CN116801904A - 包含冠状病毒衍生的受体结合域及核壳蛋白的融合蛋白及其用途 - Google Patents
包含冠状病毒衍生的受体结合域及核壳蛋白的融合蛋白及其用途 Download PDFInfo
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Abstract
本发明涉及一种融合蛋白包含SARS‑CoV‑2衍生受体结合域及核壳蛋白,及其用途。与仅包含受体结合域的免疫原组合物相比,包含冠状病毒衍生的受体结合域及核壳蛋白的融合蛋白高度适用于具有显著改善的体内半衰期且具有显著优越的功效的多价疫苗组合物。特别地,融合蛋白可以显著地改善冠状病毒特定抗体形成的力价及T细胞免疫反应,因此可用于预防及治疗包含SARS‑CoV‑2的冠状病毒。
Description
技术领域
本发明涉及一种融合蛋白,包含冠状病毒衍生的受体结合域(receptor-bindingdomain)及核壳蛋白以及其用途,特别涉及一种融合蛋白的用途用于预防或治疗冠状病毒感染。
背景技术
冠状病毒(coronavirus)为一种RNA病毒,其中包含核糖核酸(ribonucleic acid,RNA)形式的遗传信息。冠状病毒造成人类及动物的呼吸道及消化道系统感染。通常,冠状病毒很容易通过黏膜传播、飞沫传播等方式感染,并且人类通常表达出轻度的呼吸道感染,但是感染偶尔会是致命的。
世界卫生组织(WHO)命名由所述严重急性呼吸系统综合征冠状病毒2型(severeacute respiratory syndrome-coronavirus-2,SARS-CoV-2)引起的疾病为“COVID-19”。根据SARS-CoV-2感染的蔓延,WHO于1月30日宣布“国际关注的公共卫生紧急事件(PHEIC)”。因为全球的COVID-19确诊人数持续地上升,继3月11日香港流感(1968)和猪流感(swine flu)(2009)之后,WHO宣布了历史上的第三次全球大流行。
全球大约有一亿人已被感染,约两百万人死亡,每天增加成千上万的确诊患者,而且被感染的患者数量继续增加(截至2021年1月18日,COVID-19约翰·霍普金斯大学(JHU)系统科学与工程中心(CSSE)的统计表。在韩国,大约有70,000名患者被确诊,由于感染是通过当地小区传播的,因此每天新增数百例确诊病例,据报导总共有1,264人死亡(截至2021年1月18日,韩国的中央灾难与安全对策总部)。
已知感染SARS-CoV-2会引起发烧(83-99%)、咳嗽(59-82%)、食欲不振(40-84%)、疲倦(44-70%)、呼吸困难(31-40%)、痰和咳嗽(28-33%)、肌肉疼痛和其他疼痛(11-35%)等(美国疾病控制与预防中心(CDC),2020年4月6日),据报导这些症状会在潜伏期2至14天后展现。
SARS-CoV-2具有高度传染性,已知通常通过直接/间接接触或从感染者身上排出的气溶胶(aerosol)型飞沫传播,并且据报导也经常通过无症状患者传播(欧洲疾病预防和控制中心,检索于2020年4月30日)。此外,甚至完全康复后仍患有后遗症或再感染的病例已被重复报导。因此,预防SARS-CoV-2感染至关重要。为此目的,戴口罩、洗手及保持社交距离在个人/社会层面上皆积极地进行,但是SARS-CoV-2感染的病例在包含教堂在内的各种地点发生,并且其感染途径尚不清楚。因此,迫切需要开发SARS-CoV-2疫苗。目前,各种机构正在开发和研究候选疫苗,并且各种类型的疫苗(例如重组疫苗、非活性病毒疫苗和mRNA疫苗)已在临床试验中。最近,一些药厂开发的疫苗已经被紧急批准并推出,例如辉瑞(Pfizer)、莫徳纳(Moderna)和阿斯利康(Astrazeneca),但是生产和供应都不足以满足需求,而且,冠状病毒的多种变体正在陆续出现。因此,开发新疫苗的需求继续存在着。
