CN109806388B - 免疫调节疫苗 - Google Patents
免疫调节疫苗 Download PDFInfo
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- CN109806388B CN109806388B CN201811267771.1A CN201811267771A CN109806388B CN 109806388 B CN109806388 B CN 109806388B CN 201811267771 A CN201811267771 A CN 201811267771A CN 109806388 B CN109806388 B CN 109806388B
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Abstract
本发明涉及一种免疫调节疫苗。具体来说,本发明涉及一种免疫刺激疫苗,其包括‑导向佐剂,其包括连接至TLR9配体和第一肽α‑螺旋的至少抗CD32部分,和‑免疫原,其具有至少一个表位和与第一α‑螺旋缠绕的第二肽α‑螺旋,一种用于制备疫苗的试剂盒,和一种致敏疫苗,其包括在药物制剂中的连接至TLR9配体和肽的α‑螺旋的至少抗CD32部分。所述疫苗用于胃泌素依赖性疾病的免疫治疗。
Description
本申请是申请日为2013年7月2日、申请号为201380037510.X、发明名称为免疫调节疫苗的申请的分案申请。
技术领域
本发明涉及免疫调节疫苗,其包括免疫原和与之连接、由此调节对免疫原的免疫应答的导向佐剂(directed adjuvant)。本发明进一步涉及包括免疫原性组合物的疫苗,所述免疫原性组合物包括
-导向佐剂,其至少包括连接至TLR9配体的抗CD32部分,和
-免疫原,其结合至所述导向佐剂;
其用于治疗受试者以诱发针对免疫原的瞬时IgG免疫应答。
背景技术
对于包括变态反应(allergy)、癌症和自身免疫病等的免疫疾病,由Th1/Th2/Th17/Treg细胞调节的免疫平衡调节及其在新免疫治疗开发中的应用起到重要作用。
Th1细胞(1型辅助T细胞)的特征在于产生促炎性细胞因子如IFN-γ、IL-2和TNF-β。Th1细胞参与细胞介导的免疫。由Th1细胞产生的细胞因子刺激微生物病原体的吞噬和破坏。几种慢性炎性疾病已描述为Th1主导的疾病,即多发性硬化症、糖尿病和类风湿性关节炎。
Th2细胞(2型辅助T细胞)的特征在于产生IL-4、IL-5、IL-9、IL-10和IL-13。Th2细胞被认为在变态反应响应中起作用。细胞因子如IL-4通常刺激抗体的产生。IL-5刺激嗜酸性细胞应答,也是免疫应答的一部分。特应性(atopy)和变态反应被认为是Th2主导病况。
Th1/Th2或Th17/Treg免疫失衡成为各种免疫疾病的原因。
变态反应被认为是对环境中的蛋白质的超敏反应。变应原(allergen)为特应性患者在IgE抗体应答随后导致变态性反应下应答的抗原。复合体或融合蛋白中的抗原可为环境变应原(如室尘螨(house dust mite)、桦树花粉(birch pollen)、草的花粉(grasspollen)、猫抗原、蟑螂抗原),或食品变应原(如牛奶、花生、虾、大豆),或二者的组合。IgE分子因其在效应细胞(肥大细胞、嗜碱性粒细胞(basophiles)和嗜酸性粒细胞(eosinophiles))激活中的作用而是重要的。普遍接受的是,IgE还通过上调B细胞和树突细胞(DC)的抗原捕获潜能(二者借助于低亲和性受体(CD23)和高亲和性受体(FcεRI))而在变态反应性疾病的诱导阶段起到重要作用。IgE抗体的消极作用可由变应原特异性IgG抗体抵消,例如因为它们引导免疫应答远离B细胞转向单核细胞和DC,且它们能够通过这些细胞上的FcεRI与FcγRIIb(CD32b)共交联来下调IgE受体介导的效应细胞的活化。另外,它们与IgE分子竞争变应原结合位点。由此,可通过变应原特异性IgG分子(特别是IgG1)的诱导而治疗、治愈和预防变态反应。
与IgE分子的大致3天的血清半衰期相比,IgG分子具有大约3周的血清半衰期。IgE分子通过B细胞和Th2细胞之间的相互作用诱导,这提供IL-4和IL-13并伴随CD40L表达,这在记忆B细胞和浆细胞中是将类别开关(classswitch)诱导为IgE所必需的。相反,产生IFN-γ和IL-2的Th1细胞将类别开关诱导为IgG。因此,Th1而不是Th2辅助T细胞对变应原应答的诱导有益于预防、治疗和治愈变态反应性疾病。
迄今为止,使用变应原的若干种主动免疫得到应用。最常见的是所谓的"免疫治疗",其依赖于以相对高浓度的变应原频繁免疫。该技术仅在少数变态反应性疾病如蜂毒变态反应以及在鼻炎和结膜炎的某些情况中适度有效,最近某些报道已显示在较温和形式的哮喘和过敏性皮炎中的有效性。更近一些,已施用其中将增加量的变应原在相当短的时间范围内注射的快速免疫治疗,其结果稍胜一筹。通常,皮下途径用于变应原给药,但最近该途径已与口服或者甚至局部施用进行了比较,结果一般是阳性的,但并不总是一致。不同的免疫治疗技术为Saint-Remy描述的一种技术(EP0178085和EP0287361),其中使用了在体外与相关变应原复合的自身IgG抗体。该技术允许施用相当少量的变应原,并具有较少的副作用。
这些治疗背后的机理尚未清楚。在传统治疗中,如果该治疗诱导特异性IgG抗体增加,则似乎存在有益效果,尽管不是每种特异性IgG的显著增加都与成功的免疫治疗相关。之所以如此的可能观点是IgG抗体对B细胞、单核细胞和肥大细胞上的CD32的亲和性相对低。Saint-Remy法从患者选择特异性IgG抗体,随后将其于相关的变应原体外混合。这样,它们确保变应原不能与细胞或细胞上的其它抗体同种型如肥大细胞上的IgE自由反应。另外,它们声称抗独特型(anti-idiotypic)抗体相对于特异性IgG分子升高,其此后会防止变态反应。
在WO 97/07218中记载了变应原-抗CD32融合蛋白。在该公报中,避免了分离特异性IgG分子和这些IgG抗体对CD32的亲和性低的问题,并且降低了使用完整的“IgE结合”变应原的传统免疫治疗的风险因素。然而,所声称的由于将含抗CD32的疫苗单独导向到树突细胞所造成的Th1记忆应答的诱导并没有被证实。
WO2007098934A1描述了能够结合至TLR9和CD32的包括至少一个抗原的至少一个表位的分子,其生产和其作为药剂的用途,特别是用于变态反应治疗的用途。
免疫调节不仅可在变态反应性疾病的情况下起作用,而且还可在一系列其它疾病中起作用。
增强对感染剂(infectious agents)如微生物病原体的免疫应答是预防性或治疗性抗感染免疫治疗的目标。
在肿瘤免疫治疗中,目标也是使用除了细胞毒性T淋巴细胞(CTL)以外的肿瘤抗原特异性T辅助型1(Th1)细胞。
医学上已知为恶性赘生物的癌症是一组广泛的各种疾病,它们全部涉及没有调节的细胞生长。在癌症中,细胞不可控制地分裂和生长,形成恶性肿瘤,并侵袭身体的附近部位。癌症还可通过淋巴系统或血流扩散至身体更远的部位。并不是所有的肿瘤都是癌性的。良性肿瘤不是不可控地生长,不侵袭近旁组织,且不扩散至全身。有超过200种折磨人类的不同已知癌症。
确定癌症的原因是复杂的。已知许多东西增加癌症的风险,包括使用烟草、某些感染、辐射、缺乏身体运动、肥胖症和环境污染物。这些可直接损伤基因或与细胞内已存在的遗传缺陷组合而引起疾病。大约5至10%的癌症是完全遗传的。
癌症可以以多种方式检测,包括某些体征和症状的存在、筛选试验或医学影像。一旦检测到可能的癌症,通过组织样品的镜检来诊断。癌症通常用化学治疗、辐射治疗和手术治疗。疾病生存的几率根据癌症的类型和位置以及开始治疗时疾病的程度而大幅变化。虽然癌症可影响所有年龄的人群,并且少数类型的癌症更常见于儿童中,但癌症发展的风险通常随年龄增加。2007年,全球范围内癌症导致全部人类的约13%死亡(790万)。比例随着更多人群的老龄化和随着在发展世界中发生大众生活方式的改变而升高。
由于免疫系统基于自身与非自身之间的区别而对其遭遇的环境因素应答,所以因癌症发病而出现的多种肿瘤细胞或多或少地耐受患者的自身免疫系统,这是因为肿瘤细胞本质上是在没有适当地调节控制下生长、分裂和扩散的患者自身的细胞。
免疫耐受或免疫学耐受为免疫系统不攻击抗原的过程。在天然耐受或自身耐受中,身体不增加对自体抗原(self-antigen)的免疫应答。其以三种形式出现:中枢耐受、外周耐受和获得的耐受。
中枢耐受1 :
中枢耐受发生在淋巴细胞发育期间并在胸腺和骨髓中运行。这里,识别自体抗原的T和B淋巴细胞在它们发育成完全免疫活性细胞之前被删除,防止自身免疫。该过程在胎儿生命中最活跃,但随着不成熟淋巴细胞的产生而贯穿整个生命继续进行。
外周耐受2:
外周耐受为在T和B细胞成熟后发展并进入外周的免疫学耐受。离开胸腺的T细胞相对但不是完全安全。某些将具有可对自体抗原响应的受体(TCRs),所述自体抗原以足够高的浓度存在,以致它们能够结合至在胸腺中T细胞不会遇到的"弱"受体(例如,组织特异性分子,诸如朗格罕氏岛(islets of Langerhans)、脑或脊髓中的那些)。胸腺中逃脱胸腺内阴性选择的那些自身反应性T细胞可造成细胞损伤,除非它们被删除或被有效地控制在外周组织中。已知存在沉默此类潜在自身反应性T细胞的几种反馈机制。它们包括下述:无变态反应性(anergy)、活化诱导的细胞死亡、外周抑制。
获得的或诱导的耐受3:
获得的或诱导的耐受是指免疫系统对外部抗原的适应,其特征在于胸腺组织对在其它环境中会很可能诱导细胞介导的免疫或体液免疫的给定抗原的特异的非反应性。最重要的天然类型的获得的耐受之一为妊娠免疫耐受,此时胎儿和胎盘必须被母体免疫系统耐受。
靶向肿瘤相关抗原的免疫治疗:
癌症免疫治疗是使用免疫系统来排斥癌症。主要的前提是刺激患者的免疫系统来攻击引起疾病的恶性肿瘤细胞。这可通过患者的主动免疫(例如,通过给药细胞癌症疫苗,如普罗文奇(Provenge),Dendreon,西雅图,华盛顿,US)4来进行,在该情况中患者的自身免疫系统训练为识别肿瘤细胞作为要摧毁的靶标,或者通过给药治疗性抗体作为药物来进行,在该情况中患者的免疫系统被招募来通过治疗性抗体来破坏肿瘤细胞。活化患者免疫系统对抗肿瘤的另一方法为使用所谓的肿瘤相关抗原(TAA’s),该肿瘤相关抗原为自身蛋白质,其在健康正常细胞中在一定程度上表达,但在肿瘤细胞中过表达,或者它们包括使肿瘤细胞增殖的细胞激素/生长因子5。这些TAAs制成制剂并以免疫原性的方式呈递至体内,以使免疫系统将建立应答,尽管事实是这些蛋白质是自身的。很明显,该方法仅对患者已发育外周或获得的耐受所对抗
的TAAs有用。当识别TAA的T和B细胞已从免疫学组库(immunologicalrepertoire)中删除时,主动癌症免疫治疗并不是一个选项。
胃泌素:
可用作治疗消化系统癌症(gastro intestinal cancers)如胰腺癌的靶标的自身抗原(autoantigen)(激素/生长因子)的实例为小胃泌素(little gastrin)(G17)6-9。另外,G17的中和还可有益于任意胃泌素相关的病况,包括胃溃疡、胃食管反流病(GastroEsophageal Reflux Diseas,GERD)10,这是由于胃的pH受胃泌素调控,而对于终末期肾衰竭(End Stage Renal Failure,ESRF)11,则是由于在ESRF患者中胃泌素在高于正常浓度下循环。
US5023077描述了免疫原性组合物和用于治疗和预防胃和十二指肠溃疡病的方法,该免疫原性组合物基于胃泌素肽,该胃泌素肽偶联至免疫原性载体,例如白喉类毒素、破伤风类毒素、钥孔戚血蓝蛋白(keyhole limpet hemocyanin)或牛血清白蛋白。
胃泌素在胃肠道具有一些重要的功能,两个最重要的是刺激胃肠道中的酸分泌和刺激胃肠道中的细胞生长。激素以至少两种分子形式存在,十七胃泌素(heptadecagastrin),所谓的小胃泌素("G17"),和三十四胃泌素(tetratriacontagastrin)("G34"),其根据每个分子中的氨基酸残基("AA")数命名,其中G17构成G34的17个氨基末端("N-末端")。
US5609870描述了抗-G17免疫原的制备,这在哺乳动物中产生抗其自身G17的不与G34反应的抗体,所述制备包括使由对应于G17的N末端氨基酸序列直至其C末端的氨基酸残基数为12的片段序列组成的肽缀合至间隔子肽,所述间隔子肽缀合于免疫原性载体如白喉类毒素、破伤风类毒素、钥孔戚血蓝蛋白或牛血清白蛋白。
免疫平衡:
受Th1/Th2/Th17/Treg细胞调控的免疫平衡在免疫治疗开发中扮演重要作用。
自身免疫病中需要调控Th1/Th2/Th17/Treg失衡,即,在免疫系统攻击自身组织的情况下。
TLR9的作用:
Toll-样受体(TLRs)是一类在固有免疫系统中起到关键作用的蛋白质。它们是单链、跨膜的非催化性受体,通常在细胞表面上和岗哨细胞如巨噬细胞和树突细胞的内吞小泡中表达。TLR识别病原体相关分子模式(PAMPs)(其为结构上保守的分子,源自微生物),并且起始信号转导以诱导固有免疫和随后的适应性免疫所需的细胞因子的产生。
各种TLR显示不同的表达模式。该基因倾向于在免疫细胞富集的组织中表达,例如肾脏、淋巴结、骨髓和外周血白细胞。
已在人类和小鼠中共鉴定出了十三种TLR(简单命名为TLR1至TLR13,并且已经在其它哺乳动物物种中发现了这些中的许多的TLR的等同形式。然而,不是小鼠中的每个TLR受体也都发现于人类中,反之亦然。另外,不是每个TLR受体的配体和功能是已知的,例如TLR10为具有未知功能的孤儿受体(orphan receptor)。
TLR受体的活化已用于治疗各种疾病,例如TLR9被药剂活化已显示有益于治疗变态反应和肿瘤。小鼠和人类中的研究表明,TLR9的天然配体是DNA分子中未甲基化的CpG序列。与细菌基因组或病毒DNA相比,CpG位点在脊椎动物基因组中相对稀少(~1%)。TLR9由多种免疫系统细胞例如树突细胞、B淋巴细胞、单核细胞和自然杀伤(NK)细胞表达。然而,在健康人中,TLR9的表达仅限于浆细胞样树突细胞(pDCs)和B细胞。该表达是细胞内的,位于核内体小泡(endosomal compartments)内,通过结合至CpG基序富集的DNA来起到警告免疫系统的病毒和细菌感染的作用。然而,在病理学状态下,TLR9表达已报道还位于细胞的细胞表面上12-14。
已报道了许多不同的合成的TLR9激动剂分子。激动配体(TLR9活化)已分类成三组:
由CpG A类组成的组,特别是CpG-A(D)15寡脱氧核苷酸(ODN),也称作“D”-型ODN。此类TLR9激动剂诱导强IFNa诱导和树突细胞的最低成熟,且在本文中称为“组1”TLR9配体。实例为ODN221616:
GGGGGACGATCGTCGGGGGG(SEQ ID 48)
由CpG B类组成的组,特别是CpG-B(K)17寡脱氧核苷酸(ODN),也称作“K”-型ODN。此类TLR9激动剂诱导弱IFNa诱导和树突细胞成熟,且在本文中称为“组2”TLR9配体。实例为ODN200618;19:
TCGTCGTTTTGTCGTTTTGTCGTT(SEQ ID 49)
由CpG C类组成的组,也称作CpG-C20寡脱氧核苷酸(ODN)。此类TLR9激动剂诱导IFNa和未成熟树突细胞的成熟,且在本文中称为“组3”TLR9配体。实例为ODNM36221:
TCGTCGTCGTTCGAACGACGTTGAT(SEQ ID 69)
迄今为止记载的TLR9的所有配体基于核苷酸。尽管TLR9特异性抗体已报道并用于阐明受体的存在和位置,但这些分子还未描述为TLR9的配体,没有任何TLR9活化或抑制活性的报道。
CD32的作用:
CD32强表达于单核细胞/树突细胞以及B细胞上,因而此类分子被设计为将免疫应答导向重要的免疫细胞,意欲防止B细胞的抗原呈递,而促进尤其是树突细胞(DCs)的抗原呈递,当充分刺激时后者导致Th1对抗原应答的诱导。有至少两种类型的DC:骨髓样树突细胞(mDC)和浆细胞样树突细胞(pDC),已导致DC1和DC2细胞的新理念。在该理念下,DC1细胞在抗原特异性刺激之后促进Th1细胞发育的诱导,DC2细胞支持Th2细胞的发育。单核细胞衍生的DC(或mDC)通常被认为是DC1类型,而pDC被认为是DC2型。两种类型的DC表达CD32a并将诱导抗原特异性T细胞应答;然而,并不保证结果将是Th1类型。事实上,在变态反应性供体中,Th2应答是更有可能的。重要的是,pDC表达TLR9受体,TLR9受体结合CpG-ODN(含有未甲基化的CpG基序的寡脱氧核苷酸(ODN))。该受体在pDC中的活化导致非常强的IFN-α和IL-12生产,这促进Th1诱导并因而将潜在的DC2转化成DC1细胞。
因此,此类分子可将TLR9受体在pDC中的活化与抗原特异性Th1细胞的特异性刺激和诱导相结合。
在肿瘤免疫治疗中,特定的目标是使用除细胞毒素T淋巴细胞(CTL)以外的肿瘤抗原特异性T辅助型1(Th1)细胞。
卷曲螺旋(Coiled coils):
卷曲螺旋由蛋白质中的结构基序构成,其中2-7个α-螺旋缠绕在一起类似于绳索的股线;二聚体和三聚体是最常见的类型。卷曲螺旋螺旋体已用于使产生异二聚体的卷曲螺旋结构域的Fv抗体片段稳定化22。
复合蛋白质分子(proteinaceous molecules)的稳定性和折叠结构在设计免疫原时是至关重要的。因此,本发明的目的为提供具有改进的稳定性和结构用于调节对特定免疫原的免疫应答的疫苗。
进一步需要提供改进的靶向胃泌素和胃泌素依赖的病况的免疫治疗。因而,本发明的目的为提供具有改进的免疫原性、稳定性和结构以调节对特定胃泌素表位的免疫应答的疫苗。
发明内容
本发明通过所要求保护的主题解决。
根据本发明,提供有免疫调节疫苗,所述免疫调节疫苗包括
-导向佐剂,其至少包括连接至TLR9配体和第一肽α-螺旋的抗CD32部分,和
-免疫原,其具有至少一个表位和与第一肽α-螺旋缠绕的第二肽α-螺旋。
具体地,所述表位为T细胞和/或B细胞表位。
根据本发明的具体方面,所述第一和第二肽α-螺旋各自包括3-5个氨基酸重复的氨基酸基序,以小于10-6M的Kd、优选小于10-7M的Kd、更优选小于10-8M或10-9M的Kd彼此特异性结合。
根据本发明的另外的具体方面,所述抗CD32部分选自由抗CD32抗体、优选靶向CD32a的抗体片段和肽组成的组。抗体片段具体可例如为Fab、Fv、scFv、dAb、F(ab)2或Fcab片段,或任何其它可能的实体,只要其特异性结合至受体并在结合后内在化(internalized)即可。
根据本发明的另一方面,TLR9配体为选自由CpG A类组成的组的TLR9激动剂,特别是CpG-A(D)23寡脱氧核苷酸(ODN),也称作“D”-型ODN。此类TLR9激动剂诱导强IFNa诱导和最低树突细胞成熟,且在本文中称为“组1”TLR9配体。
根据本发明的另一方面,TLR9配体为由CpG B类组成的组的TLR9激动剂,特别是CpG-B(K)24寡脱氧核苷酸(ODN),也称作“K”-型ODN。此类TLR9激动剂诱导弱IFNa诱导和树突细胞成熟,且在本文中称为“组2”TLR9配体。
根据本发明的另一方面,TLR9配体具体为由CpG C类组成的组的TLR9激动剂,也称作CpG-C25;26寡脱氧核苷酸(ODN)。此类TLR9激动剂诱导IFNa和未成熟树突细胞的成熟,且在本文中称为“组3”TLR9配体。
根据本发明的另一方面,所述TLR9配体具体为模拟任意CpG A、B或C类寡脱氧核苷酸的免疫刺激肽,即特异性结合至TLR9具有活化、激动功能的肽。
根据本发明的另一方面,TLR9配体为选自由抑制性ODNs27;28寡脱氧核苷酸(有时称为抑制性CPGs)组成的组的TLR9拮抗剂,例如,包含由CCx(非-C)(非-C)xxGGG(x=任意碱基)29组成的组的抑制性基序的那些。特异性抑制性ODNs已被证实不诱导IFNa,也不诱导树突细胞成熟,还阻碍通过TLR9的激动剂的活化。
此类TLR9激动剂或拮抗剂可在以适当细胞为基础的试验中确定,该试验测定IFNa或者标记物CD80、CD83和CD86至少之一的稳定表达,反映了未成熟树突细胞(DC)的成熟。为此,如Tel等人30所述将浆细胞样树突细胞(pDCs)从健康供体的血液中纯化,并随后用适当浓度的TLR9配体温育。24h后,使用标准ELISA实验方案在上清液中测定IFNa。为了确定细胞的成熟状态,在与TLR9配体温育前后使用标准FACS步骤用商购可得的特异性抗体染色表达CD80、CD83或CD86的pDC。
IFNa的诱导可由IFNa表达水平和相对于参考水平的相应增加来确定。相对于非刺激细胞的增加可与由已确定的针对如由组1、2或3TLR9配体所定义的各类型CpG的参考诱导的诱导水平相比较,并典型地在相应参考的30%和300%之间,优选至少100%,更优选至少120%,至少150%,至少200%或至少250%。
未成熟的树突细胞的成熟可通过CD80、CD83和CD86的任意标记物的表达水平来确定。相对于非刺激细胞的相应增加可与由已确定的针对如由组1、2或3TLR9配体所定义的各类型CpG的参考诱导的诱导水平相比较,且典型地在相应参考的30%和300%之间,优选至少100%,更优选至少120%,至少150%,至少200%或至少250%。
具体地,组1和3的TLR9激动剂将导致IFNa表达增加,组2和3的TRL9激动剂将导致任意DC成熟因子CD80、CD83和CD86表达增加。甚至在组1-3各自的TLR9激动剂的存在下,TLR9拮抗剂将导致IFNa表达降低和任意DC成熟因子CD80、CD83和CD86表达降低。
根据本发明的具体实施方案,免疫原源自
-用于癌症疾病的免疫治疗的肿瘤相关抗原,或者
-用于传染病的免疫治疗的病原体,或者
-用于变态反应疾病的免疫治疗的变应原。
此类疫苗典型地为免疫刺激疫苗,例如,刺激体液和T-细胞(Th1)免疫应答。
免疫刺激疫苗的该实施方案具体采用为TLR9激动剂的TLR9配体。在该情况下疫苗主要诱导Th1对免疫原的应答。
具体地,所述抗CD32部分靶向CD32a,优选具有Kd≤10-6M,更优选小于10-7M或小于10-8M的高亲和性。
更具体地,所述抗CD32部分为特异性或选择性的CD32a结合剂,即,不靶向CD32b或以Kd>10-6M,优选高于10-5M,,更优选高于10-4M的低亲和性靶向CD32b。结合至CD32a和CD32b的差别亲和性(differential affinity)优选至少1log,更优选至少2logs或至少3logs,或者较高的Kd值差别。
在进一步采用TLR9激动剂的免疫刺激疫苗中典型地使用与CD32a而不是CD32b结合为特别优选高亲和性或高差别亲和性的抗CD32部分。进一步优选此类疫苗采用选自一系列肿瘤靶标或病原体靶标的免疫原,其中Th1应答和特异性IgG抗体对于与疾病有效斗争是必须的。
根据可选的实施方案,所述抗CD32部分靶向CD32a和CD32b二者,具有Kd≤10-6M的高亲和性,优选高于10-7M的亲和性,更优选高于10-8M的亲和性。在进一步采用TLR9激动剂的疫苗中典型地使用与CD32a和CD32b二者的结合为特别优选的高亲和性的抗CD32部分。进一步优选此类疫苗采用选自一系列变态反应靶标的免疫原,其中获得了Th2应答的重新导向以得到Th1应答。典型地,不优选对疫苗自身的抗体。另外,特异性疫苗优选以与结合至CD32a大致相同的亲和性结合至CD32b。
