供对特定疾病的主动获得性免疫的生物制剂。换言之,疫苗可用于在受体中引发保护性免疫。因此,与未接种的受试者相比,在给受试者已经接种抗原后,疫苗预防、延迟暴露于相同或相关抗原的受试者中疾病的发展或减轻疾病发展的严重性。由疫苗提供的保护性免疫可为体液(抗体介导的)免疫或细胞免疫或两者。疫苗接种可例如消除或减少病原体或感染细胞的载量,或产生任何其他可测量的感染的缓解。疫苗接种还可减少免疫(疫苗接种)受试者的肿瘤负荷。
疫苗通常含有类似于致病生物体的试剂,并且通常由灭活的或减弱的致病生物体(或关键片段、产物或衍生物)制成。通常,疫苗为含有活的、减毒的、经修饰的或灭活的生物体(或其毒素)或肿瘤抗原的悬浮液,将其给予到体内后刺激免疫系统以产生抗原特异性免疫应答、抗体和/或细胞免疫机制。
在进一步的方面,本发明涉及编码本发明的多肽的核酸序列。术语“核酸”是技术人员众所周知的,并且包括DNA(诸如cDNA)和RNA(诸如mRNA)。所述核酸可为双链或单链,线性或环状的。所述核酸分子优选包含在载体中,所述载体优选包含在宿主细胞中。所述宿主细胞例如,在用本发明的核酸序列转化或转染后能够表达所述多肽。为了这个目的,所述核酸分子与控制序列可操作地连接。
在进一步的方面,本发明涉及载体。载体为用作将(外源的)遗传物质转移到细胞中的媒介物的核酸分子。术语“载体”包括但不限于质粒、病毒、粘粒和人工染色体。通常,工程化载体包含复制起点、多克隆位点和选择性标记物。所述载体自身通常为核苷酸序列,通常为包含插入物(转基因)和用作载体“骨架”的较大序列的DNA序列。除了转基因插入物和骨架外,现有的载体可包含其他特征:启动子、遗传标记物、抗生素抗性、报告基因、靶向序列、蛋白质纯化标签。称为表达载体的载体(表达构建体)特别用于在靶细胞中转基因的表达,并且通常具有控制序列,诸如驱动转基因的表达的启动子序列。将载体插入到靶细胞通常被称为细菌细胞的“转化”,真核细胞的“转染”,尽管病毒载体的插入也称为“转导”。
在本发明中,序列用NdeI和XhoI限制性内切酶消化,并克隆到pET22b(+)载体(Novagen)中以获得最终表达载体。获得的载体用于转化大肠杆菌BL21(DE3)感受态细胞(Novagen;基因型:F-ompT hsdSB(rB-mB-)gal dcm(DE3))。
其他质粒也可用于将目的核苷酸序列引入到表达载体(诸如Pet-12a,pET-20b(+)等)。另外,其他表达系统可用于所述多肽的表达,诸如原核或真核蛋白表达系统(即细菌、酵母、植物、昆虫或哺乳动物细胞系统),甚至无细胞系统(即大肠杆菌提取物,胚芽小麦提取物)。另外,取决于选择的表达系统和最终的制剂,对于每个表达系统,可将序列克隆到其他载体中。
如本文所用,术语“宿主细胞”旨在指通过转化、转染等将编码本发明的多肽的核酸引入到其中的细胞。应当理解,这类术语不仅指特定的受试细胞,而且还指这类细胞的子代或潜在子代。因为由于突变或环境影响,某些修饰可在随后的世代中发生,所以这类子代实际上可能与亲代细胞不同,但仍包括在本文所用术语的范围内。
术语“宿主细胞”,“靶细胞”或“受体细胞”旨在包括可以是或已经/已经是载体或掺入的外源核酸分子,多核苷酸和/或蛋白质的受体的任何单个细胞或细胞培养物。它还旨在包括单细胞的子代,并且由于自然、偶然或故意的突变,所述子代不一定与原始亲本细胞完全相同(在形态或基因组或总DNA互补物)。细胞可为原核的或真核的,并且包括但不限于细菌细胞、酵母细胞、动物细胞和哺乳动物细胞,例如鼠、大鼠、猕猴或人。
合适的宿主细胞包括原核和真核宿主细胞,所述真核宿主细胞包括酵母、真菌、昆虫细胞和哺乳动物细胞。优选地,所述宿主细胞为来自大肠杆菌的BL21 DE3菌株。这些细胞是适用于转化和蛋白质表达的获自Novagen的化学感受态大肠杆菌细胞。
在一个替代的实施方案中,提供了包含本发明的多肽或根据本发明的方法产生的多肽的组合物。
本发明的特别优选的药物组合物包含一种或多种本发明的多肽。优选地,所述药物组合物包含合适的赋形剂或载体。在一个优选的实施方案中,所述药物组合物包含用于口服给药的组合物。
根据另一个实施方案,提供了用于诱导对任何抗原的免疫应答的组合物,所述组合物包含一种或多种本发明的多肽或根据本发明的方法产生的多肽。优选地,所述组合物为药物组合物。
如本文所用,术语“药物组合物”涉及用于给予受试者的组合物。
受试者,如本文所用,“受试者”意指任何动物受试者,包括哺乳动物受试者,诸如人类和驯养的哺乳动物。
如本文所公开,本发明的多肽可与任何生物学上相关的抗原结合而给予,从而获得对所述抗原的增强的免疫应答。在一个优选的实施方案中,本发明的经修饰的多肽和选择的抗原在包含有效量的多肽和有效量的选择的抗原的药物组合物中同时给予。给药方式优选为口服。多肽和抗原的各自用量将根据所采用的抗原同一性和将要免疫的动物种类而变化。因此,本发明的疫苗制剂组合物可通过将上述抗原与要求保护的多肽以所需比例混合来制备。所述制备应严格无菌进行,并且每种成分也应无菌。自然地,任何热原或过敏原都应尽可能地完全去除。
在一些实施方案中,本发明的组合物包含一种或多种药学上可接受的载体或赋形剂。赋形剂包括自身不诱导抗体产生并且对接受所述组合物的受试者无害的任何成分。合适的赋形剂通常是大的,缓慢代谢的大分子,诸如蛋白质、糖、聚乳酸、聚乙醇酸、聚合氨基酸、氨基酸共聚物、蔗糖、海藻糖、乳糖和脂质聚集体(诸如油滴或脂质体)。合适的药物载体是本领域普通技术人员众所周知的,包括但不限于稀释剂,诸如水、盐水、甘油等。适当地,无菌的无热原的磷酸盐缓冲生理盐水为药物载体。另外,可存在添加剂,诸如湿润剂或乳化剂,pH缓冲物质等。将本技术的疫苗配制成适合于将给予疫苗的受试者的剂量。所给予的剂量可随个体的病况、性别、体重和年龄;给药途径;和使用的抗原而变化。疫苗可以剂型(诸如悬浮液或液体溶液)使用。所述疫苗可与如上所述的药学上可接受的载体一起配制。