同时,血管张力素转化酶(angiotensin-converting enzyme,ACE2)已知可以通过降解第二型血管紧张素(angiotensin II)保护肾脏、肺部及心脏免于发炎,其中第二型血管紧张素为一种容易引起发炎的物质。ACE2已知在冠状病毒家族的细胞进入过程(cellentry process)中作为病毒受体的重要角色,其中冠状病毒家族例如为SARS-CoV-1及SARS-CoV-2。具体而言,SARS-CoV-2据报导通过两种机制运作,即由于与TMPRSS2的共同作用而产生的直接融合或基于ACE2与棘状蛋白(spike protein,S蛋白)结合的细胞内作用(Int.J.Mol.Sci.2020,21,5224;10.1016/j.cell.2020.02.052et al.)。因此,目前正在被研究的许多治疗剂和疫苗的开发策略均是针对棘状蛋白,特别是大多数疫苗涉及形成针对SARS-CoV-2的棘状蛋白的中和抗体(neutralizing antibody)。
仅使用病原体的遗传信息各别生产的病原体的抗原决定位(antigenicdeterminant site)引入的大多数重组疫苗,通过施用作为抗原的棘状蛋白或其片段(尤其是与ACE2结合的受体结合域),通过形成抗棘状蛋白或受体结合域(receptor-bindingdomain,RBD)的中和抗体而具有作为药理机制的抗体介导(antibody-mediated)的病毒中和作用。
尤其,SARS-CoV-2的受体结合域为与ACE2结合的特定序列的氨基酸,其为包含于SARS-CoV-2的棘状蛋白(S蛋白)中的受体,其野生型氨基酸序列(SEQ ID NO:1)已被提出,且对于其结合结构的研究结果已经被持续地提出(Nature.3月30日;Science.4月3日;Cell.4月9日)。
在这种背景技术下,由于对开发用于预防或治疗包含COVID-19的冠状病毒感染的疫苗的广泛努力,本发明的发明人制备了包含SARS-CoV-2衍生S蛋白的受体结合域的融合蛋白、核壳蛋白的RNA结合域及Fc域,并发现相较于仅包含受体结合域的融合蛋白,以所述融合蛋白接种的动物模型展现了明显更高的受体结合域特定中和抗体力价(titer)及活化的T细胞免疫反应。基于此发现,完成了本发明。
在此背景技术段落所揭露的信息仅是为了更好理解本发明的背景技术,且因此其可能不包含构成对本领域具有通常知识者而言显而易见的现有技术的信息。
发明内容
因此,鉴于上述问题提出了本发明,并且本发明的一个目的是提供一种具有冠状病毒特定免疫原性(immunogenicity)的融合蛋白及其用途。
本发明的另一目的是提供用于预防或治疗冠状病毒感染含有所述融合蛋白的组合物。
本发明的另一目的是提供一种疫苗接种方法,用于预防或治疗冠病病毒感染。
本发明的另一目的是提供一种方法,用于预防或治疗冠病病毒感染。
本发明的另一目的是提供一种核酸,编码(encoding)所述融合蛋白。
本发明的另一目的是提供一种重组载体(recombinant vector),包含所述核酸。
本发明的另一目的是提供一种宿主细胞,其中被引入所述核酸或重组载体。
本发明的另一目的是提供一种用于制备融合蛋白方法。
根据本发明的一个方面,上述及其他目的可以通过提供包含SARS-CoV-2衍生的S蛋白融合蛋白受体结合域、核壳蛋白以及Fc域而实现。
根据另一方面,本发明提供一种包含所述融合蛋白的疫苗组合物。
根据另一方面,本发明提供一种所述融合蛋白的用途,用于制备用以预防冠状病毒感染的疫苗组合物。
根据另一方面,本发明提供一种疫苗接种方法,用于对抗冠状病毒感染,所述方法包含施用所述融合蛋白和/或疫苗组合物至受试者。
根据另一方面,本发明提供一种药物组合物,用于预防或治疗冠状病毒感染,所述药物组合物包含以所述融合蛋白作为活性成分(active ingredient)。