与特异性靶向任意CD32a或CD32b或CD32a和CD32b二者的抗CD32部分的结合亲和性可以适当的试验确定,例如典型的ELISA,其使用商购可得的HIS标记的重组形式的CD32a和CD32b,涂布至Ni-NTA ELISA板,例如Ni-NTA HisSorb Plates(Qiagen,Austria)。抗CD32部分可生物素化并由此可使用链霉亲和素-HRP或链霉亲和素AP和适当的底物来检测。可选地,该部分可在FACS试验中使用表达CD32a而不是CD32b的U937细胞(如ATCC:CRL1593),和表达CD32b而不是CD32a的EBV转染的B细胞,如van Reijsen等人31记载的CFB4:2来检测。
根据本发明的其它实施方案,免疫原源自
-用于变态反应疾病的免疫治疗的变应原,或者
-用于自身免疫病的免疫治疗的人自身抗原。
用于自身免疫病的此类疫苗典型地为免疫耐受疫苗,例如包括通过调控T细胞并下调体液免疫应答诱导针对免疫原的T细胞耐受。
免疫耐受的该实施方案具体采用为1组TLR9激动剂或为TLR9拮抗剂的TLR9配体。在该情况下,疫苗将主要下调针对免疫原的Th1/2/17应答,除了活化Treg细胞外。
用于变态反应的此类疫苗可为:
-例如通过采用为1组TLR9激动剂或为TLR9拮抗剂的TLR9配体,调控T细胞并下调体液免疫应答来诱导针对免疫原的免疫耐受疫苗。在该情况下,疫苗将主要下调针对免疫原的Th1/2/17应答,除了活化Treg细胞外;
或者
-免疫刺激疫苗,采用为组3TLR9激动剂的TLR9配体诱导针对免疫原的Th1应答,同时防止针对疫苗的体液免疫应答。
根据免疫耐受疫苗的该实施方案,所述抗CD32部分特异性靶向CD32b或者CD32a和CD32b二者,具有Kd≤10-6M的高亲和性,优选具有Kd≤10-7M的较高亲和性,更优选Kd≤10- 8M。优选抗CD32部分特异性靶向CD32a和CD32b二者。
同样,对于用于变态反应的免疫刺激疫苗,所述抗CD32部分特异性靶向CD32a和CD32b,具有Kd≤10-6M的高亲和性,优选具有更高的亲和性,例如,Kd≤10-7M,更优选Kd≤10-8M。优选抗CD32部分特异性靶向CD32a和CD32b二者。
具体地,根据本发明提供疫苗,其中所述免疫原源自变应原,用于变态反应疾病的免疫治疗,和其中所述抗CD32部分靶向CD32a和CD32b。
本发明的具体实施方案可由下表描述,表明根据结合CD32a和/或CD32b的特异性和亲和性的抗CD32部分的选择、TLR9配体的类型和免疫原的类型。
表1:具体实施方案:
第2和3栏涉及抗CD32部分结合至CD32a和CD32b任一的选择性和/或亲和性:
CD32a>>CD32b意指选择性结合至CD32a(结合亲和性/Kd之差为至少1log);
CD32b=CD32a意指结合至CD32a和CD32b二者为大致相同的程度(结合亲和性/Kd之差小于1log)。
特别地,当提供抗变态反应疫苗,即用于治疗变态反应性病况的免疫耐受疫苗,或者提供抗自身免疫病的疫苗,即用于治疗自身免疫病况的免疫耐受疫苗时,抗CD32部分以大致相等的高亲和性特异性靶向CD32a和CD32b二者,例如结合至各CD32a和CD32b靶标的差别亲和性小于2logs,优选小于1log,以Kd值的差计。
根据本发明,进一步提供免疫原性组合物,所述免疫原性组合物包括
a.导向佐剂,其至少包括连接至TLR9配体和第肽一α-螺旋的抗CD32部分;和
b.胃泌素-17肽免疫原,其连接至与第一α-螺旋缠绕的第二肽α-螺旋,所述肽免疫原为下述任一种:
(i)人胃泌素-17,其包括SEQ ID 78的氨基酸序列,或其包括SEQ ID 79的氨基酸序列或SEQ ID 79的至少4个N-末端氨基酸的片段;
(ii)(i)的类似物,优选猕猴或鼠科来源;和/或
(iii)(i)或(ii)任一的功能性活性变体,其在SEQ ID 79的氨基酸序列中具有一个、两个、三个或四个点突变。
具体地,所述肽免疫原为线性肽,包括下述或由下述组成:
(i)SEQ ID 80、优选SEQ ID 81的氨基酸序列;
(ii)SEQ ID 82、优选SEQ ID 83的氨基酸序列;
(iii)SEQ ID 84、优选SEQ ID 85的氨基酸序列;或
(iii)SEQ ID 79或86的氨基酸序列。
优选本发明的免疫原性组合物包括至少两种肽免疫原,其连接至第二肽α-螺旋,优选2、3或4种肽免疫原。
当超过一种肽免疫原结合至第二α-螺旋时,肽免疫原可例如相继缀合至α-螺旋,即线性连接肽免疫原,例如将第一肽免疫原的C末端连接至第二肽免疫原的N-末端,该第一和第二肽免疫原彼此相同或不同。
可选地,或另外,其它肽免疫原可通过交联并入本发明的免疫原性组合物,例如两个以上彼此相同或不同的肽免疫原通过化学反应连接至同一α-螺旋,例如化学交联允许例如利用同型双功能试剂(homo-bifunctional reagents)如二甲基己二亚酰胺化物(Dimethyl adipimidate,DMA)、二甲基辛二亚酰胺化物(DMS)或戊二醛建立分子间交联。例如,此类交联可采用戊二醛分别借助α-螺旋或间隔子/连接子的游离赖氨酸基团交联来进行。由此,根据本发明使用的两个以上的肽免疫原平行或肩并肩地偶联至α-螺旋。
根据本发明更具体的方面,免疫原性组合物包括一个以上的连接子序列,所述连接子序列优选由甘氨酸和/或丝氨酸和/或赖氨酸残基组成,优选SEQ ID 89或90的氨基酸序列。连接子序列可为线性或支化的,从而例如提供两个以上的肽或多肽实体之间的连接或交联。
根据本发明更具体的方面,免疫原性组合物包括SEQ ID 87或SEQ ID 88的氨基酸序列,或者由SEQ ID 87或SEQ ID 88的氨基酸序列组成。
根据本发明,进一步提供包括本发明免疫原性组合物和药学可接受载体的疫苗。此类疫苗典型地为免疫刺激疫苗,例如刺激体液和T细胞(Th1)免疫应答。
根据优选的实施方案,体液和T细胞(Th1)免疫应答为瞬时的,例如典型地在接种2至8周的期间达到接种诱导的特定最大IgG滴度,接着在接种6个月内、优选在5个月内、或在4个月内、或在3个月内、或在2个月内滴度减少至少30%、优选至少40%、或至少50%、或至少60%、或至少70%、或至少80%、或至少90%或高达100%。此类减少的滴度可在加强注射(booster injection)时再次增加。在一系列接种中,在免疫原性组合物或疫苗的最后注射时可测定瞬时免疫应答。瞬时免疫应答具有例如必要时中断或终止治疗的可能性的控制治疗的优势。
本发明特别提供一种包括免疫原性组合物的疫苗,所述免疫原性组合物包括
-导向佐剂,其至少包括连接至TLR9配体的抗CD32部分,和
-免疫原,其优选通过连接或亲和结合,例如通过重组DNA技术或化学缀合的融合而结合至导向佐剂。
所述疫苗用于治疗受试者以瞬时诱发导向免疫原的IgG免疫应答,优选具有在接种时诱导的特异性最大IgG滴度,其典型地在接种2至8周期间内达到,接着在接种、例如在一系列接种的最后接种时的6个月内,滴度减少至少30%、优选至少40%、或至少50%、或至少60%、或至少70%、或至少80%、或至少90%或多至100%。
此类疫苗优选与为或包括自体抗原的抗原或表位的免疫原一起使用,所述自体抗原例如选自由肿瘤相关抗原(TAA)、前激素和激素组成的组,所述肿瘤相关抗原(TAA)优选由肿瘤细胞产生的肿瘤细胞表面受体或可溶性抗原,如Her2/neu、胃泌素、干扰素α(INFα)、表皮生长因子(EGF)、EGF受体(EGF-R)、表皮细胞粘附分子(EpCAM)、α-FP甲胎蛋白(AFP)、癌胚抗原(CEA)、MUC-1或路易斯Y,所述前激素或激素例如包括胰泌素或胰岛素等的消化性激素、甲状腺激素或性激素的任一种。
当治疗人类受试者时自体抗原特别是人源的。
通过由该类型疫苗诱导的瞬时Th1免疫应答,没有不可逆的自身免疫应答,而有可逆的自身免疫应答,其由受到特定循环IgG的水平诱导表明,例如该水平在IgG已被诱导后为小于50%的、优选小于60%的、优选小于70%的、优选小于80%的、或小于90%的,甚至多至100%的循环IgG减少。典型地紧随IgG诱导之后的是在特定时间段内,例如在最后免疫1年内、或6个月内、或3个月内的IgG诱导。
就这一点而言,本发明进一步提供治疗需要通过例如以一个或多个剂量向受试者给药有效量的疫苗来瞬时诱导自体抗原或自身抗原的受试者的方法,其中至少最后的剂量提供瞬时效果。
根据本发明,进一步提供用于制备本发明的免疫原性组合物的试剂盒,所述试剂盒包括下述组分
a.导向佐剂,其至少包括连接至TLR9配体和第一肽α-螺旋的抗CD32部分;和
b.胃泌素-17肽免疫原,其连接至与第一α-螺旋匹配的第二肽α-螺旋,其中所述肽免疫原为下述任一种
(i)人胃泌素-17,其包括SEQ ID 78的氨基酸序列,或其包括SEQ ID 79的氨基酸序列的片段,或SEQ ID 79的至少4个N末端氨基酸;
(ii)(i)的类似物,优选猕猴或鼠科来源;和/或
(iii)(i)或(ii)任一的功能性活性变体,其在SEQ ID 79的氨基酸序列中具有一个、两个、三个或四个点突变。
该试剂盒可具体地通过使用预制的导向佐剂组分与可根据受试者群体或个体受试者的需要而提供的免疫原组合来促进疫苗生产。
根据本发明,进一步提供免疫原性组合物,其用于治疗患有胃泌素依赖性疾病或病况的受试者。此类疾病或病况主要由受试者的内源性胃泌素产生或过度产生引起或与之相关。胃泌素依赖性疾病或病况具体包括胃泌素依赖性肿瘤或胃泌素依赖性癌症,例如胰腺癌,或胃肠癌、胃溃疡、胃食管反流病(GERD)、终末期肾功能衰竭(ESRF),或肥胖。
因此,本发明具体提供治疗患有胃泌素依赖性疾病的受试者的方法,所述胃泌素依赖性疾病例如胃泌素依赖性肿瘤或胃泌素依赖性癌症,例如胰腺癌,或胃肠癌、胃溃疡、胃食管反流病(GERD)、终末期肾功能衰竭(ESRF),或肥胖,所述方法通过向受试者给药有效量的本发明的免疫原性组合物或疫苗,预防性地,例如预防疾病或病况的爆发或者疾病的进展,或者治疗性地,例如改善疾病或病况。
具体地,所述组合物采用加强免疫策略以有效量给药至受试者。
具体地,有效量在每次给药0.0001至2mg范围内,优选每剂量0.001至2mg范围内。
根据本发明的具体实施方案,受试者进一步例如在治疗胃泌素依赖性癌症的过程中通过化学疗法治疗。
具体地,本发明的免疫原性组合物触发受试者的保护性免疫应答,优选对人胃泌素-17的血清IgG滴度为至少1/1000,优选至少1/104,优选至少1/105,优选至少1/106,或更低,由此,可在较高稀释度下检测。
附图说明
图1示出用于本发明的卷曲螺旋的高亲和相互作用(实施例4)。
具有卷曲-K的免疫原涂布至BIACore芯片上,具有卷曲E的弹头(warhead)位于流动缓冲液中。各卷曲包括5个七肽的重复α螺旋(heptad repeat alpha helix)
·数据证实两个螺旋彼此之间的极大亲和力(通过低关闭-速率可视化)32
·免疫原卷曲与弹头卷曲的结合是特异性的,且可通过与免疫原的预温育而封闭
图2示出免疫原3诱导的T细胞反应性(实施例6)。
将来自Der p1敏化猕猴(macaca mulatta)的PBMC用Der p1或免疫原3培养,一式三份。通过引入[3H]-胸苷来分析增殖。结果显示为每分钟的计数。另外,分析上清液的IL-10和GM-CSF水平,各自表示为pg/ml
·在对Der p1或免疫原3的应答之间没有显著差异,增殖或细胞因子产生中也没有显著差异,表明基于人HLA II型表达选择的免疫原3中的T细胞表位同样很好地由猕猴II型分子呈递并诱导同样强烈的T细胞应答
图3示出:弹头介导的增强的抗原呈递(实施例7)
猕猴(macaca mulatta)T细胞在冰上用相应的弹头和Der p1或者弹头和免疫原3预温育后,增殖24小时(通过引入[3H]-胸苷来分析)。各预温育后洗涤细胞。(bdl=在检出限以下)。
·仅当免疫原能够与弹头通过其卷曲(免疫原3)相互作用时,能够见到剂量依赖方式的T细胞增殖。Der p1在与弹头预温育时不显示应答。作为阳性对照,Der p1在过夜温育(无洗涤)后显示反应。
·弹头介导的抗原摄取比通过胞饮作用摄取更有效
图4示出由与CpG偶联的自身抗原诱导的自身免疫应答(实施例8)
将猕猴(macaca mulatta)的PBMC和正常人PBMC用CpG或CpG-biot或aCD32-biot+CpG培养24小时。收集上清液并分析IL-4和IFNg(各自表示为pg/ml)
·在CpG与biot偶联(CpG-biot)时,与无biot的CpG相比,诱导强IL-4(猕猴和人PBMC)。人PBMC还显示对CpG-biot的强IFNg应答。当biot和CpG不偶联时(aCD32-biot+CpG),与人或猕猴PBMC中的CpG相比,看到没有增加的应答
图5示出免疫原5诱导的T细胞反应性(实施例10)
将健康人供体的PBMC用Der p1或免疫原5培养24小时,一式三份。收集上清液并分析IL-10和GM-CSF水平(各自表示为pg/ml;BDL=在检出限以下)
·如通过Il-10和IFNg诱导测量的,人T细胞对免疫原5的应答与Der p1同样好。
图6示出通过弹头SG100接种诱导的自身免疫应答,其中在第28天弹头诱导对ScFV-1-卷曲以及对mAb IV.3的强的IgG1和IgG2a应答。可看出阳性应答依赖于Alum的存在。用ScFV-1-卷曲的接种仅诱导对ScFV-1-卷曲的IgGl应答,且仅在Alum的存在下,未诱导IgG2a应答。
图7(实施例12.8)
测量到对SG100的弹头和免疫原的强IgG应答,但未检测到对Der p1、Der p2、Derp5或Der p7的抗体,表明动物对测试的HDM变应原是首次试验且SG100不包含与测试的HDM变应原交叉反应的B细胞表位。
图8(实施例12.8)
当在体外用弹头、immo5、Der p1、Der p2、Der p7而不是针对Der p5刺激动物时显示强增殖。Der p5不是immo5的一部分。
图9(实施例12.8)
动物在用弹头、immo5、Der p1、Der p2、Der p7而不用Der p5刺激后产生IFNγ而不产生IL-4。Der p5不是immo5的一部分。
图10示出食蟹猴(cynomolgus monkey)中的抗体(IgG诱导)。在d0、d14和d28用疫苗(TYG100_2RM)三次注射后的时间曲线IgG抗G17诱导。
·看到对ScFV-卷曲1和G17RM和G17H的显著的IgG诱导。未见对类似分子量的对照肽的应答或者当动物用G17RM_2免疫而无弹头的存在时。所有特异性IgG滴度在最后接种后4周下降,表明加强注射对于维持IgG水平是必要的。另外,天然G17RM的存在不加强应答,且由于抗G17RM的IgG的降低显著高于对ScFV-卷曲1的降低,可总结为诱导的免疫应答是可逆的。
图11示出在抗胃泌素免疫时的重量损失。
·在用TYG100_2RM免疫后6个动物中的四个显示显著的时间依赖性重量损失。动物护理者观察到这些动物丧失对它们下午零食的欲望,而不失去对正常每日膳食的兴趣。此类观察在其它疫苗中从未观察到,因此,本发明的抗胃泌素疫苗可用于控制肥胖。
图12示出下列序列信息
SEQ ID 78:人小胃泌素,G17;
SEQ ID 79:人胃泌素肽,小胃泌素的前(N-末端)12AA(氨基酸),G12;
SEQ ID 80:小胃泌素的N-末端表位,前(N-末端)4AA,包括含点突变的特定功能性活性变体;
SEQ ID 81:小胃泌素的N-末端表位,前(N-末端)4AA,包括含点突变的更特定功能性活性变体;
SEQ ID 82:小胃泌素的N-末端表位,前(N-末端)12AA,包括含点突变的特定功能性活性变体;
SEQ ID 83:小胃泌素的N-末端表位,前(N-末端)12AA,包括含点突变的更特定功能性活性变体;
SEQ ID 84:小胃泌素的N-末端表位,前(N-末端)13AA,包括含点突变的特定功能性活性变体;
SEQ ID 85:小胃泌素的N-末端表位,前(N-末端)13AA,包括含点突变的更特定功能性活性变体;
SEQ ID 86:人胃泌素肽,小胃泌素的前(N-末端)13AA(氨基酸),G13;
SEQ ID 87:TYG100_1H的免疫原组分:本发明免疫原性组合物的一部分,包括一个SEQ ID 86的人胃泌素肽,连接子序列和肽α-螺旋(TYG100_1H)。该部分可通过卷曲螺旋键合连接至适合的导向佐剂。
粗体为肽免疫原,斜体为连接子,下划线为卷曲
SEQ ID 88:TYG100_2H的免疫原组分:本发明免疫原性组合物的一部分,包括两个SEQ ID 86的人胃泌素肽、支化的连接子序列和肽α-螺旋(TYG100_2H)。该部分可通过卷曲螺旋键合连接至合适的导向佐剂。
粗体为肽免疫原,斜体为连接子,下划线为卷曲
SEQ ID 89:线性连接子序列;
SEQ ID 90:支化的连接子序列。
具体实施方式
贯穿说明书使用的具体术语具有下列含义。
本文使用的术语“佐剂”应意指疫苗的整合的或共给药的组分,其:
-增强对特定免疫原如抗原或半抗原的免疫应答。免疫应答典型地大于由当量无佐剂下给药的免疫原性组合物所引起的免疫应答,
和/或
-佐剂用于导向特定类型或类别的对免疫原的免疫应答如Th1或Treg型免疫应答,本文理解为“导向佐剂”。
本发明佐剂的“有效量”具体为增强对免疫原的免疫应答以便,需要较低或较少剂量的免疫原性组合物来产生有效的期望类别的免疫应答的量。
根据本发明的导向佐剂不仅介导有效的免疫应答,而且还以期望的方式调节免疫应答。特别是当采用为组3的TLR9激动剂的TLR9配体时,通过将免疫原导向适当的免疫细胞用于其内化和进一步处理,诱导Th1免疫应答而不是Th2免疫应答。如果TLR9拮抗剂用于疫苗组合物,则相应的免疫应答在任何情况下都下调。如果组1的TLR9激动剂与结合CD32b的抗CD32部分组合,则通常预期Treg细胞的诱导。
本发明佐剂的“有效量”具体为增强对免疫原的免疫应答以便,例如需要较低或较少剂量的免疫原性组合物来产生有效的期望类别的免疫应答的量。
根据本发明的导向佐剂不仅介导有效的免疫应答,而且还以期望的方式调节免疫应答。特别是当采用为组3的TLR9激动剂的TLR9配体时,通过将免疫原导向适当的免疫细胞用于其内化和进一步处理,诱导Th1免疫应答而不是Th2免疫应答。如果组1的TLR9激动剂与结合CD32b的抗CD32部分组合,则通常预期Treg细胞的诱导。
例如,用于本发明疫苗的免疫原性组合物的“有效量”是指当作为疫苗给药方案的一部分给药时,在要治疗的受试者中足以显示有意义的益处的量。本领域普通技术人员将理解的是,在某些实施方案中,如果特定的组合物包含适于在特定给药方案中给药的单位剂型的量,则特定的组合物可被认为包含预防或治疗有效量,即使作为单一单位剂量给药时这类量可能对于实现有意义的益处是不足的。普通技术人员将进一步理解的是,免疫原性组合物的有效量对于接收组合物的不同受试者可能是不同的,例如取决于诸如期望的生物学终点、组合物的性质、给药途径、要治疗的受试者的健康、体重和/或年龄等这类因素。在某些实施方案中,有效量为当作为特定给药方案例如单一给药或系列给药如“强化”方案的一部分给药时与有益效果相关的量。
本文使用的术语“肽的α-螺旋”应意指基于包括若干重复(也成为卷曲重复)的肽序列的卷曲的结构基序。此类α-螺旋能够结合至另一配对物,也成为相同类型的配对α-螺旋以形成二聚体、三聚体或其它低聚体,也称为卷曲螺旋。
卷曲螺旋为多肽或肽的结构基序,其中2至7个α-螺旋像绳股一样缠绕在一起。在某些实施方案中,疫苗的卷曲螺旋与两个α-螺旋缠绕在一起。如在适当的卷曲螺旋相互作用结合试验中所测量的,此类α螺旋区域可能形成卷曲螺旋结构,并可参与卷曲重复的低聚化。
具体地,α-螺旋的二聚体可通过使两个单体相接触,以使二聚体通过两个α-螺旋卷曲螺旋结构域相互作用形成来形成。在某些实施方案中,卷曲包括含SEQ ID NO:1或2(卷曲和反卷曲)所示的氨基酸序列的肽,其包括x个重复。
EVSAL(SEQ ID 97)
E5:EVSALEKEVSALEKEVSALEKEVSALEKEVSALEK-NH2(SEQ ID 1)
KVSAL(SEQ ID 98)
K5:KVSALKEKVSALKEKVSALKEKVSALKEKVSALKE-NH2(SEQ ID 2)
可选地,可使用由Chao等33或Litowsky等34描述的任一种序列或功能等价物,其产生特异性卷曲螺旋型连接:
为了本发明的目的,优选类型的卷曲螺旋为二聚体,或者为两个不同但配对的螺旋的异质二聚体(异质卷曲),其在卷曲重复序列中至少一个氨基酸不同,或者为两个相同配对螺旋的同源二聚体,即包括配对卷曲重复序列的那些(“卷曲”)。
卷曲重复的优选数量为3-5,优选3+3、3+4、3+5、4+4、4+5、5+5、4+3、5+3或5+4任一种的组合。
作为七肽的重复的替代(氨基酸序列由7个氨基酸组成的重复,7-mers),可使用6-mers、8-mers或9-mers。
在同源二聚体卷曲螺旋的情况下,典型的卷曲重复数具体不超过5个,以便避免结构错配。在异质二聚体卷曲螺旋的情况下,典型地期望采用长度至少3个卷曲的肽序列。由此疫苗组分即导向佐剂和免疫原组分的彼此结合典型地在优选Kd小于10-7M、更优选小于10-8M或10-9M的高亲和力下实现。然而,尽管重复越多亲和力越强,但这可能以增加同源二聚为代价。
本发明免疫原性组合物的组分还可包括肽间隔子以便连接抗CD32部分和/或TLR9配体,并且任选地还分别连接表位(例如肽免疫原的)与卷曲重复。例如,肽间隔子可在卷曲螺旋的一端或两端。各肽间隔子可附着至卷曲螺旋的单一α-螺旋卷曲螺旋结构域。
肽间隔子可为例如至少5、6、7、8、9、10、15、20、25、30、35、40、45或50个氨基酸或更多的肽,线性或支化的,例如提供两个、三个、四个、或更多的支链。在某些实施方案中,肽间隔子中的氨基酸数可为20个氨基酸或多至10个氨基酸上下,依赖于卷曲的特定序列和长度。
本文使用的术语“抗CD32部分”应意指特异性结合至细胞靶标CD32,或者CD32a、CD32b或者CD32a和CD32b二者的配体。该部分可为任意结合结构,例如源自蛋白质、多肽或肽,包括抗体和抗体片段或具有结合部分的复合分子。本发明的分子或分子复合物的结合部分可包括蛋白质如抗体或抗体片段,例如Fab、Fv、VH/VL二聚体、scFv、dAb、F(ab)2、微抗体(minibody)、小突变免疫球蛋白结构域、Fcab、Mab2或其它生物学结合子(binders),例如可溶性T细胞受体、Darpins等。抗体和抗体片段以及衍生物可根据已知方法如杂交瘤技术、B细胞克隆、噬菌体展示、酵母展示、核糖体展示或抗体文库的细胞表面展示、变体抗体的阵列筛选等产生并选择用于结合CD32。典型的抗CD32部分为源自AT-1035、IV.336、2E637的抗CD32单克隆抗体scFv或任何其它aCD32单克隆抗体。
特异性结合可在适当的结合测定例如常规免疫测定中确定。
本领域已知有多种方法用于检测免疫测定中的结合。可使用本领域已知的各种免疫测定,包括使用如放射免疫测定、ELISA(酶联免疫吸附测定)、免疫放射测定、凝胶扩散沉淀反应、免疫扩散测定、免疫印迹、BIAcore等的竞争性和非竞争性测定体系的技术。
本文使用的关于抗原或抗体的术语“交叉反应性”涉及不同来源(例如来自人、猕猴或鼠科来源)抗原之间共享的表位。由G17的前4AA组成或包括G17的前4AA的N-末端表位发现在各种来源的肽中具交叉反应性,该表位触发免疫应答和与表位交叉反应的IgG抗体。
本发明的免疫原性组合物对治疗与过量胃泌素相关的胃泌素依赖性疾病或病况,例如胃泌素依赖性肿瘤或胃泌素依赖性癌症,例如胰腺癌,或胃肠癌、胃溃疡、胃食管反流病(GERD)、终末期肾功能衰竭(ESRF),或肥胖特别有用。