本发明的疫苗可为水性形式,例如但不限于溶液、颗粒或悬浮液。所述疫苗可为油和水乳剂,诸如水包油乳剂或油包水乳剂。液体制剂使所述组合物可预先包装并直接从其包装形式给予,无需重构。组合物可存在于小瓶中。
本发明的组合物可与液体或固体药物载体组合,并且所述组合物可为片剂、胶囊剂、粉剂、颗粒剂、混悬剂、糖浆剂、溶液,特别为水溶液的形式。所述组合物还可含有合适的防腐剂、着色剂和矫味剂或产生缓慢释放的试剂。可用于本发明的药物组合物的制剂的潜在载体包括但不限于明胶胶囊、糖、纤维素衍生物诸如羧甲基纤维素钠、明胶、滑石粉、硬脂酸镁、植物油诸如花生油等,甘油、山梨糖醇、琼脂和水。载体也可用作粘合剂以促进所述组合物的压片,以方便口服给药。
本发明的疫苗制剂组合物可通过冻干或通过本领域技术人员众所周知的其他方式保持在稳定的储存形式中以备使用。对于口服给药,所述疫苗制剂可在缓冲盐水、牛奶或任何其他生理相容性液体介质中重构成悬浮液。通过根据需要添加合适的着色剂和矫味剂可使制备的介质更可口。
本文中无论在何处使用的术语“和/或”均包括“和”,“或”和“由所述术语连接的要素的所有或任何其他组合”的含义。
如本文所用,术语“约(about)”或“约(approximately)”意指在给定数值或范围的±20%以内,优选地在±15%以内,更优选地在±10%以内,以及最优选地在±5%以内。
除非另有说明,否则一系列要素之前的术语“至少”应理解为是指所述系列中的每个要素。仅使用常规实验,本领域技术人员将认识到或能够确定本文所述的本发明的具体实施方案的许多等同方案。这些等同方案旨在被本发明所包括。
在整个说明书和随后的权利要求书中,除非上下文另有要求,否则词语“包括(comprise)”以及诸如“包括(comprises)”和“包含(comprising)”的变体将被理解为暗示包括在权利要求要素中未具体说明的任何要素、步骤或成分。当在本文中使用时,术语“包括”可用术语“含有(containing)”或“包括(including)”置换,或者有时当在本文中使用时可用术语“具有(having)”置换。
当在本文中使用时,“由……组成”排除未在权利要求要素中指定的任何要素、步骤或成分。当在本文中使用时,“基本上由……组成”不排除不实质性地影响权利要求的基本和新的特征的材料或步骤。
在本文的每个实例中,术语“包括”,“基本上由……组成”和“由……组成”中的任一个都可用其他两个术语中的任一个替换。
本申请通过以下实施例更好地说明,所述实施例不应被解释为限制本发明的范围。相反,应理解为,在不脱离本申请和所附权利要求的精神和范围的情况下,本领域技术人员可在阅读本发明之后对这些示例性实施方案提出修改和等同方案。
项
本发明可通过以下项进一步描述:
1.一种免疫调节和免疫刺激多肽,其具有选自SEQ ID NO.1、SEQ ID NO.2、SEQ IDNO.3、SEQ ID NO.4和SEQ ID NO.5的氨基酸序列。
2.根据项1的多肽,其中所述氨基酸序列为SEQ ID NO.1。
3.根据项1的多肽,其中所述氨基酸序列为SEQ ID NO.2。
4.根据项1的多肽,其中所述氨基酸序列为SEQ ID NO.3。
5.根据项1的多肽,其中所述氨基酸序列为SEQ ID NO.4。
6.根据项1的多肽,其中所述氨基酸序列为SEQ ID NO.5。
7.一种药物组合物,其包含(i)根据项1-6中任一项的多肽,以及任选地(ii)药学上可接受的赋形剂。
8.一种药物组合物,其包含(i)根据项1-6中任一项的多肽,(ii)一种或多种抗原以及任选地(iii)药学上可接受的赋形剂。
9.根据项8的药物组合物,其中所述抗原选自病毒、细菌、真菌、寄生物、肿瘤衍生的抗原、自身抗原和过敏原。
10.根据项7-9中任一项的药物组合物,以口服组合物的形式。
11.根据项7-9中任一项的药物组合物,以肠胃外组合物的形式。
12.一种疫苗,其包含(i)根据项1-6中任一项的多肽,(ii)抗原,以及任选地(iii)药学上可接受的赋形剂。
13.根据项12的疫苗,其中所述抗原选自病毒、细菌、真菌、寄生的和肿瘤衍生的抗原。
14.根据项12或13中任一项的疫苗,以口服组合物的形式。
15.编码根据项1-6中任一项的多肽的核酸序列,所述核酸序列选自SEQ ID NO.6至SEQ ID NO.10。
16.一种载体,其包含根据项15的核酸序列。
17.一种宿主细胞,其用项15所定义的核酸序列或用项16所定义的载体转化或转染,其中所述宿主细胞为原核或真核宿主细胞,诸如酵母菌、真菌、昆虫或哺乳动物细胞。
18.项1-6中任一项所定义的多肽,用作针对抗原的疫苗组合物的佐剂。
19.SEQ ID NO.1的多肽,用作药物组合物中的抗原。
20.项1-6中任一项所定义的多肽,用作药物组合物中的免疫调节剂。
21.项1-6中任一项所定义的多肽,用作疫苗组合物中抗原的药物递送试剂,其中所述多肽为增加疫苗组合物中抗原的半衰期的免疫调节和免疫刺激多肽。
22.项1-6中任一项所定义的多肽,用作药物组合物中的药物递送试剂。
23.一种在受试者中增强针对抗原的免疫应答的方法,包括给予所述受试者有效量的项7-11中任一项的药物组合物或项12-14中任一项的疫苗。
24.一种在受试者中调节针对抗原的免疫应答的方法,包括给予所述受试者有效量的项7-11中任一项的药物组合物或项12-14中任一项的疫苗。
25.一种在受试者中诱导对抗原的保护性免疫的方法,包括给予所述受试者至少一剂量的有效量的项1-6中任一项的一种或多种多肽。
26.一种在受试者中诱导对抗原的保护性免疫的方法,包括给予所述受试者至少一剂量的有效量的抗原和有效量的项1-6中任一项的一种或多种多肽。