根据另一方面,本发明提供所述融合蛋白在制备用于预防或治疗冠状病毒感染的药物组合物中的用途。
根据另一方面,本发明提供预防或治疗冠状病毒感染的方法,所述方法包括施用所述融合蛋白和/或药物组合物至受试者。
根据另一方面,本发明提供用于预防或治疗冠状病毒感染的所述融合蛋白的用途。
根据另一方面,本发明提供一种核酸编码所述融合蛋白。
根据另一方面,本发明提供一种包含所述核酸的重组载体(recombinantvector)。
根据另一方面,本发明提供一种宿主细胞,其中被引入所述核酸或重组载体。
根据另一方面,本发明提供一种用于制备融合蛋白的方法,所述方法包含培养所述宿主细胞。
附图说明
通过以下结合附图的详细描述,将更清楚地理解本发明的上述和其他目的、特征和其他优点,其中:
图1示出SARS-CoV-2受体结合域(RBD)与ACE2之间的结合结构(Nature.3月30日);
图2示出野生型RBD的氨基酸序列,其中每个深色部分是指受体结合基序(receptor-binding motif,RBM),而蓝色框是指第一型主要组织兼容性复合体(MHC I)及第二型主要组织兼容性复合体(MHC II)的抗原决定位(epitope);
图3为示出在实施例中制备的融合蛋白的示意图;
图4为示出IgG1-Fc的示意图(左),及示出聚丙烯酰胺胶体电泳(SDS-PAGE)对产物的分析结果(右);
图5为示出Fc-RBDwt的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图6为示出RBDwt-Fc的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图7为示出N-Fc的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图8为示出GIC-1114的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图9为示出GIC-1114N的示意图;
图10为示出对小鼠的动物模型以本发明的融合蛋白接种疫苗的示意图;
图11示出在被以IgG Fc、GIC-1114及Fc-RBDwt融合蛋白个别或其组合与佐剂(adjuvant)小鼠进行疫苗接种的小鼠动物模型中,受体结合基序特定中和抗体形成的力价;以及
图12示出当被GIC-1114、Fc-RBDwt及N-Fc融合蛋白各对应的抗原刺激时,使用GIC-1114、Fc-RBDwt及N-Fc融合蛋白接种的小鼠脾脏中T细胞的IFN-γT水平。
具体实施方式
在下文中,将详细描述本发明。然而,以下提供的详细描述仅用于说明本发明,而不应解释为限制本发明的范围。在不背离之后阐述的专利范围及其等同范围的情况下,可以进行多种修改和变更。
除有特别说明,核酸及氨基酸是以5’至3’及N末端至C末端的从左至右的顺序撰写。本文所列的数值范围包含定义所述范围的数值,及包含在所述定义范围内的任何整数及非整数分数。
除非另有定义,否则本文所用的所有技术及科学术语具有与本发明所属领域的通常知识者所理解的相同的含意。尽管在实务中可以使用与本文描述的那些类似或等同的任何方法及材料来测试本发明,但本文描述了优选的材料及方法。
SARS-CoV-2是新的冠状病毒,是一种全球大流行病,全世界确诊病例有数以千万计,数十万人死亡。尽管存在这些状况,但很少有被证明对于SARS-CoV-2有效的治疗剂及疫苗,许多研究人元及公司都正在努力研发其治疗剂及疫苗。
多数目前正被研发的SARS-CoV-2疫苗旨在使用免疫原(immunogen)、棘状蛋白(spike protein)或其片段制备中和抗体(neutralizing antibody),上述在SARS-CoV-2的感染(细胞进入)机制及症状表达扮演着重要的脚色。