本文使用的术语“胃泌素依赖性肿瘤”或“胃泌素依赖性癌症”指与之相关的肿瘤或疾病或病况,例如胃泌素依赖性结直肠腺癌和其它胃泌素依赖性癌症如胃癌、肝癌、胰腺癌和肺小细胞癌。该术语具体在本文中涉及治疗肿瘤以预防肿瘤疾病进展、阳性肿瘤应答或肿瘤缩减。该术语还适用于成功地治疗的微小残留病(minimal residual disease),例如靶向循环肿瘤细胞以减少它们的数量至特定阈值以下,例如在检出限以下。
胃溃疡疾病,可由增加的胃酸和通常保护胃粘膜免受酸损害的复杂的胃防御的破坏所引起。尽管两种病况具有不同的病因学,但二者均得益于胃酸分泌的减少。胃酸在专门的胃细胞,壁细胞中产生。壁细胞可在乙酰胆碱、组胺和胃泌素与特定受体在细胞表面结合时受这些化合物的刺激而分泌酸。这些中最有效的酸分泌刺激物为肽激素胃泌素。本文所述的抗胃泌素免疫治疗将改善胃溃疡病况。
本文使用的术语“胃泌素-17肽”或“G17肽”或“G17”应指小胃泌素G17,其由胃泌素的N-末端17AA构成。G17肽可为人源,或其它哺乳动物来源,包括猕猴或小鼠,因此具有人或其它哺乳动物序列,或可为人工构建体,从便引入如通过改变天然(自然发生)G17序列的氨基酸残基的类型和/或序列而获得的人工序列。术语应具体包括人G17的变体,具有SEQ ID78的氨基酸序列,或其片段,但与其肽序列不同的地方在于,其源自不同物种的同源序列。这些称作自然发生的变体或类似物。术语“类似物”还应指源自两个或多个来源的嵌合构建体,其中至少一部分是自然发生的,例如其构成肽免疫原的主要部分(至少50%),并且另一部分与之不同,既可为自然发生或可为合成的(人工的)。
该术语应具体包括G17的片段或功能性活性变体,例如包括一个或多个点突变的那些,或者包括除G17以外的其它氨基酸序列的肽或多肽,例如通过附加一个或多个氨基酸残基或序列来延伸N末端和/或C末端。C末端的延伸例如优选用G17序列的重复(完全相同或不同),或者用胃泌素的其它氨基酸序列。
术语应具体包括具有一个或多个修饰的氨基酸残基的肽。常见的修饰包括磷酸化、甲基化、乙酰化、酰胺化、吡咯烷酮羧酸的形成、异构化、羟基化、硫酸酯化(sulfation)、黄素-结合、半胱氨酸氧化和亚硝基化。如本文所述的示例性修饰为G17的N末端谷氨酸的修饰,即1位的pyroGlu,其也称为“吡咯烷酮羧酸(Glu)”或pGlu或pE。
本文使用的关于本发明肽免疫原的术语“功能性活性变体”应指由该序列(母本序列)例如通过插入、缺失或置换一个或多个氨基酸的修饰,例如通过重组技术或化学衍生氨基酸序列中的一个或多个氨基酸或编码核苷酸序列内的核苷酸,或序列的一个或两个远端来修饰所产生的序列,并且该修饰不影响(特别是损害)该序列的活性。在肽免疫原诱发对靶胃泌素的特定免疫应答的的情况下,肽免疫原的功能性活性变体仍将包括抗原决定簇或表位,尽管这能够改变,例如增加免疫原性。具体地,G17肽免疫原或其片段例如G12或G13片段的功能性活性变体,具有引发治疗的受试者中IgG抗胃泌素抗体的潜能,所述抗体与受试者的内源胃泌素交叉反应。
功能性活性变体可例如通过借助引入一个或多个实质上不损害交叉反应性表位的修饰来改变母本肽如人、猕猴或鼠G17肽或其片段如G12或G13肽的序列以得到具有实质上相同的免疫原性的分子来获得。本文使用的术语“实质上相同的免疫原性”是指用免疫原性组合物在治疗的受试者中诱导的免疫应答或抗胃泌素IgG抗体的量,所述量优选母本肽确定的量的至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少98%或甚至至少100%,或者至少110%、至少120%、至少130%、至少140%、至少150%、至少160%、至少170%、至少180%、至少190%,例如多达200%。
在优选的实施方案中,母本肽的功能性活性变体
a)源自至少一个氨基酸置换、插入(添加)和/或删除的肽,例如包括一个或多个点突变,其中功能性活性变体具有与母本分子特定的序列同一性,例如至少50%序列同一性、优选至少60%、更优选至少70%、更优选至少80%、仍更优选至少90%;和/或
b)由肽和另外的与所述肽异源的至少一个氨基酸组成。
功能性活性变体可通过肽序列中的序列改变例如通过一个或多个点突变来获得,其中当根据本发明使用时所述序列改变实质上保持未改变的肽序列的功能。此类序列改变或点突变可包括,但不限于,(保守的)置换、添加、删除、突变和插入,例如1、2、3或4个氨基酸的改变,或者通过添加或插入一个或几个氨基酸,例如1、2、3或4个氨基酸,或者通过化学衍生一个至几个氨基酸,例如1、2、3或4个氨基酸,或者其组合,优选通过不连续的点突变。氨基酸残基中的置换可为保守置换,例如,置换一个疏水性氨基酸为可选的疏水性氨基酸。
保守置换为在侧链和化学性质相关的氨基酸家族中发生的那些。此类家族的实例为具有碱性侧链的氨基酸、具有酸性侧链的氨基酸、具有非极性脂族侧链的氨基酸、具有非极性芳族侧链的氨基酸、具有不带电的极性侧链的氨基酸、具有小侧链的氨基酸、具有大侧链的氨基酸等。
优选的点突变是指相同极性和/或电荷的氨基酸的交换。就这一点而言,氨基酸是指由64个三联密码子编码的20种自然发生的氨基酸。这20种氨基酸可分成具有中性电荷、正电荷和负电荷的那些:
“中性”氨基酸如下所示,以它们相应的三个字母和单字母密码子和极性示出:
丙氨酸:(Ala,A)非极性,中性;
天冬酰胺:(Asn,N)极性,中性;
半胱氨酸:(Cys,C)非极性,中性;
谷氨酰胺:(Gln,Q)极性,中性;
甘氨酸:(Gly,G)非极性,中性;
异亮氨酸:(Ile,I)非极性,中性;
亮氨酸:(Leu,L)非极性,中性;
甲硫氨酸:(Met,M)非极性,中性;
苯丙氨酸:(Phe,F)非极性,中性;
脯氨酸:(Pro,P)非极性,中性;
丝氨酸:(Ser,S)极性,中性;
苏氨酸:(Thr,T)极性,中性;
色氨酸:(Trp,W)非极性,中性;
酪氨酸:(Tyr,Y)极性,中性;
缬氨酸:(Val,V)非极性,中性;和
组氨酸:(His,H)极性,正电(positive)(10%)中性(90%)。
带“正”电的氨基酸为:
精氨酸:(Arg,R)极性,正电;和
赖氨酸:(Lys,K)极性,正电。
带“负”电的氨基酸为:
天冬氨酸:(Asp,D)极性,负电;和
谷氨酸:(Glu,E)极性,负电。
关于本文所述的肽序列的“氨基酸序列同一性的百分比(%)”定义为在比对序列和引入空隙(根据需要,以实现最大序列同一性百分比)之后,且不考虑任何保守置换作为部分序列同一性,在特定肽序列中的与氨基酸残基同一的氨基酸残基的百分比。本领域技术人员可确定实适当的参数来测量比对,包括任何实现要比较的全长序列的最大比对所需的算法。
功能性活性变体可通过任何已知的诱变法获得,包括在期望位置的点突变,例如通过随机化(randomisation)技术获得。在某些情况中,例如在任何可能的氨基酸或者选择优选的氨基酸随机选择位置,从而随机化肽序列。就这一点而言,术语“诱变”是指用于改变多核苷酸或多肽序列的任何本领域认知的技术。
本文使用的术语“免疫原”应指触发受试者免疫应答的一个或多个抗原。本文使用的术语“抗原”应特别指任何抗原决定簇,其能够被抗体的结合位点可识别,或能够结合至HLA I类或II类分子的肽沟槽,并由此可充当特定T细胞的刺激物。靶抗原或者作为整个靶分子被识别或作为此类分子的片段被识别,特别是亚结构,例如靶标的多肽或糖结构,通常称作“表位”,例如为免疫相关的B-细胞表位、T-细胞表位,即还可被自然或单克隆抗体识别。这里,优选使用T细胞表位,例如以提供变态反应疫苗。
本文使用的术语“肽免疫原”应指肽结构的抗原或免疫原,特别是包括特定氨基酸序列的肽或由其组成的免疫原,所述肽以线形肽或支化肽提供,包括自然发生的氨基酸残基或修饰的氨基酸残基,例如通过修饰或化学衍生例如通过磷酸化、甲基化、乙酰化、酰胺化、吡咯烷酮羧酸的形成、异构化、羟基化、硫酸盐化、黄素-结合、半胱氨酸氧化和亚硝基化获得的衍生物。
肽免疫原具体设计为触发受试者的免疫应答,特别包括一个或多个抗原决定簇,能够被抗体的结合位点可识别,或能够结合至HLA I类或II类分子或其它抗原呈递分子如CD1的肽沟槽,并由此可充当特定T细胞的刺激物。靶抗原作为整个靶分子被识别或作为此类分子的片段被识别,特别是亚结构,例如靶标的多肽或糖结构,通常称作“表位”,例如为免疫相关的B-细胞表位、T-细胞表位,即还可被自然或单克隆抗体识别。这里,优选使用T细胞表位,例如以提供肿瘤学疫苗。
根据本发明在本文使用的术语“表位”应特别指完全组成与本发明的模块抗体(modular antibody)的结合位点特异性结合的伴侣或为特异性结合的伴侣的一部分的分子结构。术语表位还可指半抗原。在化学上,表位可由糖类、肽、脂肪酸、有机物、生化物质或无机物或其衍生物及其任意组合所组成。如果表位为多肽,其将通常包括至少3个氨基酸,优选至少4、5、6、7、8、9、10、11、12或13个氨基酸。肽的长度没有临界上限,其可包括几乎蛋白质的多肽序列的全长。表位可为线性或构象表位。线性表位包括多肽或糖链的一级序列的单片段。线性表位可连续或重叠。构象表位由通过多肽折叠形成三级结构而交汇在一起,且氨基酸在线性序列上不必彼此邻近的氨基酸或糖类构成。具体地,表位为诊断相关分子的至少一部分,即,样品中表位存在与否与患者的疾病或与健康状况或者与制造中的进程状态或者与环境和食品状况相关的定性或定量相关。表位还可为治疗相关分子的至少一部分,即可通过改变疾病进程的特异性结合结构域靶向的分子。
同一抗原或不同抗原的一个或多个表位可根据本发明使用,可包括期望调节免疫应答的所有自体抗原、病原体、变应原或自身抗原的抗原,例如期望在宿主中针对这些抗原诱导大量Th1-型应答或Treg应答(依赖于疫苗的类型)。
在癌症疾病中,期望对自体抗原的免疫应答。本文使用的术语"自体抗原"意指任何抗原,具体为由正常、健康受试者产生的本身不引起免疫应答的多肽或肽。这些自体抗原可在某些疾病状态包括癌症疾病下异常或高水平产生,所谓的肿瘤相关抗原(TAAs)。这里,人胃泌素或人G17被视为人受试者的自体抗原,并具体为患有胃泌素依赖性肿瘤的受试者中的TAA。与自身免疫病相关的自体抗原在本文称为自身抗原。
要理解的是,自体抗原可自然产生、重组或合成产生。还要理解的是,自体抗原不需与自然产生的抗原一致,而是可包括与自然产生的抗原的具有特定序列同一性、相似度或同源性的变体。
用于癌症治疗的自体抗原的选择依赖于癌症疾病的类型和阶段,并且特别依赖于例如源自肿瘤或转移瘤的癌细胞表达模式。可用于根据本发明的疫苗的选择的肿瘤相关抗原的具体实例为表皮细胞粘附分子(EpCAM)、路易斯Y、α-甲胎蛋白(AFP)和癌胚抗原(CEA)、HER2/Neu、MUC-1等。
用于自身免疫病治疗的自身抗原的选择依赖于自身免疫病的类型。可用于根据本发明的疫苗的选择的自身免疫病相关抗原的具体实例为C1q、ADAMTS13、桥粒蛋白(Desmogelin)3、角蛋白、神经节甘酯(如GM1、GD1a、GQ1b)、胶原型IV、IgM、心磷脂、膜联蛋白A5等。
在某些实施方案中,免疫原包括一个或多个特定变应原。“变应原”为可起始超敏型状态,或者其可驱使已被变应原敏化的受试者的速发型超敏反应的抗原。变应原为具有引起过敏症的性质的常见蛋白质或与蛋白质结合的化学物质。然而,变应原还可包括源自各种合成或自然来源的有机或无机物质,例如植物物质、金属、化妆品或洗涤剂中的成分或乳胶等。
用于抗变态反应治疗的变应原的选择依赖于变态反应的类型和严重程度。可用于根据本发明的疫苗的选择的变应性相关抗原的具体实例为常用作免疫原的任意变应原,具体为室尘螨变应原(如Der p1、Der p2、Der p3/------Der p23、Der f1、Der f2、Derf3/---Der f23)、猫皮屑、草或树花粉、蟑螂变应原等。
用于预防或治疗传染病的特异性诱导针对病原体的免疫应答的抗原的选择依赖于病原体的类型,例如微生物或病毒感染剂。可用于根据本发明的疫苗的选择的病原体来源的抗原的具体实例为乙型肝炎、丙型肝炎、霍乱、HIV、百日咳、流行性感冒、伤寒等。
用于根据本发明的疫苗的肽免疫原或免疫原性组合物通常以有效量包含在疫苗中,在本文具体理解为“免疫有效量”。"免疫有效量",意指以单一剂量或作为系列剂量的一部分向受试者给药的量,基于治疗或预防目的而有效。该量将依赖于要治疗的受试者的健康和生理状况、受试者年龄、免疫系统合成抗体的能力、期望的免疫应答的程度、疫苗制剂和其它状态而变化。
本发明还提供治疗受试者或增加受试者免疫应答的方法,所述方法包括给药免疫有效量的本发明的肽免疫原、免疫原性组合物或疫苗的步骤。
有效量或剂量可在向需要的受试者给药的免疫原性组合物的0.0001至2mg范围内,例如在0.001和2mg范围内。有效剂量的免疫原性组合物能够在患者中诱发有效水平的抗体滴度的免疫应答,从而在例如免疫后的1-3个月结合并中和内源成熟和前体G17。治疗的有效性可通过在从受试者采集的血样中的抗胃泌素抗体滴度来测定。
本文使用的术语“TLR9配体”以下述方式理解。
Toll-样受体9(TLR9)识别未甲基化的细菌CpG DNA并起始信号转导级联,导致促炎细胞因子的产生。已显示多种结构或序列充当TLR9的配体,即结合至该受体,从而激活(刺激,上调,TLR9激动剂)或去激活(下调,TLR9拮抗剂)TLR9。例如,微生物DNA或合成DNA,例如CpG二聚体的数量和位置以及CpG二聚体侧翼的精确的碱基序列变化的合成的CpG ODN可刺激TLR9。合成的CpG ODN与微生物DNA的不同在于,它们具有部分或完全硫代磷酸酯化骨架代替典型的磷酸二酯骨架,并在3'端、5'端或两端可或不可具有poly G尾。
本文使用的与TLR9配体缀合的术语“激动剂”应具体指在基于细胞的测定中TLR9的结合和激活。
由核苷酸序列组成的TLR9配体典型地通过化学偶联如使用来自Solulink的商购可得的KIT偶联至本免疫原性组合物的导向佐剂组分。肽的TLR9配体可使用标准肽化学偶联,或可使用重组DNA技术来整合。
示例性TLR9配体为ODN 221638(组1)、ODN 2006/ODN 200739(组2)和CpG-M36240(组3)。
另外的示例性TLR9配体可为例如通过肽文库鉴定或由肽文库获得的,模拟CpGTLR9激动剂的作用的肽(其通过结合TLR9的亲和性来选择并已证实激动活性),或者为包括特定抗体的蛋白质配体。
具体的TLR9配体为免疫刺激肽,例如模拟CpG类任一种的那些,例如选自适当肽文库的肽的那些。示例性免疫刺激肽选自由下列组成的组:ESWDKFLSHYLP(SEQ ID 50)、TDWSWFY(SEQ ID 51)、YPVYWPW(SEQ ID 52)、EWWFYWP(SEQ ID 53)、WFPIEWW(SEQ ID 54)、DQVDIGY(SEQ ID 55)、THQVYIS(SEQ ID 56)、WFPIEWWFYWP(SEQ ID 57)、5DSWQAFLTKFVL(SEQ ID 58)、HDIQWFWQHWNS(SEQ ID 59)、WSWWDHTFNYML(SEQ ID 60)、TTQQTWNVRYPY(SEQID 61)、DHTMPWTRNAKN(SEQ ID 62)、SWDPYWPFPWFS(SEQ ID 63)、AIYYVPSPMFTV(SEQ ID64)、ETTLLKMWLAQM(SEQ ID 65)、YPWLDVAVVSLY(SEQ ID 66)、VPGWHYLATLRA(SEQ ID 67)和FDPLGSRDIKGS(SEQ ID 68),和其功能性活性变体,为其片段、突变体或杂合体。
更具体地,功能性活性变体刺激pDCs,从而与阴性对照相比诱导升高水平的IL-6和TNFα。
具体地,功能性活性变体
a)具有与SEQ ID 50-68的任意肽的至少60%的同源性;
b)为SEQ ID 50-68的任意肽的突变体,可通过借助插入、删除或置换序列中的或者序列的远端之一或二者中的一个或多个氨基酸来修饰母体氨基酸序列获得;或
c)为SEQ ID 50-68的任意肽的片段,包括至少5个氨基酸。
具体免疫刺激肽包括选自由EWWFYWP(SEQ ID 53)、EWW(SEQ ID 125)、WFY(SEQ ID126)、YWP(SEQ ID 127)和QVxI组成的组的基序,x为任意氨基酸(SEQ ID 128)。
TLR9配体或激动剂或拮抗剂的功能可在适当的测定中确定,例如以下列方式确定:如Tel等人41描述的,将pDC从健康供体的血液中纯化,随后在适当浓度的TLR9配体下温育。在24小时后,使用标准ELISA实验方案在上清液中测量IFNa。为了确定细胞的突变状态,在与TLR9配体温育前后使用标准FACS步骤用商购可得的特定抗体染色表达CD80、CD83或CD86的pDC。
在暴露于根据本发明的疫苗时激活的反应性T细胞的数量可通过多种方法确定,所述方法包括ELISPOT、FACS分析、细胞因子释放或T细胞增殖测定。
如本文所述,术语“特异性”或“特异性结合”是指在异源分子群体中决定感兴趣的同源配体的结合反应。因此,在设计的条件(例如免疫测定条件)下,一个或多个抗原通过相应的结合子的一个(或多个)结合位点特异性结合,不以显著量与样品中存在的其它分子结合。特异性结合意指当选择时在靶标同一性、高、中或低结合亲和性或亲和力(avidity)方面结合是选择性的。如果结合常数或结合动力学为至少10倍不同,优选该差为至少100倍,更优选至少1000倍,则通常实现选择性结合。容易理解的是,该术语还应涉及特异性识别一种或多种不同抗原的交叉反应性或多特异性结合子。
本文使用的术语“治疗”应总是指以预防性(即预防感染和/或疾病状况)或治疗性(即,治疗疾病,而不管他们的发病机理)目的治疗受试者。受试者的治疗在变态反应性、自身免疫或癌症病况的情况下将典型的为治疗性的,或者在治疗传染病病况时是预防性的。受试者的治疗在癌症病况,包括胃泌素依赖性肿瘤或胃泌素依赖性癌症的情况下将典型地为治疗性的。然而,在患者患有原发性疾病的情况下,其处在疾病进展的风险下或处在发展继发性病况或副反应的风险下,例如其依赖于胃泌素作用的内源胃泌素产生,则该治疗可为预防性的。
再者,在变态反应患者例如由于变态反应家族史而处于发展疾病的风险的情况下,治疗可为预防性的。
此类治疗可在根据本发明的疫苗作为唯一的预防剂或治疗剂,或者与任何适当的手段组合例如包括化学治疗或抗酸药的使用下起作用。
在这一点上使用的术语“组合”,例如关于化合物或治疗的组合具体是指伴随、同时、平行或连续治疗受试者。
根据本发明治疗下列具体变态反应性疾病:过敏性鼻结膜炎(allergicrhinoconjunctivitis)(枯草热)、过敏性哮喘、过敏性湿疹,例如特应性湿疹或特应性皮炎。
对于变态反应治疗,特别是额外的治疗措施包括在过敏性哮喘中施用与支气管扩张器组合的(吸入式)皮质类固醇,(特应性湿疹)和较温和形式的变态反应(如枯草热)中应用含有霜的类固醇,抗组胺和特异性免疫治疗。
变态反应,其中极化的Th2应答,丰富的IL-4/IL-13分泌和IgE抗体应答是不宜且有害的,且刚好为失败的免疫应答的实例。其它实例的特征在于与系统性自身免疫病相关的Th1-介导的病况。
利用根据本发明的疫苗治疗自身免疫病在其它实例中可具体指糖尿病、格林巴利综合征(Guillain Barre syndrome)、系统性红斑狼疮、多发性硬化症或血小板减少症。
采用根据本发明的疫苗预防或治疗传染病具体是指病理状态,例如微生物感染,即由细菌、病毒、真菌、原生动物或肠虫病原体引起的病况。为了本发明的目的,在广义上使用术语“病原体”,指疾病或病况的特定致病试剂,且包括引发免疫应答的任何试剂。病原体包括病毒、细菌、真菌、原生动物和寄生生物等。典型的,免疫原源自由病原体产生的一种或多种肽、多肽、蛋白质或糖类抗原。用于鉴定适当抗原、获得和制备此类分子的方法是本领域公知的。
治疗由病原体引起的传染病具体是指,例如乙型肝炎、丙型肝炎、霍乱、HIV、百日咳、流行性感冒或伤寒。
如本文所述治疗肿瘤的免疫治疗具体是指根据本发明的方法和疫苗用于治疗宫颈癌、乳腺癌、结直肠癌、前列腺癌、肺癌和黑素瘤。
在癌症治疗中,额外的治疗性治疗包括例如手术切除、放射治疗、化学治疗、激素治疗、抗肿瘤疫苗、基于抗体的治疗、全身辐射、骨髓移植、外周血干细胞移植和化疗剂的施用。
对于根据本发明的免疫原性组合物或疫苗的治疗可一次给药,或可分成单独的组分和/或多个较小剂量以间隔时间给药。疫苗典型地以0.1至500μg/mL的浓度,例如皮下、皮内、肌内、静脉、口服、通过吸入或鼻内、利用或不利用附加佐剂如ALUM给药。要理解的是,精确剂量和治疗持续时间为要治疗疾病的函数,并且可使用已知的测试方案以经验确定,或由体内或体外试验数据外推来确定。
本发明的免疫原性组合物或疫苗可通过任何适合的手段和相应的制剂给药,包括但不限于,例如任何肠胃外(包括皮下、肌内、静脉和皮内)注射,或局部注射至作用部位例如关节中或注射至肿瘤内或肿瘤周围。在优选的实施方案中,疫苗以肌内、皮下或皮内注射用制剂提供。
本发明还提供递送装置,例如预填有根据本发明疫苗的注射器。
典型地,在通过根据本发明疫苗的第一次注射预激(priming)受试者时,一次或多次加强注射可在一段时期内通过相同或不同给药途径进行。在使用多次注射时,随后的注射可例如在先前注射的1至52周内或甚至更长期内进行。
疫苗典型地可包含稀释液,例如水、盐水、甘油、乙醇等。另外,作为辅助物质,例如湿润剂或乳化剂和pH缓冲物质等可存在于赋形剂中。典型地,根据本发明的疫苗制备为可注射的,为液体溶液或悬浮液,或适合于在给药前在液体载体中的溶液或悬浮液的固体形式。制剂还可为在脂质体中乳化或胶囊化。
根据本发明的疫苗的给药可适当地和另外地与任何TLR9激动剂或拮抗剂和/或另外的佐剂措施结合,以增强免疫调节效果或免疫应答。增强的免疫应答可包括一个或多个增强的Th1免疫应答、Th2免疫应答、Th17免疫应答或Treg免疫应答。
增强的Th1免疫应答可包括一种或多种与Th1免疫应答相关的细胞因子(如IFNγ)的增加,和激活的巨噬细胞的增加。
增强的Th1免疫应答可包括一种或多种抗原特异性IgG抗体、特别是IgG1抗体的增加。
例如,本发明的免疫原性组合物或疫苗,可与一种或多种佐剂和/或药学可接受赋形剂相关(例如通过亲和结合或单独组分的混合物化学或重组连接、结合)。根据本发明的疫苗可包括一种或多种药学可接受赋形剂或载体,例如水、盐水、甘油、乙醇等。另外,辅助物质,如湿润剂或乳化剂和pH缓冲物质等可存在于此类载体中。佐剂可特别地用于增强疫苗的有效性。佐剂可直接加入疫苗组合物中,或可单独给药,与疫苗给药同时或在疫苗给药之后不久。
适合的佐剂包括辅助协调对免疫原的免疫应答的细胞因子和类似的化合物。如本文使用的,术语"细胞因子"用作以纳摩至皮摩浓度充当体液调节剂的不同类群的可溶性蛋白质和肽的通用名称,其在正常或病理条件下,调节个体细胞和组织的功能活性。这些蛋白质还直接介导细胞之间的相互作用并调节发生在细胞外环境中的进程。
细胞因子的实例包括IL-1、IL-4、TNFα、IFNα、INFγ、GM-CSF、G-CSF。
CpG寡核苷酸也可用作与相应表位的呈递协同的佐剂。其它佐剂包括alum、(不)完全弗氏佐剂、百日咳杆菌(B.pertussis)或其毒素、IC31等。
免疫原性组合物的组分,即导向佐剂组分,例如连接至TLR9配体和第一肽α-螺旋的抗CD32部分,以及免疫原组分,例如包括连接至与第一α-螺旋相匹配的第二肽α-螺旋的肽免疫原,以及免疫原性组合物或疫苗,或任何其结合部分或配体,和含有或不含有卷曲重复的免疫原,可通过本领域已知的各种方法获得,例如通过从细胞培养物中纯化或分离、重组技术或通过化学合成来获得。