27.一种在受试者中诱导保护性免疫的方法,包括给予所述受试者至少一剂量的有效量的项1-6中任一项的一种或多种多肽。
28.一种在受试者中调节免疫应答的方法,包括给予所述受试者有效量的项7-11中任一项的药物组合物或项12-14中任一项的疫苗。
29.一种非特异性刺激受试者免疫系统的方法,包括给予所述受试者有效量的项1-6中任一项的至少一种多肽或项7-11中任一项的药物制剂或项12-14的疫苗制剂。
30.项26、27、28或29的方法,其中所述方法选自通过口服或注射给予受试者项1-6中任一项的至少一种多肽或项7-11中任一项的药物制剂或项12-14的疫苗制剂。
31.项30的方法,其中所述药物制剂以片剂、混悬剂、溶液、乳剂、胶囊剂、粉剂、糖浆剂、饮用水组合物和进料组合物的形式给予。
实施例
实施例1-多肽的表达和纯化
将选自SEQ ID NO.6至SEQ ID NO.10的核苷酸序列用NdeI和XhoI限制性酶消化并克隆到pET22b(+)载体(Novagen,产品目录编号69744-3)中,(参见图1),以获得最终表达载体。获得的载体用于转化大肠杆菌BL21(DE3)感受态细胞(Novagen;基因型:F-ompT hsdSB(rB-mB-)gal dcm(DE3))。
所述核苷酸序列为:
1-来自沙门氏菌的无信号肽的经修饰的大肠杆菌素。SEQ ID NO.6
2-来自铜绿假单胞菌的经修饰的碱性蛋白酶抑制剂(无信号肽)。SEQ ID NO.7
3-来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶B。SEQ ID NO.8
4-来自金黄色葡萄球菌的经修饰的葡萄球菌半胱氨酸蛋白酶A。SEQ ID NO.9
5-来自幽门螺杆菌的经修饰的丝氨酸羧肽酶Y抑制剂。SEQ ID NO.10
根据供应商,pET22b(+)载体含有以下序列标记:
-T7启动子361-377
-T7转录起始360
-pelB编码序列224-289
-多克隆位点
-(Nco I-Xho I)158-225
-His·Tag编码序列140-157
-T7终止子26-72
-lacI编码序列764-1843
-pBR322起点3277
-bla编码序列4038-4895
-f1起点5027-5482
在N或C端含有His-Tag的重组多肽在感受态大肠杆菌(BL21 DE3)细胞中表达。将转化的细胞铺在LB+氨苄青霉素(100μg/ml)琼脂平板上并在37℃下孵育。然后,将菌落悬浮在37℃的LB加氨苄青霉素(100μg/ml),并在200rpm下震荡。测量600nm处的光密度(OD),并在OD 0.6-0.8时,在18℃(180rpm)下在16小时期间用IPTG(1mM)诱导细胞培养物。将细菌细胞培养物在4℃下以6000×g离心10分钟。沉淀(pellet)储存在-20℃。将细胞培养物沉淀悬浮在冰上超声处理(30秒的3个脉冲)的pH:8缓冲液(NaH2PO4 50mM,NaCl 300mM)中,并在14000×g下离心30分钟。由于多肽含有His-Tag,因此使用Ni-NTA琼脂糖柱通过FPLC纯化蛋白质。通过SDS-PAGE 15%(图2A),通过使用单克隆抗His-Tag抗体的蛋白质免疫印迹(图2B)和通过质谱(未显示)确认了蛋白质同一性。琼脂糖多粘菌素B吸附了来自多肽的LPS污染。内毒素的测定采用美洲鲎试剂(Limulus amebocyte lysate,LAL)显色测定法进行。使用的所有多肽制剂含有<0.1内毒素单位/mg蛋白质。
本发明的多肽的氨基酸序列示于下表1中。
表1
实施例2-具有免疫刺激特性的多肽
树突状细胞(DC)的成熟是诱导适应性免疫应答的关键步骤。因此,评估了SEQ IDNO.1-5的多肽在抗原存在下体外诱导DC成熟的能力。将来自野生型BALB/c骨髓来源的树突状细胞(BMDC)(CD11c+MHCII低)(1x106细胞/ml)用卵清蛋白抗原(OVA,纯化的鸡卵OVA等级V,来自Sigma)刺激18h或用OVA加不同浓度的(1、10或50μg/ml)表1的每种多肽刺激18h。然后培养上清液中促炎细胞因子的产生通过ELISA确定。与单独用OVA刺激相比,用OVA加SEQID NO.1的大肠杆菌素、SEQ ID NO.4的葡萄球菌半胱氨酸蛋白酶A(STA)、SEQ ID NO.3的葡萄球菌半胱氨酸蛋白酶B(STB)或SEQ ID NO.5的Y抑制剂(Y INH)刺激DC,诱导促炎细胞因子(IL-6和TNF-α)的显著产生(图3A和图3B)。这些结果表明,经修饰的大肠杆菌素、葡萄球菌半胱氨酸蛋白酶A(STA)、葡萄球菌半胱氨酸蛋白酶B(STB)和Y抑制剂(Y INH)多肽对DC具有免疫刺激活性。
实施例3-多肽诱导C3H/Hej小鼠中的树突状细胞激活
C3H/Hej小鼠对LPS无反应(22,23)。将来自C3H/HeJ小鼠的BMDC与不同浓度的SEQID NO.1-5的每种多肽单独以不同浓度(25、50或100μg/ml)孵育18h。然后,培养上清液中促炎细胞因子的产生通过ELISA评估。IL-6的产生以pg/ml显示。大肠杆菌素(SEQ ID NO.1)、碱性蛋白酶抑制剂(SEQ ID NO.2)和STA(SEQ ID NO.4)诱导C3H/Hej DC产生显著水平的促炎细胞因子(IL-6)(图4)。这些结果表明,经修饰的大肠杆菌素、碱性蛋白酶抑制剂和STA多肽以TLR4独立的方式激活DC。
实施例4-多肽诱导树突状细胞激活