在本发明的一实施方案中,融合蛋白是通过融合核壳蛋白及SARS-CoV-2衍生棘状蛋白受体结合域与Fc域制备而成。包含Fc域的融合蛋白可以表达改善的生物特性,例如延长的半衰期及增加的表达程度(expression level)同时最小化生物活性的丧失。
在本发明的另一实施方案中,以包含受体结合域的融合蛋白对小鼠动物模型进行接种疫苗的结果中,相较于不包含核壳蛋白的融合蛋白,本发明的核壳蛋白及Fc域示出了根据本发明的融合蛋白展现了SARS-CoV-2受体结合蛋白特定中和抗体形成的显著高的力价,且当被核壳蛋白(N-Fc)刺激时,以根据本发明的融合蛋白接种从小鼠脾脏得的T细胞展现了高的IFN-γT水平,表示融合蛋白能够活化T细胞免疫反应。
在一方面,本发明涉及包含SARS-CoV-2衍生S蛋白受体结合域的融合蛋白、核壳蛋白及Fc域。
如本文所用,术语“受体结合域(RBD)”是指与ACE2结合的特定氨基酸序列,ACE2为冠状病毒的棘状蛋白的受体,且受体结合域包含受体结合基序(receptor-binding motif,RBM)。优选地,受体结合域可以为SARS-CoV-2衍生棘状蛋白的域。例如,SARS-CoV-2衍生受体结合域的野生型氨基酸序列(SEQ ID NO:1)已被提出(Nature.3月30日)。
如本文所用,术语“受体结合基序(RBM)”是指包含在受体结合域(RBD)中的氨基酸序列,且具有接触受体ACE2的位置。例如,SARS-CoV-2衍生受体结合基序的野生型氨基酸序列(SEQ ID NO:1的120-188氨基酸)已被提出(Nature.3月30日)。
冠状病毒棘状蛋白已知不仅在冠状病毒的细胞感染,更在病毒重组(reassembly)及释放中扮演重要的脚色。尤其,受体结合域为直接参与ACE2的结合及相互作用的域,其中ACE2为棘状蛋白的受体,且棘状蛋白的受体结合域的特征在于其序列在冠状病毒种中为高度保守(conserved)。
在本发明中,冠状病毒受体结合域或受体结合基序可以为目前提出的冠状病毒的棘状蛋白的受体结合域或基序,或者具有基因突变的变异的冠状病毒的棘状蛋白的受体结合域或基序。
在本发明中,受体结合域可以为自SARS-CoV-2衍生,但不限于此。
在本发明中,受体结合域可以由SEQ ID NO:1的氨基酸序列表示,但不限于此。受体结合域可以具有与SEQ ID NO:1的氨基酸序列有高度同源性的序列,例如,具有80%或更高、90%或更高、优选为95%或更高,且最优选为99%或更高的高度同源性的序列。
如本文所用,术语“核壳蛋白”是指病毒的遗传物质及围绕RNA的冠状病毒的壳蛋白。核壳蛋白的表达已被提出在被冠状病毒感染的细胞中显著地增加,特别是,核壳蛋白的RNA结合域为高度保守的序列。在本发明中,术语“核壳蛋白”为高度保守的序列。在本发明中,术语“核壳蛋白”与“N蛋白”可互换使用,具有与上述相同的含义。
在本发明中,核壳蛋白旨在涵盖不只整个核壳蛋白,而是更涵盖核壳蛋白的特定域或其片段,且优选包含核壳蛋白的RNA结合域或包含其的片段。
在本发明中,N蛋白可由SEQ ID NO:3序列表示,或可以包含由SEQ ID NO:3序列表示的序列。
在本发明中,融合蛋白可以包含N蛋白的RNA结合域。
在本发明中,RNA结合域可以由SEQ ID NO:4表示。
如本文所用,术语“Fc域”是指受体的抗体的尾部区域(tail region),且所述区域与免疫球蛋白中补体系统的蛋白及细胞表面上的受体相互作用,Fc域包含重链稳定域(heavy-chain constant domain)CH2及CH3,且更可以包含重链稳定域的枢纽区(hingeregion)。在本发明中,Fc域旨在涵盖免疫球蛋白的所有Fc域、其片段及其变体。
在本发明中,Fc域可以为哺乳动物的免疫球蛋白Fc域,优选为小鼠、兔子或人类的免疫球蛋白Fc域,且更优选为人类的免疫球蛋白Fc域,但不限于此。