根据特定的实施方案,免疫原性组合物和/或导向佐剂组分和/或其免疫原组分例如通过重组DNA技术生产为重组多肽。如本文使用的,术语“重组”是指不在宿主细胞中天然产生的分子或构建体。在某些实施方案中,重组核酸分子包含以不是天然产生的方式连接在一起的两个或多个天然产生的序列。重组蛋白是指由重组核酸编码和/或表达的蛋白质。在某些实施方案中,“重组细胞”表达未在细胞的天然(即,非重组)形式中的同一形式中发现的基因,和/或表达由故意的人为干涉引起的另外的异常过表达的、表达不足的和/或根本不表达的天然基因。重组细胞包含至少一种重组多核苷酸或多肽。“重组作用”、“重组”和产生“重组的”核酸一般囊括至少两个核酸片段的组装。在某些实施方案中,重组蛋白和重组核酸仍保留功能,即在宿主细胞中保持它们的活性或显示增强的活性。
因此,本发明进一步指免疫原性组合物或其组分的生产,此类生产用重组手段,包括编码氨基酸序列的核酸,包括编码要表达的氨基酸序列的核酸的表达盒、载体或质粒,以及包括任何此类手段的宿主细胞。适合的标准重组DNA技术在本领域是已知的,且特别记载于Sambrook等人的“Molecular Cloning:A Laboratory Manual”(1989),第2版(冷泉港实验室出版社)。
术语“敏化疫苗”在本文理解为下列方式。受试者可进行对除免疫原以外的疫苗组分的特殊敏化,从而诱导特定的体液免疫应答。根据本发明,受试者例如通过根据本发明的敏化疫苗的处理来敏化,所述疫苗包括导向佐剂和肽的α-螺旋,优选卷曲螺旋或双螺旋来稳定化分子。因此,如在根据本发明的免疫调节疫苗中使用的免疫原具体不用于此类敏化疫苗。在给药此类敏化疫苗至受试者时,受试者可发展对敏化疫苗的表位的免疫应答。同一受试者用根据本发明的免疫调节疫苗进一步处理将接着诱导对治疗或预防疾病所需的免疫原的特异性免疫应答。由于敏化,例如在变态反应性患者的情况下,潜在有害的已存在的对部分免疫原的免疫记忆将不会诱导对疫苗的那些部分产生不期望的免疫反应,患者对于疫苗的这些部分在免疫前是首次接触的。
这里,术语“受试者”理解为包括人或哺乳动物受试者,包括牲畜动物、宠物和实验动物,特别是人类,其为患有特定疾病病况的患者,或为健康受试者。
本发明进一步提供用于制备本发明免疫原性组合物的组分的试剂盒,例如包括一个或多个填充有组分的容器的药物试剂盒。该试剂盒可用于上述方法。在特定的实施方案中,试剂盒进一步包括使用本发明免疫原性组合物的组分或制备的免疫原性组合物或疫苗的说明书。
疫苗组分,即导向佐剂组分和免疫原组分,以及疫苗,或其任何结合部分或配体,和含有或不含卷曲重复的免疫原,可通过本领域已知的各种方法获得,例如通过从细胞培养物中纯化或分离、重组技术或通过化学合成来获得。
因此,本发明提供独特的疫苗和相应的应用。
根据特定实例,根据本发明的疫苗包括SEQ ID 19的重组多肽,
SEQ ID 19:
N-末端下划线:特异性结合至CD32a的ScFV序列;
斜体:连接子;可使用常用于scFv制备的任何可选的连接子。
粗体:StrepTag II,用于纯化,可使用任何可选的标签,例如flag标签或HIS标签。
C-末端双下划线:七肽的重复α螺旋(pepE),以与免疫原中配对的七肽的重复α螺旋(pepK)形成卷曲螺旋。
在该实例中(SEQ ID 19),使用5个重复;更多重复可引起自身聚集,更少重复可减少亲和性。优选的卷曲使用的重复的最小功能数为3,优选的最大功能数为542-44,但更多的重复是可行的,依赖于使用何种类型的α螺旋。极限将为开始诱导同二聚化的重复数。因此,同二聚化被特别地排除。
类似的多肽可包括前导序列、例如为重组scFv的特异性抗CD32部分的氨基酸序列、连接子、用于纯化目的的标签和肽的α-螺旋pepE的序列。含有或不含有TLR9配体的该构建体也称为“弹头”,其可接着用于通过与连接至配对的α-螺旋pepK的免疫原组合来构建疫苗。
根据另一具体实例,抗CD32部分为具有用作ScFv替代物的SEQ ID 20:ADGAWAWVWLTETAVGAA45的序列的抗CD32a肽。
根据另一实例,制备包括变应原如Der P1和Der P2T细胞表位的包含卷曲的免疫原。肽的α-螺旋通过连接子适当连接至免疫原以允许柔性。
根据另一实例,稳定的卷曲螺旋在弹头scFv和免疫原之间建立。
根据另一实例,制备包含卷曲的免疫原,其包括变应原的约29个不同的T细胞表位。
在另一实例中,可显示弹头介导的增强的抗原呈递。当含有卷曲(pepK卷曲)的免疫原与含有配对卷曲(pepE卷曲)的弹头相互作用时,T细胞被有效地刺激。
在另一实例中,已证实TLR9激动剂CpG介导自身免疫反应性T细胞的激活。
仍在另一实例中,描述了使用弹头治疗变态反应,弹头采用通过卷曲螺旋与变应原特异性免疫原连接的抗CD32scFv或抗CD32a肽。
根据另一实例,稳定的卷曲螺旋在弹头scFv和免疫原之间建立。
已证实,PBMC能够被此类免疫原或疫苗有效地刺激。
在另一实例中,能够显示弹头介导的增强的抗原呈递。当含有卷曲(pepK卷曲)的免疫原与含有配对卷曲(pepE卷曲)的弹头相互作用时,T细胞被有效地刺激。
在另一实例中,描述了在小鼠模型和猕猴模型中使用弹头治疗胰腺癌,弹头采用通过卷曲螺旋连接至G13肽免疫原的抗CD32scFv或抗CD32a肽。在猕猴模型中描述了食欲减少和食欲控制。
因此,本发明提供独特的免疫原性组合物和疫苗,以及相应的应用。
参考下列实施例,前述描述将更完全地理解。然而,此类实施例仅为实施本发明的一个或多个实施方案的代表性方法,而不应理解为限定本发明的范围。
实施例
实施例1:含有卷曲的ScFV弹头
氨基酸序列1.(SEQ ID 21)
AA 1-19:前导序列(以分泌产物)
ScFV的IAA 20-271序列(VH结构域为下划线,Vl为双下划线,VH和VL结构域的顺序可交换)
IAA140-154连接子可改为用于ScFV制备的任何连接子。
AA 272-279:StrepTag II,用于纯化,可交换为任何可选的标签,例如flag标签或HIS标签。
AA280-281:短连接子(也许更长)
AA282-316:七肽的重复α-螺旋(pepE),以与免疫原中配对的七肽的重复α-螺旋(pepK)形成卷曲螺旋。在本实施例中,使用5个重复,更多重复可引起自身聚集,更少重复可减少亲和性,然而,4个重复仍具功能性。使用的卷曲重复的最小功能数为3和546-48。
TRL9激动剂如CpG可使用化学偶联例如使用Solulink抗体–低聚偶联KIT偶联至弹头。肽TRL9激动剂可使用标准肽化学偶联。
实施例2:包含卷曲螺旋的肽弹头
氨基酸序列2(SEQ ID 22):
aCD32a肽的AA1-19的序列,由Berntzen等人45公布
IAA20-24和AA32-33:连接子,可改为任何连接子,也可改为较长的连接子,以允许两个相连序列之间的柔性。
AA24-31:StrepTag II,用于纯化,可交换为任何可选的标签,例如flag标签或HIS标签。
AA34-68:七肽的重复α-螺旋(pepE),以与免疫原中配对的七肽的重复α-螺旋(pepK)形成卷曲螺旋。在本实施例中,使用5个重复,更多重复可引起自身聚集,更少重复可减少亲和性,然而,4个重复仍具功能性。卷曲使用的重复的最小功能数为3和549-51。
TRL9激动剂如CpG可使用化学偶联例如使用Solulink抗体–低聚偶联KIT偶联至弹头。肽TRL9激动剂可使用标准肽化学偶联。
实施例3:含有卷曲的免疫原3(基于人II类表达的Der P1和Der P2T细胞表位)
氨基酸序列3(SEQ ID 23):
用于纯化的AA1-6His标签可交换为任何类型的标签,例如flag标签或StrepTagII。标签还可位于连接子和α-螺旋之间(参见实施例4)。C末端不优选,这是由于其可干扰卷曲螺旋的功能性。
AA208-219:变应原肽之间的连接子,且连接子可交换为任何其它的连接子,以允许两个相连序列之间的柔性。下划线半胱氨酸可从序列中除去。
AA220-254:七肽的重复α-螺旋(pepK),以与弹头中配对的七肽的重复α-螺旋(pepE)形成卷曲螺旋。在本实施例中,使用5个重复,更多重复可引起自身聚集,更少重复可减少亲和性,然而,4个重复仍具功能性。卷曲使用的重复的最小功能数为3和552-54。
AA6-54:来自Der p1的T细胞表位(天然蛋白质的AA181-220):
粗体和斜体为预测的由HLA类呈递的T细胞表位
AA55-88:来自Der p1的T细胞表位(95-128):
粗体和斜体为预测的由HLA类呈递的T细胞表位
AA89-108:来自Der p2的T细胞表位:(天然蛋白质的AA85-104):
粗体和斜体为预测的由HLA类呈递的T细胞表位
AA109-134:来自Der p2的T细胞表位:(天然蛋白质的AA105-130):
粗体和斜体为预测的由HLA类呈递的T细胞表位
AA135-183:来自Der p1的T细胞表位(天然蛋白质的AA228-276):
粗体和斜体为预测的由HLA类呈递的T细胞表位
AA184-208:来自Der p2的T细胞表位:(天然蛋白质的AA11-45):
粗体和斜体为预测的由HLA类呈递的T细胞表位
实施例4:弹头ScFV和免疫原3之间稳定卷曲螺旋的形成。
使用标准步骤将免疫原3固定化至流动池1、2、3芯片上的BIACore CM5,产生~700个应答单元,随后将弹头(10μg/ml,PBS中)注射至流动池1中,并测量时间依赖性质量增加(进行速率(on rate)),在~160秒后,缓冲液改为仅PBS。截止速率(off rate)表示弹头与免疫原细胞之间结合的稳定性,仅注射有PBS。当弹头与pepK卷曲预温育,随后注射至流动池2中时,未见弹头与芯片的结合。类似地,当芯片与pep E在注射弹头前预温育时(流动池3),未见弹头与免疫原的结合。(参见图1)
实施例5:含有卷曲的免疫原5-12(~29个Der p1、Der p2、Der p3、Der p4、Derp7、Der p9、Der p10、Der p11、Der p14、Der p15的T细胞表位,基于人II类表达)
氨基酸序列3(SEQ ID 30):
免疫原5-12:
AA1369-274,用于纯化的His标签,可交换为任何类型的标签,例如flag标签或StrepTag II。标签还可位于连接子和α-螺旋之间(参见实施例4)。C末端不优选,这是由于其可干扰卷曲螺旋的功能性。
AA365-368和375-381:变应原肽HIS标签和pepK之间的连接子。连接子可交换为任何其它的连接子,以允许两个相连序列之间的柔性。下划线半胱氨酸(Cys379)可从序列中除去。
AA382-416:七肽的重复α-螺旋(pepK),以与弹头中配对的七肽的重复α-螺旋(pepE)形成卷曲螺旋。在本实施例中,使用5个重复,更多重复可引起自身聚集,更少重复可减少亲和性,然而,4个重复仍具功能性。卷曲使用的重复的最小功能数为3和555-57。
弹头(基于ScFV卷曲1IV.3+ODNM362)与免疫原5-12以下列比例混合:表示为弹头的10%至100%通过卷曲螺旋结构结合至免疫原,优选其中没有或小于50%的游离免疫原,并在Alum上配制。
作为实施例并在下文中进一步描述,根据优选的实施方案,本发明提供其中本发明免疫调节疫苗包括下述的疫苗:
-导向佐剂,其由连接至第一α-螺旋的抗CD32部分组成,包括SEQ ID 70的序列或由其组成,例如以1:1-18的比例(分子/分子)偶联至SEQ ID 69的TLR9配体;和
-免疫原,其包括连接至第二α-螺旋、优选SEQ ID 75、或其功能性活性变体(优选其中Cys379除去的变体)的SEQ ID 30的免疫原,或由其组成,其中变应原来源的肽的顺序可改变,
其中,导向佐剂和免疫原通过由第一和第二α-螺旋形成的卷曲螺旋结构而彼此结合。
T细胞表位(在immo5-12中存在15个变应原来源的肽:1-2-3-4-5-6-7-8-9-10-11-12-13-14-15)。源自HDM变应原的肽的顺序为溶解度而优化,但任何其它顺序也将是可行的。
1)AA:1-14 Der p2(天然蛋白质的AA116-129)
粗体和斜体为预测的由HLA类呈递的T细胞表位
2)AA:15-51 Der p11(天然蛋白质的AA697-733)
粗体和斜体为预测的由HLA类呈递的T细胞表位
3)AA:52-72 Der p1(天然蛋白质的AA95-115)
粗体和斜体为预测的由HLA类呈递的T细胞表位
4)AA:73-92 Der p10(天然蛋白质的AA219-238)
粗体和斜体为预测的由HLA类呈递的T细胞表位
5)AA:93-106 Der p2:(天然蛋白质的AA85-98)
粗体和斜体为预测的由HLA类呈递的T细胞表位
6)AA:107-132 Der p1(天然蛋白质的AA251-276)
粗体和斜体为预测的由HLA类呈递的T细胞表位
7)AA:133-150 Der p4(天然蛋白质的AA2-19):
粗体和斜体为预测的由HLA类呈递的T细胞表位
8)AA:151.181 Der p7(天然蛋白质的AA66-96):
粗体和斜体为预测的由HLA类呈递的T细胞表位
9)AA:182-203 Der p1(天然蛋白质的AA228-252)
粗体和斜体为预测的由HLA类呈递的T细胞表位
10)AA:204-235 Der p9(天然蛋白质的AA54-85):
粗体和斜体为预测的由HLA类呈递的T细胞表位
11)AA:236-260 Der p1(天然蛋白质的AA181-205)
粗体和斜体为预测的由HLA类呈递的T细胞表位
12)AA:261-271 Der p2(天然蛋白质的AA105-115)
粗体和斜体为预测的由HLA类呈递的T细胞表位
13)AA:272-294 Der p15(天然蛋白质的AA251-273)
粗体和斜体为预测的由HLA类呈递的T细胞表位
14)AA:295-327 Der p3(天然蛋白质的AA58-90)
粗体和斜体为预测的由HLA类呈递的T细胞表位
15)AA:328-364 Der p14(天然蛋白质的AA1061-1097)
粗体和斜体为预测的由HLA类呈递的T细胞表位
实施例6:猴PBMC用免疫原3的刺激
Der p1敏化的猕猴(macaca mulatta)的PBMC(100.000/孔)在培养基3Der p1或3和5μg/ml的免疫原3中,一式三份,在37℃/5%CO2下在20U/ml IL-2的存在下培养。增殖通过在2天培养的最后18小时期间并入[3H]-胸苷(0.5μCi/孔)来分析。收集细胞用于β-闪烁计数(β-scintillation counting,Topcount NXT,Packard,Ramsey,MN,USA)。结果以每分钟计数表示。另外,从平行培养中,一式两份使用商购可得的ELISA试剂盒(U-Cytech,Utrecht,The Netherlands)根据制造商的说明分析上清液的IL-10和GM-CSF的水平。参见图2。
在增殖或在细胞因子生产中都不存在对Der p1或对免疫原3的应答之间的非显著性差异,表明基于人HLA II类表达选出的免疫原3中的T细胞表位同样好地由猕猴II类分子呈递。
实施例7:WH介导增强的抗原呈递
Der p1敏化的猕猴(macaca mulatta)的PBMC(100.000/孔)用1μg/ml的弹头ScFV预温育(10分钟,冰上)并用PBS洗涤3次,或仅用PBS预温育并洗涤三次。随后,这些细胞用不同浓度的免疫原3或3μg/ml的Der p1温育(30分钟,冰上)并用PBS洗涤3次,其后将细胞在37℃/5%CO2下在20U/ml IL-2的存在下培养48小时。作为阳性对照,PBMCs(无弹头温育)用3μg/ml Der P1温育而不洗涤,并在37℃/5%CO2下在20U/ml IL-2的存在下培养。增殖通过在2天培养的最后18小时期间并入[3H]-胸苷(0.5μCi/孔)来分析。收集细胞用于β-闪烁计数(Topcount NXT,Packard,Ramsey,MN,USA)。结果以每分钟计数表示。参见图3。
为了刺激T细胞,抗原需要内化并由抗原呈递细胞加工。这可通过在抗原的存在下培养T细胞和APC或者通过将抗原靶向能够内化并迁移至溶酶体的细胞表面受体来实现58-62。在与文献一致下,PBMC用预温育的免疫原在弹头的缺失下刺激并不导致增殖(数据未示出)。再者,用Der p1在弹头的存在下预温育并不导致增殖。然而,当PBMC用1μg/ml弹头ScFV预温育、洗涤并随后用不同的免疫原3浓度温育并洗涤时,可见剂量依赖性刺激,在PBMC在3μg/ml的Der p1的存在下培养48小时而不洗涤下甚至高于阳性对照。所以,仅当免疫原(包含pepK卷曲)能够与弹头(包含pepE卷曲)反应以便形成稳定的卷曲螺旋时,可见刺激。与Der P1组合的弹头并不导致刺激,这是由于Der P1缺乏卷曲且不与PBMCs结合。
实施例8.CpG介导的自身免疫反应性T细胞的激活
Der p1敏化的猕猴(macaca mulatta)或正常人供体的PBMC(100.000/孔)用50μMCpG或CpG-biot温育,一式三份。平行地,PBMCs预温育(30分钟,冰上)1μg/ml生物素化弹头ScFV,洗涤3x,随后用50μM CpG温育。一式两份使用商购可得的ELISA试剂盒根据制造商的说明分析上清液的IL-4和IFNγ的水平。参见图4。
CpG不诱导猴或人细胞中的特异性T细胞应答(左侧柱),也不增强或诱导对共给药的生物素化蛋白质的T细胞应答(右侧柱)。仅当CpG和生物素物理连接时(绿色柱),才诱导对生物素的特异性应答。由于生物素(也称为维生素b7、维生素H或维生素B8)为自体分子,不应发生免疫应答。然而,当生物素通过TLR9激活的APC呈递时,T细胞耐受被破坏,表明物理连接TLR9激动剂至自体蛋白将导致免疫应答,在自体蛋白为肿瘤相关抗原(TAA)的情况下可用于治疗癌症。物理连接意指直接偶联至TAA或使用弹头和TAA间接与卷曲偶联(或包含),该卷曲与弹头的卷曲相互作用。优选后者。TRL9激动剂与TAA之间任何其它形式的复合体可很好地使用,只要保证TLR9激动剂和TAA被同一APC吸收即可。
实施例9:癌症治疗
与治疗变应性相反,用于治疗癌症的弹头应主要结合至CD32a而不是CD32b。来自实施例1和2的弹头优选用于癌症治疗。
实施例10:人PBMC用免疫原5-12的刺激
Der p1敏化的正常供体的PBMC(100.000/孔)在培养基3μg/ml Der p1或5、1或0.5μg/ml免疫原5-12(Immo5-12)中,一式三份,在37℃/5%CO2下在20U/ml IL-2的存在下培养。一式两份使用商购可得的ELISA试剂盒(eBioscience)根据制造商的说明分析上清液的IL-10和IFNg的水平。参见图5。
实施例11:自身免疫病的治疗
疫苗包括识别CD32a和CD32b卷曲螺旋的弹头和与自身抗原结合的诱导抑制性TLR9信号转导(参考)的TLR9拮抗剂或激动剂。此类疫苗将不诱导针对疫苗任何部分(包括自身抗原)的新抗体,因此对于此类患者使用是安全的。在该疫苗中抑制性CpG(抑制性ODN)的使用将诱导T reg细胞针对包括自身抗原的疫苗。同样发生在使用组1或2的CpG激动剂时。组3的TLR9激动剂不优选,虽然这将导致更多的自身免疫的诱导。参见图4。
实施例12:代表性结合子
12.1.CD32结合区,本文也称为抗CD32部分或CD32结合子
CD32a结合子:
特异性结合至CD32a的抗体:mAb IV.3(Stuart等(1987)J.Exp.Med.166:1668)
源自mAb IV.3的ScFV(VH-连接子-VL):(SEQ ID 44)
下划线:VH结构域
粗体:HL结构域
正常类型设定。柔性连接子(可为任何连接子)
抗CD32a肽:Berntzen等人(J.Biol.Chem.(2009)284:1126-1135):
(SEQ ID 45)
ADGAWAWVWLTETAVGAAK
组CD32a+b结合子:
特异性结合至CD32a和CD32b的抗体:mAb AT-10(AbD Serotec)
源自mAb AT-10的ScFV(VH-连接子-VL):(SEQ ID 46)
下划线:VH结构域
粗体:HL结构域
正常类型设定。柔性连接子(可为任何连接子)
IgG1Fc片段(CH2-CH3结构域):(SEQ ID 47)
()之间为铰链区,可删除
下划线:CH2结构域
粗体:CH3结构域
12.2TLR9结合区或部分,本文还称为TLR9结合子或TLR9配体
CpG A类
组CpG-A:
ODN2216:(SEQ ID 48)
GGGGGACGATCGTCGGGGGG
CpG B类
组CpG-B:
天然配体:
ODN2006:(SEQ ID 49)
TCGTCGTTTTGTCGTTTTGTCGTT
肽的配体(免疫刺激肽):
名称 | SEQ ID | 序列 |
12-2 | 50 | ESWDKFLSHYLP |
7-6 | 51 | TDWSWFY |
7-7 | 52 | YPVYWPW |
7-12 | 53 | EWWFYWP |
7-13 | 54 | WFPIEWW |
7-37 | 55 | DQVDIGY |
7-38 | 56 | THQVYIS |
7-12/13 | 57 | WFPIEWWFYWP |
12-1 | 58 | DSWQAFLTKFVL |
12-3 | 59 | HDIQWFWQHWNS |
12-4 | 60 | WSWWDHTFNYML |
12-6 | 61 | TTQQTWNVRYPY |
12-8 | 62 | DHTMPWTRNAKN |
12-12 | 63 | SWDPYWPFPWFS |
12-14 | 64 | AIYYVPSPMFTV |
12-16 | 65 | ETTLLKMWLAQM |
12-18 | 66 | YPWLDVAVVSLY |
12-20 | 67 | VPGWHYLATLRA |
12-21 | 68 | FDPLGSRDIKGS |
此类免疫刺激肽可优选用作CpG模拟物。同样地,可使用其功能性活性变体,为片段、突变体或杂合子,包括它们的组合。
功能性活性变体具体的特征在于,它们刺激pDCs,从而与阴性对照相比,诱导IL-6和/或TNFα和/或IFNα的增加水平。
免疫刺激性TLR9结合肽的功能性活性变体具体
a)具有与SEQ ID 73-91中的任意肽的至少60%的同源性或序列同一性,优选至少70%、至少80%或至少90%;
b)为SEQ ID 50-68中的任意肽的突变体,可通过借助插入、删除或置换序列中的或序列远端之一或二者中的一个或多个氨基酸来修饰母本氨基酸序列来获得,优选小于5、4、3、2或1个点突变;或
c)为SEQ ID 50-68中的任意肽的片段,包括至少50%的母本序列、或至少60%、至少70%、至少80%、或至少90%;或至少5个氨基酸,优选至少6个、至少7个、至少8个、至少9个、至少10个或至少11个氨基酸。
CpG C类
组CpG-C
ODNM362:(SEQ ID 69)
TCGTCGTCGTTCGAACGACGTTGAT
12.3代表性含卷曲的CD32结合产物
ScFV-卷曲1(IV.3):(SEQ ID 70)
下划线:VH结构域
粗体:HL结构域
正常类型设定。柔性连接子(可为任何连接子)
斜体:pepE卷曲+C’StrepTag II序列,“GP”连接子可为任何柔性连接子(StrepTagII可除去或被HIS标签或任何其它标签替代)
ScFV-卷曲2(AT10):(SEQ ID 71)
下划线:VH结构域
粗体:HL结构域
正常类型设定。柔性连接子(可为任何连接子)
斜体:pepE卷曲+C’StrepTag II序列,“GP”连接子可为任何柔性连接子(StrepTagII可除去或被HIS标签或任何其它标签替代)
肽-卷曲:(SEQ ID 72)
ADGAWAWVWLTETAVGAAKGPEVSALEKEVSALEKEVSALEKEVSALEKEVSALEK
斜体:pepE卷曲+“GP”连接子可为任何柔性连接子