评估了本发明的多肽在体外诱导树突状细胞(DC)的激活/成熟的能力。将来自C57BL/6小鼠骨髓来源的DC(BMDC)用不同浓度的表1的每种多肽(1、10或50μg/ml)孵育18h。然后培养上清液中促炎细胞因子的产生通过ELISA确定。与单独用培养基相比,用SEQ IDNO.1的大肠杆菌素,SEQ ID NO.2的碱性蛋白酶抑制剂,SEQ ID NO.4的葡萄球菌半胱氨酸蛋白酶A(STA),SEQ ID NO.3的葡萄球菌半胱氨酸蛋白酶B(STB)或SEQ ID NO.5的Y抑制剂(Y INH)刺激DC,诱导促炎细胞因子TNF-α的产生(图5A)。与单独用培养基相比,用SEQ IDNO.1的大肠杆菌素或SEQ ID NO.4的葡萄球菌半胱氨酸蛋白酶A(STA)诱导IL-6的产生(图5B)。这些结果表明,经修饰的大肠杆菌素、碱性蛋白酶抑制剂、葡萄球菌半胱氨酸蛋白酶A(STA)、葡萄球菌半胱氨酸蛋白酶B(STB)和Y抑制剂(Y INH)多肽对DC具有免疫刺激活性。
实施例5-多肽能够诱导效应CD4+ T细胞
为了研究SEQ ID NO.1-5的多肽是否具有促进效应特异性CD4+ T细胞应答的能力,DO11.10小鼠被用作OVA特异性CD4+ T细胞的来源。将来自BALB/c小鼠骨髓来源的树突状细胞(BMDC)(CD11c+MHCII低)(1x106)用完全培养基(RPMI),单独的OVA,OVA加每种多肽或OVA加LPS脉冲18小时,洗涤然后与来自DO11.10转基因小鼠的脾脏CD4+ T细胞(2x106个细胞)在37℃下共培养23h。在最后5小时期间,用布雷菲德菌素A处理细胞。之后,收获细胞并用特异性抗体抗CD4染色,固定,用皂苷透化,并用抗IFN-γAb进行细胞内染色。由特异性CD4+T细胞产生的IFN-γ通过流式细胞术测量。在图6中,结果表示为产生IFN-γ的CD4+ T细胞的百分比。用两种不同浓度(1和25μg/ml)的所有多肽孵育的DC诱导DO11.10CD4+ T细胞(范围为10%-13%的T细胞增殖)中IFN-γ产生的水平高于与单独OVA脉冲的DC共培养的T细胞(6.35%)。LPS处理的BMDC也诱导D011.10细胞强烈产生IFN-γ(48.6%)。这些结果表明,大肠杆菌素(SEQ ID NO.1)、碱性蛋白酶抑制剂(SEQ ID NO.2)、葡萄球菌半胱氨酸蛋白酶A(STA,SEQ ID NO.4)、葡萄球菌半胱氨酸蛋白酶B(STB,SEQ ID NO.3)或Y抑制剂(Y INH,SEQ ID NO.5)促进DC激活CD4+ T细胞。
实施例6-口服共给予多肽与抗原后,多肽诱导粘膜免疫应答
抗原特异性抗体(Ab)粘膜应答对于实现针对许多传染病的保护性应答很重要。为了测试SEQ ID NO.1-5的多肽引发Ab应答的能力,本发明人使用了来自霍乱弧菌的霍乱毒素亚单位B(CTB)和破伤风类毒素(TT)作为示例性疫苗Ag。目前,CTB用于口服霍乱疫苗的制剂中,用于人道主义紧急情况,以及TT用于抗破伤风疫苗。
根据以下方案,在第0、7和14天单独用CTB(5μg)或CTB加每种多肽(100μg),对2月龄的雌性BALB/c小鼠(n=5/组)经胃内进行免疫:i)CTB,ii)CTB+SEQ ID NO.1的大肠杆菌素,iii)CTB+SEQ ID NO.2的碱性蛋白酶抑制剂,iv)CTB+SEQ ID NO 4的葡萄球菌半胱氨酸蛋白酶A,v)CTB+SEQ ID NO.3的葡萄球菌半胱氨酸蛋白酶B或vi)CTB+SEQ ID NO.5的Y抑制剂。BALB/c小鼠的其它组(n=5/组)在第0、7和14天单独用TT(100μg)或TT加每种多肽(150μg)经胃内进行免疫。
每次免疫后1周收集粪便和血清,以评估诱导的特异性全身和粘膜抗体应答。粪便和血清的特异性抗体应答(抗CT或抗TT IgG和IgA)通过间接ELISA在不同的时间点进行评估。
在第二口服剂量的Ag加多肽后一周,评估抗体应答。在这个时间点,与来自单独CTB免疫的小鼠的抗CT IgA相比,经修饰的大肠杆菌素、碱性蛋白酶抑制剂、葡萄球菌半胱氨酸蛋白酶A或葡萄球菌半胱氨酸蛋白酶B多肽与CTB的口服共递送增加了粪便和血清中的抗CT IgA(图7A,7C)。此外,来自共给予CTB加STA或STB的动物粪便中的抗CT IgG增加(图7B),而在大肠杆菌素、STA、STB或Y抑制剂加CTB共递送的小鼠中血清中的CT特异性IgG增加(图7D)。第三次免疫后一周,与单独用CTB相比,来自口服共给予CTB加大肠杆菌素、碱性蛋白酶抑制剂、STA或STB的小鼠粪便中的CT特异性IgA增加(图8A)。在用CTB加大肠杆菌素或STB口服共递送的小鼠中粪便中的CT特异性IgG增加(图8B)。在共给予CTB加所有多肽的那些小鼠血清中CT特异性IgG增加(图8D)。总而言之,这些结果表明,将本发明的多肽加入到口服疫苗制剂增加了针对共递送抗原的粘膜和全身抗体应答。
血清中特异性抗体应答抗每种多肽IgG通过ELISA在不同时间点进行评估。在图9中,显示了抗大肠杆菌素IgG,抗碱性蛋白酶抑制剂IgG,抗葡萄球菌半胱氨酸蛋白酶A IgG,抗葡萄球菌半胱氨酸蛋白酶B IgG和抗Y抑制剂IgG OD结果。值得注意的是,未诱导出针对多肽的Ab应答。这是重要的,因为对于其他佐剂和递送系统的记载表明,针对其自身的抗体应答可能抑制后续效用。因此,这些结果将支持重复使用不同疫苗制剂中包含的本发明的多肽,从而避免该问题。
这些结果共同表明本发明的SEQ ID NO.1-5的多肽与抗原的共递送增加了针对共递送的Ag的Ag特异性粘膜以及全身Ab应答。
实施例7-口服共给予多肽与Ag之后,多肽诱导体内抗原特异性细胞免疫应答
在用TT加SEQ ID NO.1-5的每种多肽免疫的小鼠中评估了延迟型超敏应答(DTH)。简而言之,在最后一次免疫后三周,将20μg的Ag(TT)皮内注射到小鼠的一个脚垫中,并将等体积的盐水(作为阴性对照)注射到对侧脚垫中。在48和72小时后,使用具有0.01mm的精度的数字卡尺测量脚垫肿胀,并且将脚垫厚度的平均增加量(mm)计算为:(脚垫厚度)Ag-(脚垫厚度)盐水。