在本发明中,Fc域可以为IgA、IgM、IgE、IgD或IgG的Fc域、其片段或其变体,且优选地,Fc域为IgG(IgG1、IgG2a、IgG2b、IgG3或IgG4的Fc域)的Fc域,但不限于此。
在本发明中,Fc域可以为人类的IgG1的Fc域。更具体地,Fc域可以为自IgG1、IgG2a、IgG2b、IgG3或IgG4衍生的Fc域,其为从有机体衍生的同型(isotype)IgG。
在本发明中,Fc域最优选由SEQ ID NO:2的序列表示,或包含所述序列,但不限于此。
此外,Fc域可以包含糖链(sugar chain),或者Fc域可以使用相较于原始形式增加或减少的糖链,或使用相较于原始形式糖链被移除的形式。所述糖链的增加、减少或移除可以由本案所属领域中的传统方法执行,例如化学方法、酶方法及使用微生物的基因工程方法。于此,从Fc域移除糖链显著地降低对主要补体成分(C1)的C1q的结合亲和力,并导致抗体依赖性细胞介导的细胞毒性(antibody-dependent cell-mediated cytotoxicity,ADCC)或补体依赖性细胞毒性(complement-dependent cytotoxicity,CDC)的减少或丧失,进而防止了体内不良的免疫反应。
在本发明中,融合蛋白可以包含两个或更多个蛋白,其中所述两个或更多个蛋白包含受体结合域、核壳蛋白及Fc域。
在本发明中,融合蛋白可以蛋白的二聚体(dimer),其中所述蛋白包含受体结合域、核壳蛋白及Fc域。
在本发明中,二聚体可以通过每个Fc域的一个或多个半胱氨酸(cysteine)残基的双硫键(disulfide bond)形成。
在本发明中,融合蛋白可以为蛋白的异型二聚体(heterodimer)或同型二聚体(homodimer),其中所述蛋白包含受体结合域、核壳蛋白及Fc域。在本发明的一实施方案中,融合蛋白被制备为同型二聚体,但不限于此。
本文中受体结合域、核壳蛋白及Fc域等的氨基酸序列是解读为包含其中氨基酸残基在特定的氨基酸残基位置被保守地取代的变体或其片段。
如本文所用,术语“保守取代”是指包含以具有相似的生化特性的氨基酸取代一个或多个氨基酸,而不造成对应蛋白的生物或生化功能损失的更动。
术语“保守的氨基酸取代”是指以其他具有相似侧链的氨基酸残基取代氨基酸残基。例如,具有相似侧链的氨基酸残基类别在本领域是常规的。这些类别包含具有基本侧链的氨基酸(如赖氨酸、精氨酸、组氨酸)、具有酸性侧链的氨基酸(如天冬氨酸、谷氨酸)、具有不带电荷的极性侧链的氨基酸(如甘氨酸、天冬酰胺、谷氨酰氨酸、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、具有非极性侧链的氨基酸(如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、具有β-支链侧链(如苏氨酸、缬氨酸、异亮氨酸)及具有芳侧链的氨基酸(如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。
在本发明中,受体结合域基于受体结合基序与ACE2结合。因此,在本发明中,保守取代优选发生在氨基酸序列的部分而非受体结合域及基序,但本发明不限于此。
在本发明中,包含于融合蛋白中的受体结合域、Fc域及核壳蛋白可以通过共价链等彼此直接连接,且可以通过其他分子(例如,接头)彼此间接连接。
在本发明中,受体结合域、核壳蛋白及Fc域优选通过甘氨酸–丝氨酸接头(glycine-serine linker,GS linker)连接至彼此,更优选为GS4接头。在本发明中,优选地,受体结合域、核壳蛋白及Fc域优选通过包含SEQ ID NO:5和/或SEQ ID NO:6的氨基酸序列的接头彼此连接。
在本发明的一实施方案中,融合蛋白是通过将自SARS-CoV-2衍生的受体结合域或N蛋白使用接头连接至Fc域的C末端和/或N末端制备而成,其中所述接头是由GGGGSGGGGSGGGGS(SEQ ID NO:5)或