IgG1Fc fragment-coil:(SEQ ID 73)
()之间为铰链区
下划线:CH2结构域
粗体CH3结构域
斜体:pepE卷曲+“GP”连接子可为任何柔性连接子
12.4.代表性TLR9与SH基的结合产物,用于与CD32结合子化学交联
组CpG-A:
ODN2216_SH:(SEQ ID 48)
GGGGGACGATCGTCGGGGGG-SH
粗体的柔性连接子含有SH基用于与ScFV-卷曲化学交联(可为任何连接子,和化学反应基团如NH2,适于化学交联)
组CpG-B:
天然配体:
ODN2006_SH:(SEQ ID 49)
TCGTCGTTTTGTCGTTTTGTCGTT-SH
肽的配体_SH:
粗体的柔性连接子含有SH基用于与ScFV-卷曲化学交联(可为任何连接子,和化学反应基团如NH2,适于化学交联)
组CpG-C
ODNM362_SH:(SEQ ID 69)
TCGTCGTCGTTCGAACGACGTTGAT-SH
粗体的柔性连接子含有SH基用于与ScFV-卷曲化学交联(可为任何连接子,和化学反应基团如NH2,适于化学交联)
12.5代表性弹头,即包括CD32结合子和TLR9结合子的结构
来自CD32结合子群体的任何代表通过任何方法与TLR9结合子全体的任何代表化学键合,其中优选例如TLR9结合子偶联至CD32结合子中可获得的赖氨酸(K)。再者,不同TLR9结合子的混合物可偶联,例如CpG-B天然或肽的结合子。
ScFV-卷曲1(IV.3)(SEQ ID 70)
优选卷曲结构中的赖氨酸(斜体)
或
肽-卷曲:(SEQ ID 72)
优选卷曲结构中的赖氨酸
12.6.代表性免疫原,本文还称为抗原
包含卷曲的免疫原3(Der P1和Der P2T细胞表位,基于人II类表达)
(SEQ ID 74)
下划线:HIS标签(可除去)
粗体:连接子(可为任何连接子)
斜体:pepK卷曲,用于与弹头相互作用
包含卷曲的免疫原5-12(~29个Der p1、Der p2、Der p3、Der p4、Der p7、Der p9、Der p10、Der p11、Der p14、Der p15的T细胞表位,基于人II类表达)
(SEQ ID 75)
下划线:HIS标签(可除去)
粗体:连接子(可为任何连接子)
斜体:pepK卷曲,用于与弹头相互作用
12.7对屋尘螨(HDM)的代表性变应性疫苗SG100
典型的分子复合体通过化学键合、融合和/或亲和结合,特别通过卷曲螺旋结构形成T。
弹头(基于ScFVcoil1IV.3+ODNM362)与免疫原5-12以下列比例混合,其中表示90%的弹头与免疫原复合,没有游离的免疫原(摩尔比~1:1.5)并在Alum上配制。
12.8SG100在猕猴中的效力:
方法:
5个健康屋尘螨(HDM)首试猕猴用在Alum上吸收的SG100(100μg/注射量)在d0、d14和d28免疫3x。在d0和d49采集血样用于T细胞激活和抗体生产。
抗体免疫应答:
在标准ELISA中试验血清样品的针对弹头、immo 5-12(Immo5)、Der p1、Der p2、Der p5和Der p7的IgG抗体。抗原涂布至maxisorb平板(1μg/ml I PBS)4℃下过夜,洗涤两次,用PBS 1%BSA封闭,洗涤两次,用血清以1:1000的稀释度4℃下温育,洗涤两次,随后检测抗-人-IgG-PO(与猕猴IgG交叉反应)。
细胞免疫应答:
增殖:PBMC(105/孔)培养4天(37℃/5%CO2/99%湿度),在8个plex中,含有培养基弹头(2μg/ml)、免疫原(2μg/ml)、Der p1(2μg/ml)、Der p2(2μg/ml)、Der p5(2μg/ml)和Derp7(2μg/ml)。作为阳性对照,使用Con A(刀豆球蛋白A,Sigma)。通过[3H]-胸苷(0.5μCi/孔)在4天培养的最后18小时期间测量增殖。收集细胞用于β-闪烁计数(Topcount NXT,Packard,Ramsey,MN,USA)。通过从由不同抗原诱导的计数中减去培养基对照的计数来计算每分钟净计数。
细胞因子产生:
8plex增殖刺激实验的各孔中,在24小时后采集50μl上清液并合并。使用商购可得的ELISA试剂盒(来自U-Cytech,Utrecht The Netherlands)试验合并的上清液的IFNγ和IL-4的存在。
结果:
抗体应答:
测量对SG100的弹头和免疫原的强IgG应答,但未检测到针对Der p1、Der p2、Derp5或Der p7的抗体(图7),表明动物为试验的HDM变应原的首次试验,且SG100不包含与试验的HDM变应原交叉反应的B细胞表位。
T细胞应答:
在图8中,当用弹头、immo5、Der p1、Der p2、Der p7体外刺激时可见动物显示强增殖,但没有针对Der p5。再者,在来自用弹头、immo5、Der p1、Der p2,、Der p7体外培养物的上清液中测定IFNγ而不是IL-4,而不针对Der p5(图9)。在用Con A刺激后可见IL-4(数据未示出)。
结论:
用SG100免疫诱导针对疫苗的Th1型记忆应答,如通过IgG抗体的存在以及T细胞的诱导所表示的,当由弹头或Immo5刺激时产生IFNγ而不是IL-4。正如预期的,没有诱导针对Der p1、Der p2、Der p5或Der p7的IgG(=B细胞记忆),这是因为疫苗不包含来自这些变应原的B细胞表位。然而,针对存在于疫苗Der p1、Der p2、Der p7中的屋尘螨变应原的T细胞表位诱导Th1型记忆。没有诱导针对不包括在疫苗中的Der p5的Th1型记忆。
这证实SG100的内容物。
12.9代表性疫苗,弹头用于肿瘤学
ScFV-coil 1(IV.3):(SEQ ID 70)
下划线:VH结构域
粗体:HL结构域
正常类型设定。柔性连接子(可为任何连接子)
斜体:pepE卷曲+C’StrepTag II序列,“GP”连接子可为任何柔性连接子(StrepTagII可除去或被HIS标签或任何其它标签替代)
含ODNM362的弹头
ODNM362_SH(SEQ ID 69)
TCGTCGTCGTTCGAACGACGTTGAT-SH
ODN-M362可偶联至ScFV-1-卷曲中的任何可得的赖氨酸
弹头(SG100):
ScFV-1-卷曲与ODN-M362-SH化学键合。制剂为与1至18个分子ODN-M362连接的ScFV-1-卷曲的混合物,优选与偶联至ScFV-1-卷曲的1-6个分子ODN-M362混合物。所有这些混合物可命名为弹头或ScFv-1-卷曲-M362。
背景:
活性免疫治疗的肿瘤学靶标几乎相对于每个定义的在肿瘤细胞中过表达的自身抗原。这些抗原称为肿瘤相关抗原(TAA),且免疫系统不能针对这些抗原应答,这是因为它们被识别为自体的。使疫苗系统能够产生特异性抗体和/或针对自身抗原的细胞免疫应答的疫苗制剂潜在地适于用作抗肿瘤疫苗。
SG100的弹头能够自身免疫应答:
24只小鼠(6/组)用在Alum上配制或在PBS中稀释的150μl ScFV-1-卷曲中的35μg或用弹头(ScFV-1-卷曲-M362)皮下免疫2x。免疫在d0和d14进行,在d0(免疫前)和d28采集血清,并通过标准ELISA分析针对ScFV-1-卷曲(表示为ScFV)和mAb IV.3的IgG1和IgG2a。参见图6。
如图6可见,用弹头免疫在第28天诱导了对ScFV-1-卷曲以及对mAb IV.3的强IgG1和IgG2a应答。阳性应答可见不依赖于Alum的存在。用ScFV-1-卷曲免疫仅在Alum的存在下仅诱导对ScFV-1-卷曲的IgG1应答,没有诱导IgG2a应答。这些数据符合CpG(M362)诱导Th1型应答(IgG2a)和Alum诱导TH2型应答(IgG1)的概念。针对ScFV-1-卷曲的应答表明该蛋白质在小鼠中为免疫原性的,的确StrepTagII(氨基酸序列“SAWSHPQFEK”(SEQ ID 76))和pepE(氨基酸序列“EVSALEKEVSALEKEVSALEKEVSALEKEVSALEK”SEQ ID 77)二者为IgG应答的靶标(数据未示出)。然而,ScFV-1-卷曲还包含“小鼠自体序列”,这是因为ScFV包含小鼠mAbIV.3的VH和VL结构域。因此,对IV.3的免疫应答表明自身免疫抗体的存在。的确,仅含有或不含Alum的弹头能够诱导该类型的免疫应答。因此,在ScFV-1-卷曲上存在M362能够破坏对母本抗体的自身抗原VH和VL结构域的耐受。通过借助于弹头的pepE的高亲和相互作用而结合自身抗原如TAA,弹头将能够诱导必要的对TAA的自身免疫应答。含TAA的弹头复合体(ScFV-1-卷曲-M362)形成用于治疗癌症的有效疫苗,其中TAA在疫苗中过表达。此类疫苗可用任何佐剂,例如在Alum上配制。
实施例13:使用肿瘤学技术平台,免疫原G17。
弹头基于ScFV-卷曲1(IV.3)+ODNM362,和来自猕猴和食蟹猴的免疫原G17(G17RM)。在下述中,pE理解为pyroGlu。
人免疫原小胃泌素的序列(G17H,第一13AA,SEQ ID 86):
pEGPWLEEEE EAYG
猕猴和食蟹猴免疫原小胃泌素的序列
(G17RM,第一13AA,SEQ ID 99):
pEGPWMEEEE AAYG
小鼠免疫原小胃泌素的序列(G17M,第一13AA,SEQ ID 100):
pERPRMEEEE EAYG
与G17RM的差异粗体
终产物免疫原G17RM_1-卷曲和G17H_1-卷曲:
G17RM_1-卷曲,SEQ ID 101:
pEGPWMEEEEAAYGGGSGGKVSALKEKVSALKEKVSALKEKVSALKEKVSALKE
G17H_1-卷曲,SEQ ID 102
粗体:连接子(可为任意连接子)
斜体:pepK卷曲,用于与弹头相互作用
即用型(终产物)TYG100_1RM和TYG100_1H
如上所述的弹头(基于ScFV-卷曲1IV.3)与G17RM_1-卷曲或G17H_1-卷曲以下述比例混合,所述比例表示100%的弹头与G17RM_1-卷曲或G17H_1-卷曲复合,而无G17游离免疫原存在(摩尔比~1:1)并在Alum上配制。从而,生产TYG100_1RM和TYG100_1H。
实施例14:TYG100_1RM,用于治疗胃泌素依赖性癌症如胰腺癌:
6只Balb/c小鼠在第0天、第14天和第35天用包含猕猴G17的TYG100_1RM或G17_1RM(不含弹头)(58,4μg/注射量,0.5ml)免疫3次。最后免疫两周后,采集血清并分析针对G17RM、G17H和G17M(=G17,来自小鼠)IgG抗体的存在。
表2
表2示出所有小鼠用IgG对疫苗的2个组分(弹头和G17RM)应答。重要的是,所有小鼠产生与人G17交叉反应的IgG,并且针对较少掺入小鼠G17(G17M)。后者是值得注意的,因为小鼠G17的前13个免疫酸(pERPRMEEEE EAYG,SEQ ID 86)与G17RM存在3个AA的不同(不同表示为粗体和下划线),且G17M为小鼠的自身抗原。因此,识别G17M的抗体为自身抗体,表明TYG100_1RM已能够破坏对自身抗原G17M的天然耐受。在G17-肽不用弹头免疫时对G17没有应答。
疫苗诱导自身免疫应答的能力是抗癌疫苗的先决条件,其中所有肿瘤相关抗原(TAA)为过表达的、例如在肿瘤细胞上过表达的自身抗原。因此,由结合有人G17的TYG100_1RM的弹头作为免疫原组成的疫苗可用作用于治疗胃泌素依赖性肿瘤如胰腺癌的疫苗。
实施例15:包括肽免疫原的二聚体的代表性产物
终产物免疫原G17RM_2-卷曲和G17H_2-卷曲:
G17RM(小胃泌素的第一13AA)的二聚体使用连接2个肽与一个pepK卷曲的特定柔性连接子化学合成。
G17RM_2-卷曲:(SEQ ID 103:本发明的免疫原性组合物的一部分,包括两个SEQID 99的猕猴胃泌素肽、支化的连接子序列和肽的α-螺旋(TYG100_2RM)。该部分可通过卷曲螺旋键合连接至适合的导向佐剂)
粗体为特定柔性连接子(可为连接三个肽的任何连接子)
斜体为pepK卷曲,用于与弹头相互作用
G17H_2-卷曲:(SEQ ID 88:本发明的免疫原性组合物的一部分,包括两个SEQ ID86的人胃泌素肽、支化的连接子序列和肽的α-螺旋(TYG100_2H)。该部分可通过卷曲螺旋键合连接至适合的导向佐剂)
粗体为特定柔性连接子(可为连接三个肽的任何连接子)
斜体为pepK卷曲,用于与弹头相互作用
终产物TYG100_2RM和TYG100_2H
如上所述的弹头(基于ScFV-卷曲1;IV.3)与G17RM_2-卷曲或G17H_2-卷曲以下述比例混合,所述比例表示100%的弹头与G17RM_2-卷曲或G17H_2-卷曲免疫原复合,而无G17游离免疫原存在(摩尔比~1:1)并在Alum上配制。从而,生产TYG100_2RM和TYG100_2H。
实施例16:TYG100_2RM,用于治疗胃泌素依赖性癌症如胰腺癌
6只Balb/c小鼠在第0天、第14天和第35天用包含猕猴G17的前13个免疫酸的TYG100_2RM(66.8μg/注射量,0.5ml)免疫3次。最后免疫两周后,采集血清并分析针对G17RM、G17H和G17M(=G17,来自小鼠)IgG抗体的存在。
表3
表3示出所有小鼠用IgG对疫苗的2个组分(弹头和G17RM)应答。重要的是,所有小鼠产生与人G17交叉反应的IgG,并且针对较少掺入小鼠G17(G17M)。后者是值得注意的,因为小鼠G17的前13个免疫酸(pERPRMEEEE EAYG,SEQ ID 86)与G17RM存在3个AA的不同(不同表示为粗体和下划线),且G17M为小鼠的自身抗原。因此,识别G17M的抗体为自身抗体,表明TYG100_2RM已能够破坏对自身抗原G17M的天然耐受。在G17-肽不用弹头免疫时对G17没有应答。
疫苗诱导自身免疫应答的能力是抗癌疫苗的先决条件,其中所有肿瘤相关抗原(TAA)为过表达的、例如在肿瘤细胞上过表达的自身抗原。因此,由结合有人G17的TYG100_2RM的弹头作为免疫原组成的疫苗可用作用于治疗胃泌素依赖性肿瘤如胰腺癌的疫苗。由TYG100_2RM诱导的对所有3种类型的G17的应答比由TYG100_1RM诱导的那些(表2)强,表明二聚体在疫苗中是优选的。
实施例17:TYG100_2RM,用于治疗胃泌素依赖性癌症如胰腺癌:
在d0、d14和d28,6只食蟹猴用TYG100_2RM免疫,6只用G17RM_2-卷曲免疫,在d0、d14和d28、42和d56,使用Meso Scale Discovery(MSD)的多重ELISA体系根据MSD手册分析血清的针对自体小胃泌素(G17RM)、来自人的小胃泌素(G17H)、类似的MW作为胃泌素的不相关对照肽(对照肽)或针对弹头(ScFV-卷曲1)的IgG抗体的存在。
在图10中,可见所有6只动物显示对弹头(ScFV-卷曲1)以及对G17RM和G17H的强的时间依赖性IgG应答,对对照肽未见应答。三次免疫后对G17RM的应答为对ScFV-卷曲1的应答的75%。这是值得注意的,这是由于G17RM为仅~1.2kDa的100%自体蛋白,而ScFV-卷曲1为>30kDa的100%异体蛋白。抗G17RM抗体与G17H强烈交叉反应。当使用G17RM_2-卷曲肽而无弹头时,对G17RM没有应答。d42和56之间针对G17RM的IgG滴度的降低比针对ScFV的强,表明IgG抗体的一部分被内源G17中和。重要的是,内源G17的存在不加强对G17RM的应答。
图10中的数据显示,疫苗能够诱导真实的(bonavide)自身抗体应答,其为可逆的。这是抗癌疫苗的先决条件,这是由于肿瘤相关抗原(TAA)为过表达的、例如在肿瘤细胞上过表达但也在正常健康细胞上以低表达水平存在的自身抗原。因此,疫苗如TYG100_2RM或TYG100_2H可用作用于治疗胃泌素依赖性肿瘤如胰腺癌。一旦癌症已完全痊愈,治疗可停止,并且诱导的抗G17抗体将从循环中清除。为了维持稳态(在治疗期间),自身免疫应答需要通过重复注射疫苗来加强。利用该类型的疫苗不诱导不可逆的自身免疫病N。
实施例18:TYG100_2RM,用于治疗肥胖症:
监控来自实施例14的动物的食欲,并在d0,d14、d28、d42和d56测量体重。在用TYG100_2RM两次注射后,6只动物中的4只丧失了日常零食(饼干)的兴趣,而基础食物摄取保持正常。这伴随有显著的重量损失(图11),但没有不期望的副反应的证据。迄今为止,此类观察从未在用基于弹头和卷曲螺旋相互作用如靶向除胃泌素免疫原以外的免疫原的疫苗的其它疫苗接种中进行过(数据未示出)。
这些数据表明TYG100_2RM减少对零食的渴望(在食物之间),而不影响健康生活所需的基础食物摄取。动物正常活动且心情愉悦。因此,TYG100_2RM可用于治疗肥胖症。
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20 25
<210> 9
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 9
Lys Ile Ser Ala Leu Lys Glu Lys Ile Ser Ala Leu Lys Glu Lys Ile
1 5 10 15
Ser Ala Leu Lys Glu
20
<210> 10
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 10
Lys Ile Ser Ala Leu Lys Glu Lys Ile Ser Ala Leu Lys Glu Lys Ile
1 5 10 15
Ser Ala Leu Lys Glu Lys Ile Ser Ala Leu Lys Glu
20 25
<210> 11
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 11
Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val
1 5 10 15
Ala Ala Leu Glu Lys
20
<210> 12
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 12
Glu Val Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys Glu Val
1 5 10 15
Ala Ala Leu Glu Lys Glu Val Ala Ala Leu Glu Lys
20 25
<210> 13
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 13
Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val
1 5 10 15
Ala Ala Leu Lys Glu
20
<210> 14
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 14
Lys Val Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu Lys Val
1 5 10 15
Ala Ala Leu Lys Glu Lys Val Ala Ala Leu Lys Glu
20 25
<210> 15
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 15
Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val
1 5 10 15
Ser Ala Leu Glu Lys
20
<210> 16
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 16
Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val
1 5 10 15
Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys
20 25
<210> 17
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 17
Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val
1 5 10 15
Ser Ala Leu Lys Glu
20
<210> 18
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 18
Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val
1 5 10 15
Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
20 25
<210> 19
<211> 297
<212> PRT
<213> 人工序列
<220>
<223> ScFV-卷曲
<400> 19
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Leu Asn Thr Tyr Thr Gly Glu Ser Ile Tyr Pro Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Ser Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Asp Tyr Gly Tyr Asp Asp Pro Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ala Ala Pro
130 135 140
Ser Val Pro Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Lys Ser Leu Leu His Thr Asn Gly Asn Thr Tyr Leu His Trp Phe
165 170 175
Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser
180 185 190
Val Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Ala Phe Thr Leu Ser Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Phe Tyr Cys Met Gln His Leu Glu Tyr Pro Leu Thr Phe Gly Ala
225 230 235 240
Gly Thr Lys Leu Glu Leu Lys Gly Ser Ile Ser Ala Trp Ser His Pro
245 250 255
Gln Phe Glu Lys Gly Pro Glu Val Ser Ala Leu Glu Lys Glu Val Ser
260 265 270
Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu
275 280 285
Glu Lys Glu Val Ser Ala Leu Glu Lys
290 295
<210> 20
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 20
Ala Asp Gly Ala Trp Ala Trp Val Trp Leu Thr Glu Thr Ala Val Gly