在48h时,与单独用TT免疫的小鼠相比,共给予经修饰的大肠杆菌素、碱性蛋白酶抑制剂、STA和Y抑制剂多肽的小鼠中TT特异性DTH增加(图10A),而在72h时,所有多肽均增加了TT特异性DTH(图10B)。这些结果表明,当与Ag共递送时,这些多肽能够在体内诱导抗原特异性细胞免疫应答。
实施例8-多肽在体内诱导Ag特异性T细胞的增殖
还进行了使用TCR转基因DO11.10或OTI小鼠的过继转移测定法,以确定在用OVA加SEQ ID NO.1-5的多肽口服免疫后,在体内转基因CFSE+标记的T细胞的主要抗原特异性克隆扩增。
来自DO11.10或OT-1小鼠的脾脏和淋巴结细胞的单细胞悬浮液用5μM CFSE标记。将标记的细胞(10x106)静脉内注射到野生型BALB/c性别匹配的受体中。一天后,转移的小鼠接受单次口服剂量的盐水,OVA(500μg)或OVA加每种多肽(250μg,通过灌胃法)。在免疫后三天,处死小鼠并获得脾细胞,并用抗CD4抗体标记,通过流式细胞术研究转基因CD4+ T细胞上CFSE的稀释度。OVA与大肠杆菌素和碱性蛋白酶抑制剂的共给予显示出脾脏中的特异性CD4+ T细胞增殖比单独用OVA免疫的小鼠更高(图11)。
向另一组WT C57BL/6小鼠转移来自用CFSE标记的OTI小鼠的脾细胞。一天后,口服给予小鼠盐水,OVA(1mg)或OVA加每种多肽(250μg)。三天后,获得脾脏和MLNs,并通过流式细胞术分析细胞悬浮液的CFSE稀释度。结果显示为点图,代表性直方图(图12A和图12B)和柱状图(图12C-12D)。数据表示为CD8+ CFSE+增殖性T细胞的百分比。与单独递送的OVA相比,OVA加大肠杆菌素、碱性蛋白酶抑制剂、STA、STB或Y INH的共给予提高了脾脏(12C)和MLN(12D)的CD8+T细胞增殖。这些结果表明,与Ag口服共给予的这些多肽增强了在全身(脾脏)和粘膜部位如MLN的体内Ag特异性CD8+ T细胞应答。
总而言之,这些结果表明多肽增加了针对共给予的Ag的CD4+和CD8+ T细胞免疫应答。
实施例9-多肽的口服递送限制了来自派尔集合淋巴结(PP)和肠系膜淋巴结(MLN)的细胞内共给予的Ag的蛋白水解
为了诱导适应性免疫应答,Ag必须到达胃肠道免疫系统的诱导部位(PP和MLN)。然后,重要的是Ag可抵抗肠道的恶劣环境(高度降解)。
OVADQ用作Ag,OVADQ被淬灭且其水解缓解了淬灭,生成亮绿色的荧光肽。荧光的增加与蛋白质消化成正比。将单独的OVADQ,OVADQ加SEQ ID NO.1-5的每种多肽或PBS胃内给予至BALB/c小鼠(n=3/组)。给予后6小时,处死小鼠,并去除PP和MLN。制备单细胞悬浮液,通过不锈钢筛过滤,并在PBS溶液中洗涤两次以去除任何细胞外的Ag,因此荧光测定与Ag消化成正比。使用台盼蓝(Trypan Blue)对总活细胞计数。在1x106个细胞中确定任意单位的荧光强度(FI)。
经修饰的大肠杆菌素的口服递送减少了其共给予后6h到达派尔集合淋巴结的降解Ag(OVA-DQ)的量(图13A)。以相同的方式,在口服共递送6h后,经修饰的大肠杆菌素和经修饰的Y抑制剂减少了在MLN处消化的OVA的量(图13B)。Ag的降解状态的降低可增加到达这些诱导部位的Ag的量。这将有助于减少制剂中需要的Ag量,从而降低成本。
实施例10-多肽保护共给予的Ag免受肠道恶劣环境的影响
研究了SEQ ID NO.1-5的多肽保护Ag免受胃或肠提取物消化的能力。使用小鼠胃和肠提取物或猪胰腺提取物评估在多肽存在下酪蛋白BODIPY的消化。在室温下,在适当的缓冲液中将不同量的提取物与不同量的多肽孵育1小时,然后加入底物(酪蛋白BODIPY,1μg/ml)。在荧光板读数器中测量荧光,并计算蛋白水解活性的百分比。
将肠提取物与缓冲液、每种多肽(1.25、6.25或12.5μg/ml)预孵育1h,抑制剂混合物(来自Sigma Aldrich,在DMSO的即用型溶液中含有AEBSF 104mM,抑肽酶80μM,苯丁抑制素(Bestatin)4mM,E-641.4mM,亮抑酶肽(Leupeptin)2mM和胃蛋白酶抑制剂(Pepstatin)A1.5mM)或BSA(12.5μg)分别作为阳性和阴性对照。然后,加入底物酪蛋白BODIPY FL(1μg/ml),并在荧光板读数器中测量荧光强度。结果在图14中显示为平均蛋白水解活性%±SEM。***P<0.001相对BSA组。
将胃提取物与缓冲液、每种多肽(3、31.2或62.5μg)预孵育1h,抑制剂混合物或BSA(62.5μg)分别作为阳性和阴性对照。然后,加入底物酪蛋白BODIPY FL(1μg/ml),并在荧光板读数器中测量荧光强度。结果在图15中显示为平均蛋白水解活性%±SEM。**P<0.01,***P<0.001对BSA组。
大肠杆菌素、碱性蛋白酶抑制剂和Y抑制剂能够降低肠提取物对Ag的消化,而只有Y抑制剂具有保护Ag免受胃提取物降解的能力。BSA对照在体外不抑制胃或肠提取物的蛋白水解活性,然而蛋白酶抑制剂混合物则可以抑制。
商业胰酶——一种通常用于体外消化率分析的由猪胰腺的外分泌细胞产生的蛋白酶的广谱混合物——用于评估Ag对这一内含物的易感性。将胰酶与缓冲液、每种多肽(5、10、20或40μg/ml)预孵育1h,抑制剂混合物或BSA(40μg)分别作为阳性或阴性对照。然后,加入底物酪蛋白BODIPY FL(1μg/ml),并在荧光板读数器中测量荧光强度。结果显示为平均蛋白水解活性%±SEM。*P<0.05,**P<0.01,***P<0.001相对BSA组。
结果表明,不同量的本发明的所有多肽可保护Ag(酪蛋白)免受猪胰腺提取物的消化(图16)。