GGGGSGGGGSGGGGSGGGGS(SEQ ID NO:6)表示,但本发明不限于此。
在本发明中,优选地,融合蛋白可以有受体结合域与冠状病毒衍生的核壳蛋白连接至Fc域的结构。
在本发明中,受体结合域可以连接至Fc域的N末端和/或C末端,且优选连接于其C末端。
在本发明中,受体结合域可以连接至Fc域的N末端或C末端,而核壳蛋白(N蛋白)可以连接至剩余者。
在本发明中,优选地,受体结合域可以连接至Fc域的C末端,而核壳蛋白可以连接至Fc域的N末端。
在本发明中,受体结合域连接至Fc域的N末端及C末端的其中一者,而核壳蛋白的RNA结合域可以连接至剩余者。
在本发明中,融合蛋白可以具有受体结合域、Fc域及核壳蛋白以此顺序连接的结构,或核壳蛋白、Fc域及受体结合域以此顺序连接的结构。
在本发明中,融合蛋白优选是由SEQ ID NO:19或SEQ ID NO:20的氨基酸序列表示,或包含所述氨基酸序列。
在本发明中,融合蛋白可以为受体结合域及核壳蛋白连接至的Fc域的二聚体。
在本发明中,融合蛋白为“受体结合域–Fc域–核壳蛋白”和/或“核壳蛋白–Fc域–受体结合域”的同型二聚体或异型二聚体。
所述“受体结合域–Fc域–核壳蛋白”及“核壳蛋白–Fc域–受体结合域”是指其中各别元素(受体结合域、Fc域及核壳蛋白)的蛋白依序从C末端连接至N末端。
在本发明中,融合蛋白优选为由SEQ ID NO:19或SEQ ID NO:20的氨基酸序列表示或是包含所述氨基酸序列的蛋白的同型二聚体或异型二聚体。
在本发明中,融合蛋白最优选为由SEQ ID NO:19或SEQ ID NO:20表示的蛋白的同型二聚体。
在本发明中,受体结合域及核壳蛋白可以通过共价链直接地连接至Fc域,且可以通过例如为接头、蛋白或多糖的接头的其他分子间接地连接至Fc域。
在本发明中,以融合蛋白进行疫苗接种能够在小鼠中和抗体形成及T细胞免疫应的力价上引起显著的改善、避免病毒感染、抑制病毒增生以及消除病毒。
如本文所用,术语“冠状病毒”是指属于冠状病毒科(Coronavirinae)属的RNA病毒(Ninth Report of the International Committee on Taxonomy of Viruses.Elsevier,Oxford.pp.806–828)。冠状病毒科属被分为四个属,即α、β、γ和δ冠状病毒属。能够感染人类的冠状病毒的实例包含SARS-CoV、MERS-CoV、SARS-CoV-2、HCoV-229E、HCoV-OC43、HKU1、HCoV-NL63等,但不限于此。
在本发明的一实施方案中,与SARS-CoV-2衍生受体结合域的蛋白及RNA结合域融合的蛋白被制备,但所有的冠状病毒都有共同的棘状蛋白,且通过与ACE2结合进入并扩散进宿主细胞,其中ACE2为其宿主细胞的受体。特别地,每个物种的S1亚基中包含的受体结合结构域显然是高度保守的,因此本发明的融合蛋白不限于包含SARS-CoV-2衍生分子。
在本发明中,融合蛋白可以包含除了冠状病毒衍生受体结合域、核壳蛋白及Fc域之外的分子,且更可以例如包含冠状病毒衍生的分子(优选为SARS-CoV-2衍生分子)、接头、佐剂、抗原、抗体等,但不限于此。
在本发明中,冠状病毒衍生物质是指自冠状病毒衍生的任何物质,例如冠状病毒衍生蛋白、核酸(优选为RNA)或多糖。
在本发明中,冠状病毒衍生物质可以是指冠状病毒所含的或由冠状病毒制备的任何物质,例如从冠状病毒分离出来的蛋白、核酸(优选为RNA)或多糖,例如N蛋白、M蛋白、ORF蛋白等。举例而言,本发明的融合蛋白更可以包含M蛋白,但不限于此。
在本发明中,冠状病毒衍生物质可以是冠状病毒衍生蛋白或其片段。