1 5 10 15
Ala Ala
<210> 21
<211> 316
<212> PRT
<213> 人工序列
<220>
<223> ScFV-卷曲
<400> 21
Met Glu Leu Gly Leu Ser Trp Ile Phe Leu Leu Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys
20 25 30
Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp
50 55 60
Met Gly Trp Leu Asn Thr Tyr Thr Gly Glu Ser Ile Tyr Pro Asp Asp
65 70 75 80
Phe Lys Gly Arg Phe Ala Phe Ser Ser Glu Thr Ser Ala Ser Thr Ala
85 90 95
Tyr Leu Gln Ile Asn Asn Leu Lys Gly Met Asn Glu Asp Met Ala Thr
100 105 110
Tyr Phe Cys Ala Arg Gly Asp Tyr Gly Tyr Asp Asp Pro Leu Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gly Ser Gly Gly Gly Asp Ile Val Met Thr Gln
145 150 155 160
Ala Ala Pro Ser Val Pro Val Thr Pro Gly Glu Ser Val Ser Ile Ser
165 170 175
Cys Arg Ser Ser Lys Ser Leu Leu His Thr Asn Gly Asn Thr Tyr Leu
180 185 190
His Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
195 200 205
Arg Met Ser Val Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
210 215 220
Gly Ser Gly Thr Ala Phe Thr Leu Ser Ile Ser Arg Val Glu Ala Glu
225 230 235 240
Asp Val Gly Val Phe Tyr Cys Met Gln His Leu Glu Tyr Pro Leu Thr
245 250 255
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Ser Ile Ser Ala Trp
260 265 270
Ser His Pro Gln Phe Glu Lys Gly Pro Glu Val Ser Ala Leu Glu Lys
275 280 285
Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val
290 295 300
Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys
305 310 315
<210> 22
<211> 68
<212> PRT
<213> 人工序列
<220>
<223> 肽-卷曲
<400> 22
Ala Asp Gly Ala Trp Ala Trp Val Trp Leu Thr Glu Thr Ala Val Gly
1 5 10 15
Ala Ala Lys Gly Gly Gly Ser Trp Ser His Pro Gln Phe Glu Lys Gly
20 25 30
Pro Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu
35 40 45
Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val Ser
50 55 60
Ala Leu Glu Lys
65
<210> 23
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-卷曲
<400> 23
His His His His His His Tyr Tyr Arg Tyr Val Ala Arg Glu Gln Ser
1 5 10 15
Cys Arg Arg Pro Asn Ala Gln Arg Phe Gly Ile Ser Asn Tyr Cys Gln
20 25 30
Ile Tyr Pro Pro Asn Val Asn Lys Ile Arg Glu Ala Leu Ala Gln Thr
35 40 45
His Ser Ala Ile Ala Val Asp Leu Arg Gln Met Arg Thr Val Thr Pro
50 55 60
Ile Arg Met Gln Gly Gly Cys Gly Ser Cys Trp Ala Phe Ser Gly Val
65 70 75 80
Ala Ala Thr Glu Ser Ala Tyr Leu Gln Gln Tyr Asp Ile Lys Tyr Thr
85 90 95
Trp Asn Val Pro Lys Ile Ala Pro Lys Ser Glu Asn Val Val Val Thr
100 105 110
Val Lys Val Met Gly Asp Asp Gly Val Leu Ala Cys Ala Ile Ala Thr
115 120 125
His Ala Lys Ile Arg Asp Asp Ala Phe Arg His Tyr Asp Gly Arg Thr
130 135 140
Ile Ile Gln Arg Asp Asn Gly Tyr Gln Pro Asn Tyr His Ala Val Asn
145 150 155 160
Ile Val Gly Tyr Ser Asn Ala Gln Gly Val Asp Tyr Trp Ile Val Arg
165 170 175
Asn Ser Trp Asp Thr Asn Trp His Glu Ile Lys Lys Val Leu Val Pro
180 185 190
Gly Cys His Gly Ser Glu Pro Cys Ile Ile His Arg Gly Lys Pro Phe
195 200 205
Gly Gly Gly Ser Gly Gly Gly Ser Cys Gly Gly Lys Val Ser Ala Leu
210 215 220
Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
225 230 235 240
Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
245 250
<210> 24
<211> 48
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 24
Tyr Tyr Arg Tyr Val Ala Arg Glu Gln Ser Cys Arg Arg Pro Asn Ala
1 5 10 15
Gln Arg Phe Gly Ile Ser Asn Tyr Cys Gln Ile Tyr Pro Pro Asn Ala
20 25 30
Asn Lys Ile Arg Glu Ala Leu Ala Gln Thr His Ser Ala Ile Ala Val
35 40 45
<210> 25
<211> 34
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 25
Asp Leu Arg Gln Met Arg Thr Val Thr Pro Ile Arg Met Gln Gly Gly
1 5 10 15
Cys Gly Ser Cys Trp Ala Phe Ser Gly Val Ala Ala Thr Glu Ser Ala
20 25 30
Tyr Leu
<210> 26
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 26
Gln Gln Tyr Asp Ile Lys Tyr Thr Trp Asn Val Pro Lys Ile Ala Pro
1 5 10 15
Lys Ser Glu Asn
20
<210> 27
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 27
Val Val Val Thr Val Lys Val Met Gly Asp Asp Gly Val Leu Ala Cys
1 5 10 15
Ala Ile Ala Thr His Ala Lys Ile Arg Asp
20 25
<210> 28
<211> 49
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 28
Asp Ala Phe Arg His Tyr Asp Gly Arg Thr Ile Ile Gln Arg Asp Asn
1 5 10 15
Gly Tyr Gln Pro Asn Tyr His Ala Val Asn Ile Val Gly Tyr Ser Asn
20 25 30
Ala Gln Gly Val Asp Tyr Trp Ile Val Arg Asn Ser Trp Asp Thr Asn
35 40 45
Trp
<210> 29
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 29
His Glu Ile Lys Lys Val Leu Val Pro Gly Cys His Gly Ser Glu Pro
1 5 10 15
Cys Ile Ile His Arg Gly Lys Pro Phe
20 25
<210> 30
<211> 416
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-卷曲
<400> 30
Gly Val Leu Ala Cys Ala Ile Ala Thr His Ala Lys Ile Arg Glu Gln
1 5 10 15
Glu Arg Leu Val Lys Leu Glu Thr Val Lys Lys Ser Leu Glu Gln Glu
20 25 30
Val Arg Thr Leu His Val Arg Ile Glu Glu Val Glu Ala Asn Ala Leu
35 40 45
Ala Gly Gly Asp Leu Arg Gln Met Arg Thr Val Thr Pro Ile Arg Met
50 55 60
Gln Gly Gly Cys Gly Ser Cys Trp Glu Ala His Glu Gln Gln Ile Arg
65 70 75 80
Ile Met Thr Thr Lys Leu Lys Glu Ala Glu Ala Arg Gln Gln Tyr Asp
85 90 95
Ile Lys Tyr Thr Trp Asn Val Pro Lys Ile Ala Val Asn Ile Val Gly
100 105 110
Tyr Ser Asn Ala Gln Gly Val Asp Tyr Trp Ile Val Arg Asn Ser Trp
115 120 125
Asp Thr Asn Trp Tyr His Asn Pro His Phe Ile Gly Asn Arg Ser Val
130 135 140
Ile Thr His Leu Met Glu Asp Leu Lys Gly Glu Leu Asp Met Arg Asn
145 150 155 160
Ile Gln Val Arg Gly Leu Lys Gln Met Lys Arg Val Gly Asp Ala Asn
165 170 175
Val Lys Ser Glu Asp Asp Ala Phe Arg His Tyr Asp Gly Arg Thr Ile
180 185 190
Ile Gln Arg Asp Asn Gly Tyr Gln Pro Asn Tyr Leu Asp Glu Tyr Trp
195 200 205
Ile Leu Thr Ala Ala His Cys Val Asp Gly Gln Thr Val Ser Lys Leu
210 215 220
Ile Arg Ser Lys Val Leu Gly Glu Lys Ile Ser Tyr Tyr Arg Tyr Val
225 230 235 240
Ala Arg Glu Gln Ser Cys Arg Arg Pro Asn Ala Gln Arg Phe Gly Ile
245 250 255
Ser Asn Tyr Cys Val Val Val Thr Val Lys Val Met Gly Asp Asp Glu
260 265 270
Leu His Thr Tyr Phe Asn Val Asn Tyr Thr Met His Tyr Tyr Leu Asn
275 280 285
Asn Gly Ala Thr Arg Asp Ile Leu Asp Glu Tyr Trp Ile Leu Thr Ala
290 295 300
Ala His Cys Val Ala Gly Gln Thr Ala Ser Lys Leu Ser Ile Arg Tyr
305 310 315 320
Asn Ser Leu Lys His Ser Leu Phe Lys Tyr Arg Pro Phe Lys Val Asn
325 330 335
Glu Leu Asn Leu Glu Gly Glu Phe Gly Arg Glu Leu Gln His Lys Phe
340 345 350
Arg Leu Met Arg Asn Ser Gln Met Glu Val Glu Glu Gly Gly Gly Ser
355 360 365
His His His His His His Gly Gly Gly Ser Cys Gly Gly Lys Val Ser
370 375 380
Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu
385 390 395 400
Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
405 410 415
<210> 31
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 31
Gly Val Leu Ala Cys Ala Ile Ala Thr His Ala Lys Ile Arg
1 5 10
<210> 32
<211> 37
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 32
Glu Gln Glu Arg Leu Val Lys Leu Glu Thr Val Lys Lys Ser Leu Glu
1 5 10 15
Gln Glu Val Arg Thr Leu His Val Arg Ile Glu Glu Val Glu Ala Asn
20 25 30
Ala Leu Ala Gly Gly
35
<210> 33
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 33
Asp Leu Arg Gln Met Arg Thr Val Thr Pro Ile Arg Met Gln Gly Gly
1 5 10 15
Cys Gly Ser Cys Trp
20
<210> 34
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 34
Glu Ala His Glu Gln Gln Ile Arg Ile Met Thr Thr Lys Leu Lys Glu
1 5 10 15
Ala Glu Ala Arg
20
<210> 35
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 35
Gln Gln Tyr Asp Ile Lys Tyr Thr Trp Asn Val Pro Lys Ile
1 5 10
<210> 36
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 36
Asp Leu Lys Gly Glu Leu Asp Met Arg Asn Ile Gln Val Arg Gly Leu
1 5 10 15
Lys Gln Met Lys Arg Val Gly Asp Ala Asn Val Lys Ser Glu Asp
20 25 30
<210> 37
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 37
Asp Ala Phe Arg His Tyr Asp Gly Arg Thr Ile Ile Gln Arg Asp Asn
1 5 10 15
Gly Tyr Gln Pro Asn Tyr
20
<210> 38
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 38
Leu Asp Glu Tyr Trp Ile Leu Thr Ala Ala His Cys Val Asp Gly Gln
1 5 10 15
Thr Val Ser Lys Leu Ile Arg Ser Lys Val Leu Gly Glu Lys Ile Ser
20 25 30
<210> 39
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 39
Tyr Tyr Arg Tyr Val Ala Arg Glu Gln Ser Cys Arg Arg Pro Asn Ala
1 5 10 15
Gln Arg Phe Gly Ile Ser Asn Tyr Cys
20 25
<210> 40
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 40
Val Val Val Thr Val Lys Val Met Gly Asp Asp
1 5 10
<210> 41
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 41
Glu Leu His Thr Tyr Phe Asn Val Asn Tyr Thr Met His Tyr Tyr Leu
1 5 10 15
Asn Asn Gly Ala Thr Arg Asp
20
<210> 42
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 42
Ile Leu Asp Glu Tyr Trp Ile Leu Thr Ala Ala His Cys Val Ala Gly
1 5 10 15
Gln Thr Ala Ser Lys Leu Ser Ile Arg Tyr Asn Ser Leu Lys His Ser
20 25 30
Leu
<210> 43
<211> 37
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 43
Phe Lys Tyr Arg Pro Phe Lys Val Asn Glu Leu Asn Leu Glu Gly Glu
1 5 10 15
Phe Gly Arg Glu Leu Gln His Lys Phe Arg Leu Met Arg Asn Ser Gln
20 25 30
Met Glu Val Glu Glu
35
<210> 44
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> ScFV
<400> 44
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Leu Asn Thr Tyr Thr Gly Glu Ser Ile Tyr Pro Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Ser Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Asp Tyr Gly Tyr Asp Asp Pro Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ala Ala Pro
130 135 140
Ser Val Pro Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Lys Ser Leu Leu His Thr Asn Gly Asn Thr Tyr Leu His Trp Phe
165 170 175
Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser
180 185 190
Val Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Ala Phe Thr Leu Ser Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Phe Tyr Cys Met Gln His Leu Glu Tyr Pro Leu Thr Phe Gly Ala
225 230 235 240
Gly Thr Lys Leu Glu Leu Lys Gly Ser Ile
245 250
<210> 45
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 45
Ala Asp Gly Ala Trp Ala Trp Val Trp Leu Thr Glu Thr Ala Val Gly
1 5 10 15
Ala Ala Lys
<210> 46
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> ScFV
<400> 46
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Asn
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Asn Arg Arg Asp Glu Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Ser Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala
145 150 155 160
Ser Glu Ser Val Asp Asn Phe Gly Ile Ser Phe Met Asn Trp Phe Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr Gly Ala Ser Asn
180 185 190
Gln Gly Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Ser Leu Asn Ile His Pro Val Glu Glu Asp Asp Ala Ala Met
210 215 220
Tyr Phe Cys Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys Gly Ser Ile
245
<210> 47
<211> 230
<212> PRT
<213> 人工序列
<220>
<223> IgG1 Fc
<400> 47
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Glu
1 5 10 15
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
20 25 30
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
35 40 45
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
50 55 60
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
65 70 75 80
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
100 105 110
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
115 120 125
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
130 135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
145 150 155 160
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
165 170 175
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
180 185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
195 200 205
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
210 215 220
Ser Leu Ser Pro Gly Lys
225 230
<210> 48
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 48
Gly Gly Gly Gly Gly Ala Cys Gly Ala Thr Cys Gly Thr Cys Gly Gly
1 5 10 15
Gly Gly Gly Gly
20
<210> 49
<211> 24
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 49
Thr Cys Gly Thr Cys Gly Thr Thr Thr Thr Gly Thr Cys Gly Thr Thr
1 5 10 15
Thr Thr Gly Thr Cys Gly Thr Thr
20
<210> 50
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 50
Glu Ser Trp Asp Lys Phe Leu Ser His Tyr Leu Pro
1 5 10
<210> 51
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 51
Thr Asp Trp Ser Trp Phe Tyr
1 5
<210> 52
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 52
Tyr Pro Val Tyr Trp Pro Trp
1 5
<210> 53
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 53
Glu Trp Trp Phe Tyr Trp Pro
1 5
<210> 54
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 54
Trp Phe Pro Ile Glu Trp Trp
1 5
<210> 55
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 55
Asp Gln Val Asp Ile Gly Tyr
1 5
<210> 56
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 56
Thr His Gln Val Tyr Ile Ser
1 5
<210> 57
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 57
Trp Phe Pro Ile Glu Trp Trp Phe Tyr Trp Pro
1 5 10
<210> 58
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 58
Asp Ser Trp Gln Ala Phe Leu Thr Lys Phe Val Leu
1 5 10
<210> 59
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 59
His Asp Ile Gln Trp Phe Trp Gln His Trp Asn Ser
1 5 10
<210> 60
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 60
Trp Ser Trp Trp Asp His Thr Phe Asn Tyr Met Leu
1 5 10
<210> 61
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 61
Thr Thr Gln Gln Thr Trp Asn Val Arg Tyr Pro Tyr
1 5 10
<210> 62
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 62
Asp His Thr Met Pro Trp Thr Arg Asn Ala Lys Asn
1 5 10
<210> 63
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 63
Ser Trp Asp Pro Tyr Trp Pro Phe Pro Trp Phe Ser
1 5 10
<210> 64
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 64
Ala Ile Tyr Tyr Val Pro Ser Pro Met Phe Thr Val
1 5 10
<210> 65
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 65
Glu Thr Thr Leu Leu Lys Met Trp Leu Ala Gln Met
1 5 10
<210> 66
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 66
Tyr Pro Trp Leu Asp Val Ala Val Val Ser Leu Tyr
1 5 10
<210> 67
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 67
Val Pro Gly Trp His Tyr Leu Ala Thr Leu Arg Ala
1 5 10
<210> 68
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 68
Phe Asp Pro Leu Gly Ser Arg Asp Ile Lys Gly Ser
1 5 10
<210> 69
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 69
Thr Cys Gly Thr Cys Gly Thr Cys Gly Thr Thr Cys Gly Ala Ala Cys
1 5 10 15
Gly Ala Cys Gly Thr Thr Gly Ala Thr
20 25
<210> 70
<211> 297
<212> PRT
<213> 人工序列
<220>
<223> ScFV-卷曲
<400> 70
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Leu Asn Thr Tyr Thr Gly Glu Ser Ile Tyr Pro Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Ser Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Asp Tyr Gly Tyr Asp Asp Pro Leu Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ala Ala Pro
130 135 140
Ser Val Pro Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Lys Ser Leu Leu His Thr Asn Gly Asn Thr Tyr Leu His Trp Phe
165 170 175
Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser
180 185 190
Val Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Ala Phe Thr Leu Ser Ile Ser Arg Val Glu Ala Glu Asp Val Gly
210 215 220
Val Phe Tyr Cys Met Gln His Leu Glu Tyr Pro Leu Thr Phe Gly Ala
225 230 235 240
Gly Thr Lys Leu Glu Leu Lys Gly Ser Ile Ser Ala Trp Ser His Pro
245 250 255
Gln Phe Glu Lys Gly Pro Glu Val Ser Ala Leu Glu Lys Glu Val Ser
260 265 270
Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu
275 280 285
Glu Lys Glu Val Ser Ala Leu Glu Lys
290 295
<210> 71
<211> 296
<212> PRT
<213> 人工序列
<220>
<223> ScFV-螺旋
<400> 71
Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Tyr Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Asn
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Asn Arg Arg Asp Glu Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Ser Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala
145 150 155 160
Ser Glu Ser Val Asp Asn Phe Gly Ile Ser Phe Met Asn Trp Phe Gln
165 170 175
Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr Gly Ala Ser Asn
180 185 190
Gln Gly Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Asp Phe Ser Leu Asn Ile His Pro Val Glu Glu Asp Asp Ala Ala Met
210 215 220
Tyr Phe Cys Gln Gln Ser Lys Glu Val Pro Trp Thr Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Glu Ile Lys Gly Ser Ile Ser Ala Trp Ser His Pro Gln
245 250 255
Phe Glu Lys Gly Pro Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala
260 265 270
Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu
275 280 285
Lys Glu Val Ser Ala Leu Glu Lys
290 295
<210> 72
<211> 56
<212> PRT
<213> 人工序列
<220>
<223> 肽-螺旋
<400> 72
Ala Asp Gly Ala Trp Ala Trp Val Trp Leu Thr Glu Thr Ala Val Gly
1 5 10 15
Ala Ala Lys Gly Pro Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala
20 25 30
Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu
35 40 45
Lys Glu Val Ser Ala Leu Glu Lys
50 55
<210> 73
<211> 267
<212> PRT
<213> 人工序列
<220>
<223> IgG1 Fc-螺旋
<400> 73
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Pro Glu
1 5 10 15
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
20 25 30
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
35 40 45
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
50 55 60
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
65 70 75 80
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
100 105 110
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
115 120 125
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
130 135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
145 150 155 160
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
165 170 175
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
180 185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
195 200 205
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
210 215 220
Ser Leu Ser Pro Gly Lys Gly Pro Glu Val Ser Ala Leu Glu Lys Glu
225 230 235 240
Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val Ser
245 250 255
Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys
260 265
<210> 74
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-螺旋
<400> 74
His His His His His His Tyr Tyr Arg Tyr Val Ala Arg Glu Gln Ser
1 5 10 15
Cys Arg Arg Pro Asn Ala Gln Arg Phe Gly Ile Ser Asn Tyr Cys Gln
20 25 30
Ile Tyr Pro Pro Asn Val Asn Lys Ile Arg Glu Ala Leu Ala Gln Thr
35 40 45
His Ser Ala Ile Ala Val Asp Leu Arg Gln Met Arg Thr Val Thr Pro
50 55 60
Ile Arg Met Gln Gly Gly Cys Gly Ser Cys Trp Ala Phe Ser Gly Val
65 70 75 80
Ala Ala Thr Glu Ser Ala Tyr Leu Gln Gln Tyr Asp Ile Lys Tyr Thr
85 90 95
Trp Asn Val Pro Lys Ile Ala Pro Lys Ser Glu Asn Val Val Val Thr
100 105 110
Val Lys Val Met Gly Asp Asp Gly Val Leu Ala Cys Ala Ile Ala Thr
115 120 125
His Ala Lys Ile Arg Asp Asp Ala Phe Arg His Tyr Asp Gly Arg Thr
130 135 140
Ile Ile Gln Arg Asp Asn Gly Tyr Gln Pro Asn Tyr His Ala Val Asn
145 150 155 160
Ile Val Gly Tyr Ser Asn Ala Gln Gly Val Asp Tyr Trp Ile Val Arg
165 170 175
Asn Ser Trp Asp Thr Asn Trp His Glu Ile Lys Lys Val Leu Val Pro
180 185 190
Gly Cys His Gly Ser Glu Pro Cys Ile Ile His Arg Gly Lys Pro Phe
195 200 205
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Lys Val Ser Ala Leu Lys
210 215 220
Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys
225 230 235 240
Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
245 250
<210> 75
<211> 416
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-螺旋
<400> 75
Gly Val Leu Ala Cys Ala Ile Ala Thr His Ala Lys Ile Arg Glu Gln
1 5 10 15
Glu Arg Leu Val Lys Leu Glu Thr Val Lys Lys Ser Leu Glu Gln Glu
20 25 30
Val Arg Thr Leu His Val Arg Ile Glu Glu Val Glu Ala Asn Ala Leu
35 40 45
Ala Gly Gly Asp Leu Arg Gln Met Arg Thr Val Thr Pro Ile Arg Met
50 55 60
Gln Gly Gly Cys Gly Ser Cys Trp Glu Ala His Glu Gln Gln Ile Arg
65 70 75 80
Ile Met Thr Thr Lys Leu Lys Glu Ala Glu Ala Arg Gln Gln Tyr Asp
85 90 95
Ile Lys Tyr Thr Trp Asn Val Pro Lys Ile Ala Val Asn Ile Val Gly
100 105 110
Tyr Ser Asn Ala Gln Gly Val Asp Tyr Trp Ile Val Arg Asn Ser Trp
115 120 125
Asp Thr Asn Trp Tyr His Asn Pro His Phe Ile Gly Asn Arg Ser Val
130 135 140
Ile Thr His Leu Met Glu Asp Leu Lys Gly Glu Leu Asp Met Arg Asn
145 150 155 160
Ile Gln Val Arg Gly Leu Lys Gln Met Lys Arg Val Gly Asp Ala Asn
165 170 175
Val Lys Ser Glu Asp Asp Ala Phe Arg His Tyr Asp Gly Arg Thr Ile
180 185 190
Ile Gln Arg Asp Asn Gly Tyr Gln Pro Asn Tyr Leu Asp Glu Tyr Trp
195 200 205
Ile Leu Thr Ala Ala His Cys Val Asp Gly Gln Thr Val Ser Lys Leu
210 215 220
Ile Arg Ser Lys Val Leu Gly Glu Lys Ile Ser Tyr Tyr Arg Tyr Val
225 230 235 240
Ala Arg Glu Gln Ser Cys Arg Arg Pro Asn Ala Gln Arg Phe Gly Ile