总而言之,这些结果表明,通过口服途径共给予本发明的多肽与Ag可保护Ag通过胃肠道,从而增加了Ag在诱导部位:PP和MLN的细胞内的半衰期。
实施例11-口服疫苗制剂中的大肠杆菌素多肽保护小鼠免受沙门氏菌感染
BALB/c小鼠在第0、15和30天用生理溶液(SF),大肠杆菌素(100μg),大肠杆菌素(100μg)+CT(10μg),大肠杆菌素(100μg)+U-Omp19(150μg)进行胃内免疫,或用大肠杆菌素(20μg)加弗氏不完全佐剂FIA-(100μL)进行腹膜内免疫。在最后一次免疫后30天,通过腹膜内注射用有毒的沙门氏菌4208激发动物。四天后,杀死动物,将脾脏和肝脏均质化并铺在琼脂加链霉素中,以评估每克组织的CFU量。
结果表明,单独递送的大肠杆菌素,加CT或FIA不能诱导针对沙门氏菌感染的保护作用。但是,与单独递送SF或大肠杆菌素相比,当与佐剂U-Omp19(来自流产布鲁氏菌的无脂外膜蛋白)共配制并口服给予时,它会诱导脾脏(图17A)和肝脏(图17B)中的CFU量显著降低。如先前报道的那样,单独的Omp19不能诱导针对沙门氏菌的保护作用(24),本发明的结果表明,当与Omp19共配制时,大肠杆菌素是针对沙门氏菌的疫苗制剂的良好Ag。
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<223> 来自金黄色葡萄球菌(Staphylococcus aureus)的经修饰的葡萄球菌半胱氨酸蛋白酶A
<400> 4
Met His His His His His His Glu Gln Phe Glu Leu Phe Ser Ile Asp
1 5 10 15
Lys Phe Lys Cys Asn Ser Glu Ala Lys Tyr Tyr Leu Asn Ile Ile Glu
20 25 30
Gly Glu Trp His Pro Gln Asp Leu Asn Asp Ser Pro Leu Lys Phe Ile
35 40 45
Leu Ser Thr Ser Asp Asp Ser Asp Tyr Ile Cys Lys Tyr Ile Asn Thr
50 55 60
Glu His Lys Gln Leu Thr Leu Tyr Asn Lys Asn Asn Ser Ser Ile Val
65 70 75 80
Ile Glu Ile Phe Ile Pro Asn Asp Asn Lys Ile Leu Leu Thr Ile Met
85 90 95
Asn Ile Glu Ala Leu Gly Thr Ser Pro Arg Met Thr Phe Ile Lys His
100 105 110
Lys Ser
<210> 5
<211> 191
<212> PRT
<213> 人工序列
<220>
<223> 来自幽门螺杆菌(Helicobacter pylori)的经修饰的丝氨酸羧肽酶Y抑制剂
<400> 5
Met Lys Thr Phe Glu Val Met Ile Gln Thr Asp Ser Glu Gly Tyr Leu
1 5 10 15
Asp Ala Lys Phe Gly Gly Asn Ala Pro Arg Gly Phe Leu Asn Pro Asn
20 25 30
Gly Leu Pro Thr Tyr Ser Pro Lys Ile Ser Trp Gln Lys Val Glu Gly
35 40 45
Ala Gln Ser Tyr Ala Leu Glu Leu Ile Asp His Asp Ala Gln Lys Val
50 55 60
Cys Gly Met Ser Phe Ile His Trp Val Val Gly Asn Ile Ser His Asn
65 70 75 80
Val Leu Glu Glu Asn Ala Ser Met Met Asp Lys Arg Ile Thr Gln Gly
85 90 95
Val Asn Ser Leu Thr Gln Gly Phe Ile Arg Ser Pro Leu Asn Glu Ser
100 105 110
Glu Lys Gln Arg Ser Asn Leu Asn Asn Ser Val Tyr Ile Gly Pro Met
115 120 125
Pro Pro Asn Gly Asp His His Tyr Leu Ile Gln Val Tyr Ala Leu Asp
130 135 140
Ile Pro Lys Leu Ala Leu Lys Ala Pro Phe Phe Leu Gly Asp Leu His
145 150 155 160
Asp Lys Met Arg Asn His Ile Ile Ala Ile Gly Arg Lys Glu Phe Leu
165 170 175
Tyr Lys Gln Phe Met Arg Lys Leu Glu His His His His His His
180 185 190
<210> 6
<211> 447
<212> DNA
<213> 人工序列
<220>
<223> 编码来自沙门氏菌(Salmonella)的无信号肽的经修饰的大肠杆菌素的核苷酸序列
<400> 6
catatggcta acaatggcga taccgcccag ccgctggaaa aaatcgcccc ctatccgcag 60
gcggaaaaag gaatgaagcg gcaagtgata acccttaccc ctcagcagga tgaatctacc 120
ctcaaagtgg aactgttgat tggccaaacg ctgaatgtgg attgtaacca gcatcgcctc 180