245 250 255
Ser Asn Tyr Cys Val Val Val Thr Val Lys Val Met Gly Asp Asp Glu
260 265 270
Leu His Thr Tyr Phe Asn Val Asn Tyr Thr Met His Tyr Tyr Leu Asn
275 280 285
Asn Gly Ala Thr Arg Asp Ile Leu Asp Glu Tyr Trp Ile Leu Thr Ala
290 295 300
Ala His Cys Val Ala Gly Gln Thr Ala Ser Lys Leu Ser Ile Arg Tyr
305 310 315 320
Asn Ser Leu Lys His Ser Leu Phe Lys Tyr Arg Pro Phe Lys Val Asn
325 330 335
Glu Leu Asn Leu Glu Gly Glu Phe Gly Arg Glu Leu Gln His Lys Phe
340 345 350
Arg Leu Met Arg Asn Ser Gln Met Glu Val Glu Glu Gly Gly Gly Ser
355 360 365
His His His His His His Gly Gly Gly Ser Cys Gly Gly Lys Val Ser
370 375 380
Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu
385 390 395 400
Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
405 410 415
<210> 76
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 76
Ser Ala Trp Ser His Pro Gln Phe Glu Lys
1 5 10
<210> 77
<211> 35
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 77
Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val
1 5 10 15
Ser Ala Leu Glu Lys Glu Val Ser Ala Leu Glu Lys Glu Val Ser Ala
20 25 30
Leu Glu Lys
35
<210> 78
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 78
Glu Gly Pro Trp Leu Glu Glu Glu Glu Glu Ala Tyr Gly Trp Met Asp
1 5 10 15
Phe
<210> 79
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 79
Glu Gly Pro Trp Leu Glu Glu Glu Glu Glu Ala Tyr
1 5 10
<210> 80
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (2)..(2)
<223> X为任意氨基酸
<220>
<221> 肽
<222> (4)..(4)
<223> X为任意氨基酸
<400> 80
Glu Xaa Pro Xaa
1
<210> 81
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (2)..(2)
<223> X为G或R任一
<220>
<221> 肽
<222> (4)..(4)
<223> X为W或R任一
<400> 81
Glu Xaa Pro Xaa
1
<210> 82
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (2)..(2)
<223> X为任意氨基酸
<220>
<221> 肽
<222> (4)..(4)
<223> X为任意氨基酸
<220>
<221> 肽
<222> (5)..(5)
<223> X为任意氨基酸
<220>
<221> 肽
<222> (10)..(10)
<223> X为任意氨基酸
<400> 82
Glu Xaa Pro Xaa Xaa Glu Glu Glu Glu Xaa Ala Tyr
1 5 10
<210> 83
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (2)..(2)
<223> X为G或R任一
<220>
<221> 肽
<222> (4)..(4)
<223> X为 W或R任一
<220>
<221> 肽
<222> (5)..(5)
<223> X为L或M任一
<220>
<221> 肽
<222> (10)..(10)
<223> X 为E或A任一
<400> 83
Glu Xaa Pro Xaa Xaa Glu Glu Glu Glu Xaa Ala Tyr
1 5 10
<210> 84
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (2)..(2)
<223> X为任意氨基酸
<220>
<221> 肽
<222> (4)..(4)
<223> X为任意氨基酸
<220>
<221> 肽
<222> (5)..(5)
<223> X为任意氨基酸
<220>
<221> 肽
<222> (10)..(10)
<223> X为任意氨基酸
<400> 84
Glu Xaa Pro Xaa Xaa Glu Glu Glu Glu Xaa Ala Tyr Gly
1 5 10
<210> 85
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (2)..(2)
<223> X为G或R任一
<220>
<221> 肽
<222> (4)..(4)
<223> X为W或R任一
<220>
<221> 肽
<222> (5)..(5)
<223> X为L或M任一
<220>
<221> 肽
<222> (10)..(10)
<223> X为E或A任一
<400> 85
Glu Xaa Pro Xaa Xaa Glu Glu Glu Glu Xaa Ala Tyr Gly
1 5 10
<210> 86
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 86
Glu Gly Pro Trp Leu Glu Glu Glu Glu Glu Ala Tyr Gly
1 5 10
<210> 87
<211> 53
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-螺旋
<400> 87
Glu Gly Pro Trp Leu Glu Glu Glu Glu Glu Ala Tyr Gly Gly Gly Ser
1 5 10 15
Gly Gly Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
20 25 30
Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val
35 40 45
Ser Ala Leu Lys Glu
50
<210> 88
<211> 56
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-螺旋
<220>
<221> 肽
<222> (16)..(16)
<223> 其中肽序列EGPWLEEEEEAYGGG进一步经C末端G连接至16位的K
<400> 88
Glu Gly Pro Trp Leu Glu Glu Glu Glu Glu Ala Tyr Gly Gly Gly Lys
1 5 10 15
Gly Gly Ser Gly Gly Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala
20 25 30
Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys
35 40 45
Glu Lys Val Ser Ala Leu Lys Glu
50 55
<210> 89
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 89
Gly Gly Ser Gly Gly
1 5
<210> 90
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (3)..(3)
<223> 其中肽序列GG进一步经C末端G连接至3位的K。
<400> 90
Gly Gly Lys Gly Gly Ser Gly Gly
1 5
<210> 91
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 91
Glu Ile Ala Ala Leu
1 5
<210> 92
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 92
Lys Ile Ala Ala Leu
1 5
<210> 93
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 93
Glu Ile Ser Ala Leu
1 5
<210> 94
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 94
Lys Ile Ser Ala Leu
1 5
<210> 95
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 95
Glu Val Ala Ala Leu
1 5
<210> 96
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 96
Lys Val Ala Ala Leu
1 5
<210> 97
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 97
Glu Val Ser Ala Leu
1 5
<210> 98
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 98
Lys Val Ser Ala Leu
1 5
<210> 99
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 免疫原
<400> 99
Glu Gly Pro Trp Met Glu Glu Glu Glu Ala Ala Tyr Gly
1 5 10
<210> 100
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 免疫原
<400> 100
Glu Arg Pro Arg Met Glu Glu Glu Glu Glu Ala Tyr Gly
1 5 10
<210> 101
<211> 53
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-螺旋
<400> 101
Glu Gly Pro Trp Met Glu Glu Glu Glu Ala Ala Tyr Gly Gly Gly Ser
1 5 10 15
Gly Gly Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
20 25 30
Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val
35 40 45
Ser Ala Leu Lys Glu
50
<210> 102
<211> 53
<212> PRT
<213> 人工序列
<220>
<223> 免疫原-螺旋
<400> 102
Glu Gly Pro Trp Leu Glu Glu Glu Glu Glu Ala Tyr Gly Gly Gly Ser
1 5 10 15
Gly Gly Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu
20 25 30
Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val
35 40 45
Ser Ala Leu Lys Glu
50
<210> 103
<211> 56
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (16)..(16)
<223> 其中肽序列EGPWMEEEEAAYGGG进一步经C末端G连接至16位的K。
<400> 103
Glu Gly Pro Trp Met Glu Glu Glu Glu Ala Ala Tyr Gly Gly Gly Lys
1 5 10 15
Gly Gly Ser Gly Gly Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala
20 25 30
Leu Lys Glu Lys Val Ser Ala Leu Lys Glu Lys Val Ser Ala Leu Lys
35 40 45
Glu Lys Val Ser Ala Leu Lys Glu
50 55
<210> 104
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 104
Ala Val Asn Ile Val Gly Tyr Ser Asn Ala Gln Gly Val Asp Tyr Trp
1 5 10 15
Ile Val Arg Asn Ser Trp Asp Thr Asn Trp
20 25
<210> 105
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 105
Tyr His Asn Pro His Phe Ile Gly Asn Arg Ser Val Ile Thr His Leu
1 5 10 15
Met Glu
<210> 106
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 106
Ser Trp Asp Pro Tyr Trp Pro Phe Pro Trp Phe Ser Gly Gly Gly Ser
1 5 10 15
<210> 107
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 107
Thr Asp Trp Ser Trp Phe Tyr Gly Gly Gly Ser
1 5 10
<210> 108
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 108
Tyr Pro Val Tyr Trp Pro Trp Gly Gly Gly Ser
1 5 10
<210> 109
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 109
Glu Trp Trp Phe Tyr Trp Pro Gly Gly Gly Ser
1 5 10
<210> 110
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 110
Trp Phe Pro Ile Glu Trp Trp Gly Gly Gly Ser
1 5 10
<210> 111
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 111
Asp Gln Val Asp Ile Gly Tyr Gly Gly Gly Ser
1 5 10
<210> 112
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 112
Thr His Gln Val Tyr Ile Ser Gly Gly Gly Ser
1 5 10
<210> 113
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 113
Trp Phe Pro Ile Glu Trp Trp Phe Tyr Trp Pro Gly Gly Gly Ser
1 5 10 15
<210> 114
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 114
Asp Ser Trp Gln Ala Phe Leu Thr Lys Phe Val Leu Gly Gly Gly Ser
1 5 10 15
<210> 115
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 115
Glu Ser Trp Asp Lys Phe Leu Ser His Tyr Leu Pro Gly Gly Gly Ser
1 5 10 15
<210> 116
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 116
His Asp Ile Gln Trp Phe Trp Gln His Trp Asn Ser Gly Gly Gly Ser
1 5 10 15
<210> 117
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 117
Trp Ser Trp Trp Asp His Thr Phe Asn Tyr Met Leu Gly Gly Gly Ser
1 5 10 15
<210> 118
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 118
Thr Thr Gln Gln Thr Trp Asn Val Arg Tyr Pro Tyr Gly Gly Gly Ser
1 5 10 15
<210> 119
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 119
Asp His Thr Met Pro Trp Thr Arg Asn Ala Lys Asn Gly Gly Gly Ser
1 5 10 15
<210> 120
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 120
Ala Ile Tyr Tyr Val Pro Ser Pro Met Phe Thr Val Gly Gly Gly Ser
1 5 10 15
<210> 121
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 121
Glu Thr Thr Leu Leu Lys Met Trp Leu Ala Gln Met Gly Gly Gly Ser
1 5 10 15
<210> 122
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 122
Tyr Pro Trp Leu Asp Val Ala Val Val Ser Leu Tyr Gly Gly Gly Ser
1 5 10 15
<210> 123
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 123
Val Pro Gly Trp His Tyr Leu Ala Thr Leu Arg Ala Gly Gly Gly Ser
1 5 10 15
<210> 124
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 124
Phe Asp Pro Leu Gly Ser Arg Asp Ile Lys Gly Ser Gly Gly Gly Ser
1 5 10 15
<210> 125
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 125
Glu Trp Trp
1
<210> 126
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 126
Trp Phe Tyr
1
<210> 127
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 肽
<400> 127
Tyr Trp Pro
1
<210> 128
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 肽
<220>
<221> 肽
<222> (3)..(3)
<223> X为任意氨基酸
<400> 128
Gln Val Xaa Ile
1
Claims (9)
1.一种免疫刺激疫苗,其包括
-导向佐剂,其至少包括连接至TLR9配体的抗CD32部分,其中,所述抗CD32部分融合至第一肽α-螺旋,和
-免疫原,其具有至少一个融合至与所述第一肽α-螺旋缠绕的第二肽α-螺旋的表位,
其中所述第一肽α-螺旋和所述第二肽α-螺旋形成卷曲螺旋,所述卷曲螺旋为两个不同的螺旋的异质卷曲,其中,所述第一肽α-螺旋和第二肽α-螺旋各自由氨基酸基序的3-5个氨基酸重复组成,以小于10-6M的Kd彼此特异性结合;
其中所述疫苗包括成为异二聚体的所述导向佐剂和所述免疫原;
其中,所述TLR9配体是合成的TLR9激动剂,其选自由CpG寡脱氧核苷酸A类、B类、C类组成的组;
其中,所述免疫原包含选自由包含如SEQ ID NO:78,SEQ ID NO:79,SEQ ID NO:80,SEQID NO:81,SEQ ID NO:82,SEQ ID NO:83,SEQ ID NO:84,SEQ ID NO:85,SEQ ID NO:86所示的氨基酸序列的肽组成的组中的胃泌素-17肽。
2.根据权利要求1所述的疫苗,其中所述免疫原包含至少2个所述胃泌素-17肽。
3.根据权利要求1所述的疫苗,其中所述免疫原向所述第二肽α-螺旋的融合包含如SEQID NO:87或SEQ ID NO:88所示的氨基酸序列。
4.根据权利要求1所述的疫苗,其中所述抗-CD32部分选自由抗-CD32抗体、抗体片段和肽组成的组。
5.根据权利要求1所述的疫苗,其中所述TLR9配体是选自由CpG寡脱氧核苷酸C类组成的组的TLR9激动剂。
6.根据权利要求1所述的疫苗,其中所述抗CD32部分靶向CD32a。
7.根据权利要求1所述的疫苗,其配制用于胃泌素依赖性疾病的免疫治疗。
8.根据权利要求7所述的疫苗,其中所述胃泌素依赖性疾病是任意肿瘤或癌症疾病。
9.根据权利要求7所述的疫苗,其中所述胃泌素依赖性疾病选自由胰腺癌,胃肠癌,胃溃疡,胃食管反流病,终末期肾功能衰竭或肥胖组成的组。
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