ggcggcacgc tggaaacaaa aacgctggaa ggctggggct atgactatta tgtctttgat 240
aacgtcacct ctccggtatc aaccatgatg gcctgccctg aaggtaagaa agagcaaaaa 300
ttcgtcaccg cctggctggg tgaagacggg atgctgcgct acaacagcaa gctgccgatc 360
gtggtgtata ccccggcgaa tgtggacgtg aaataccgca tctggaaagc ggacgctaac 420
gtacagaacg ccgtcgcgcg actcgag 447
<210> 7
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> 编码来自铜绿假单胞菌(Pseudomonas aeruginosa)的的经修饰的碱性蛋白酶抑制剂(无信号肽)的核苷酸
<400> 7
catatggcca gcagtctgat tcttctcagc gcttccgatc tcgccgggca atggaccctg 60
cagcaggacg aggcgcccgc gatctgccac ctggagctgc gcgacagcga agtggcggaa 120
gccagtggct acgacctggg cggcgatacc gcctgcctca cgcgctggct gcccagcgag 180
ccgcgcgcct ggaggcctac cccggccggg atcgcgctgc tcgaacgcgg cggcctgacc 240
ctgatgctcc tcggtcgcca gggcgagggc gactaccggg tgcagaaggg cgacggcggg 300
cagttggtgc tgcgccgcgc gacgcccctc gag 333
<210> 8
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 编码来自金黄色葡萄球菌(Staphylococcus aureus)的经修饰的葡萄球菌半胱氨酸蛋白酶B的核苷酸
<400> 8
catatgcacc accaccacca ccactatcaa ctacaattta taaatttagt ttacgacaca 60
accaaactca cacatctaga acaaaccaat atcaatttat tcattggtaa ttggagtaat 120
catcaattac aaaaatcaat ttgtatacgt catggcgatg atacaagtca caatcaatat 180
catattcttt ttatagatac ggcacatcaa cgcattaaat tttcatctat tgataatgaa 240
gaaatcattt atattcttga ttatgatgat acacagcata tcctcatgca aacgtcatcc 300
aaacaaggta ttggcacttc gcgcccaatc gtttatgagc gcttagtata actcgag 357
<210> 9
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 编码来自金黄色葡萄球菌(Staphylococcus aureus)的经修饰的葡萄球菌半胱氨酸蛋白酶A的核苷酸
<400> 9
catatgcacc accaccacca ccacgaacaa tttgaattat ttagtattga taaattcaaa 60
tgtaattcag aggctaagta ttatcttaat attattgagg gagaatggca tcctcaagat 120
ttaaatgata gccctttaaa atttattctc agtacctcag acgattctga ttacatttgc 180
aaatatataa atacagaaca caaacaactc acattatata ataaaaataa tagctcaatt 240
gttattgaaa tatttatacc aaatgataat aaaatactac taacaattat gaacatagaa 300
gctttaggaa cttctcctag aatgactttc attaagcata aaagttaact cgag 354
<210> 10
<211> 558
<212> DNA
<213> 人工序列
<220>
<223> 编码来自幽门螺杆菌(Helicobacter pylori)的经修饰的丝氨酸羧肽酶Y抑制剂的核苷酸
<400> 10
catatgaaaa cttttgaagt gatgattcaa accgattcag aagggtattt ggacgctaaa 60
tttggcggta acgctcctag agggtttctc aatccaaacg gcttacccac ttattcgcct 120
aaaatctcat ggcaaaaagt agaaggtgct caaagctatg cgttagaact tattgatcat 180
gacgcgcaaa aagtgtgcgg catgtcgttt atccattggg tcgtgggcaa tatctctcat 240
aatgttttag aagaaaacgc ctccatgatg gataaaagga ttactcaagg ggtcaattcg 300
cttactcaag gctttatccg ttctcctctt aatgaaagcg aaaaacaacg ctccaatctc 360
aataacagcg tctatatcgg ccccatgcct cctaatggcg atcaccatta cttgattcaa 420
gtgtatgccc tagacattcc taaactcgcc ttaaaagccc cttttttctt aggcgatttg 480
catgacaaaa tgcgcaacca tatcatcgcc atagggagaa aggaatttct atacaagcag 540
tttatgagga aactcgag 558
Claims (31)
1.一种免疫调节和免疫刺激多肽,其具有选自SEQ ID NO.1、SEQ ID NO.2、SEQ IDNO.3、SEQ ID NO.4和SEQ ID NO.5的氨基酸序列。
2.根据权利要求1的多肽,其中所述氨基酸序列为SEQ ID NO.1。
3.根据权利要求1的多肽,其中所述氨基酸序列为SEQ ID NO.2。
4.根据权利要求1的多肽,其中所述氨基酸序列为SEQ ID NO.3。
5.根据权利要求1的多肽,其中所述氨基酸序列为SEQ ID NO.4。
6.根据权利要求1的多肽,其中所述氨基酸序列为SEQ ID NO.5。
7.一种药物组合物,其包含(i)根据权利要求1-6中任一项的多肽,以及任选地(ii)药学上可接受的赋形剂。
8.一种药物组合物,其包含(i)根据权利要求1-6中任一项的多肽,(ii)一种或多种抗原,以及任选地(iii)药学上可接受的赋形剂。
9.根据权利要求8的药物组合物,其中所述抗原选自病毒、细菌、真菌、寄生的、肿瘤衍生的抗原、自身抗原和过敏原。
10.根据权利要求7-9中任一项的药物组合物,以口服组合物的形式。
11.根据权利要求7-9中任一项的药物组合物,以肠胃外组合物的形式。
12.一种疫苗,其包含(i)根据权利要求1-6中任一项的多肽,(ii)抗原,以及任选地(iii)药学上可接受的赋形剂。
13.根据权利要求10的疫苗,其中所述抗原选自病毒、细菌、真菌、寄生的和肿瘤衍生的抗原。
14.根据权利要求11的疫苗,以口服组合物的形式。
15.编码根据权利要求1-6中任一项的多肽的核酸序列,所述核酸序列选自SEQ IDNO.6至SEQ ID NO.10。
16.一种载体,其包含根据权利要求15的核酸序列。
17.一种宿主细胞,其用权利要求13所定义的核酸序列或用权利要求14所定义的载体转化或转染,其中所述宿主细胞为原核或真核宿主细胞,诸如酵母菌、真菌、昆虫或哺乳动物细胞。
18.权利要求1-6中任一项所定义的多肽,用作针对抗原的疫苗组合物的佐剂。
19.SEQ ID NO.1的多肽,用作药物组合物中的抗原。
20.权利要求1-6中任一项所定义的多肽,用作药物组合物中的免疫调节剂。
21.权利要求1-6中任一项所定义的多肽,用作疫苗组合物中抗原的药物递送试剂,其中所述多肽为增加疫苗组合物中抗原的半衰期的免疫调节和免疫刺激多肽。
22.权利要求1-6中任一项所定义的多肽,用作药物组合物中的药物递送试剂。
23.一种在受试者中增强针对抗原的免疫应答的方法,包括向所述受试者给予有效量的权利要求7-11中任一项的药物组合物或权利要求12-14中任一项的疫苗。
24.一种在受试者中调节针对抗原的免疫应答的方法,包括向所述受试者给予有效量的权利要求7-11中任一项的药物组合物或权利要求12-14中任一项的疫苗。
25.一种在受试者中诱导对抗原的保护性免疫的方法,包括向所述受试者给予至少一剂量的有效量的权利要求1-6中任一项的一种或多种多肽。
26.一种在受试者中诱导对抗原的保护性免疫的方法,包括向所述受试者给予至少一剂量的有效量的抗原和有效量的权利要求1-6中任一项的一种或多种多肽。
27.一种在受试者中诱导保护性免疫的方法,包括向所述受试者给予至少一剂量的有效量的权利要求1-6中任一项的一种或多种多肽。
28.一种在受试者中调节免疫应答的方法,包括向所述受试者给予有效量的权利要求7-11中任一项的药物组合物或权利要求12-14中任一项的疫苗。
29.一种非特异性刺激受试者免疫系统的方法,包括向所述受试者给予有效量的权利要求1-6中任一项的至少一种多肽或权利要求7-11中任一项的药物制剂或权利要求12-14的疫苗制剂的步骤。
30.权利要求26、27、28或29的方法,其中所述方法选自向受试者口服或注射给予权利要求1-6中任一项的至少一种多肽或权利要求7-11中任一项的药物制剂或权利要求12-14的疫苗制剂。
31.权利要求30的方法,其中所述药物制剂以片剂、混悬剂、溶液、乳剂、胶囊剂、粉剂、糖浆剂、饮用水组合物和进料组合物的形式给予。
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PCT/IB2019/051026 WO2019155415A1 (en) | 2018-02-09 | 2019-02-08 | Immunomodulating and immunostimulating polypeptides for drug-delivery |
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CN113144182A (zh) * | 2021-04-22 | 2021-07-23 | 成都亿妙生物科技有限公司 | 一种幽门螺杆菌口服缓释疫苗及其制备与应用 |
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AR114683A1 (es) | 2020-10-07 |
EP3749364A1 (en) | 2020-12-16 |
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