在本发明的一实施方案中,发现的是通过连接受体结合域至Fc域的一端(N末端或C末端)及连接核壳蛋白的RNA结合域至其另一端制备而成的融合蛋白具有高力价的中和抗体形成及T细胞免疫反应诱发能力。
本发明的融合蛋白展现免疫原性病因此可以诱导体内各种免疫反应,且例如可以诱导中和抗体的形成、刺激胞毒型T淋巴球的分化,及刺激辅助型T细胞(Th细胞)的分化。在本发明的一实施方案中,发现的是,相较于包含受体结合域及Fc域的受体结合域,本发明的融合蛋白可以诱导中和抗体形成的显著更高的力价及优选的T细胞免疫反应。
据此,在另一方面,本发明涉及疫苗组合物包含本发明的融合蛋白。
如本文所用,术语“疫苗组合物”是指一种组合物,其包含在体内或体外作为抗原或免疫原以诱发免疫反应的物质,且可以与具有上述含义的“疫苗”或“免疫原性组合物”互换使用。
如本文所用,术语“免疫反应”旨在涵盖先天(innate)免疫反应及后天(adaptive)免疫反应,例如,补体介导(complement-mediated)免疫反应、细胞(T细胞)介导免疫反应和/或抗体(B细胞)反应。
本发明的疫苗组合物可以诱导或改善被施用所述疫苗组合物的受试者对抗冠状病毒的免疫反应,且更具体地,当所述受试者被SARS-CoV-2感染时,本发明的疫苗组合物可以诱导对抗SARS-CoV-2病毒的中和抗体的形成、诱导和/或增加胞毒型淋巴球的分化以及预防、改善、消除或降低病毒再活化的机会,和/或预防或降低关联于病毒再活化的其他疾病或并发症发作的机会。
在本发明中,疫苗组合物可以进一步包含佐剂。
如本文所用,术语“佐剂”是指基于Alexander Glenny发现铝盐增加免疫反应的概念,并且是指被添加的辅助成分,以在受施用疫苗组合物或疫苗接种的受试者中诱导更强的免疫反应。佐剂的实例可以包含铝盐(例如磷酸铝或氢氧化铝)、含鲨烯的乳化剂(例如MF59)或其类似物(与MF59相似的物质))、AS03或其类似物(与AS03相似的物质)、AF03或其类似物(与AF03相似的物质)及SE或其类似物(与SE相似的物质)、钙盐、双股核糖核酸(dsRNA)类似物、脂多糖、脂肪A(lipid A)类似物(MPL-A、GLA等)、鞭毛蛋白、咪唑喹啉、CpG寡脱氧核苷酸、矿物油、类Toll受体(Toll-like receptor,TLR)拮抗剂、C型凝集素配体、CD1d配体(α-半乳糖脑苷脂(α-galactosylceramide))、清洁剂(detergent)、脂质体、石碱(saponin)(例如QS21)、细胞激素及肽等,但不限于此。
在本发明的一实施方案中,作为佐剂的AddaVax(例如MF59等)、MPLA、明矾(Alum)等被单独使用或合并使用,且确认的是在所有情况下均增强了免疫反应。
因此,在本发明中,佐剂优选是自由MF59、MPLA、明矾及其组合组成的群组选择,且优选为单独的MF59、单独的MPLA或明矾与MPLA的组合,但不限于此。
本发明的疫苗组合物的最优选剂量可以通过标准研究来判定,所述研究涉及观测受试者中合适的免疫反应。初次接种疫苗后,可以适当的时间间隔对受试者进行一次或多次加强免疫。在本发明的一实施方案中,在小鼠动物模型中初次接种疫苗的两周后,又对小鼠进行一次疫苗接种,但不限于此。
本发明的疫苗组合物可以以药学上的有效量被施用,而术语“药学上的有效量”是指足够诱发或增强免疫反应的量,而不造成副作用或严重或过度免疫反应。合适的剂量可以根据包含制药方法、施药模式、病人的年纪、体重、性别及病理状况、饮食、施药时间、给药途径、排泄速率及反应敏感度的各种因素而改变。确认药物有效剂量的各种通常考虑已为本领域中具有通常知识者所知,且以提出于参考文献中,如“Gilman et al.,eds.,GoodmanAnd Gilman's:The Pharmacological Bases of Therapeutics,8th ed.,PergamonPress,1990”及“Remington's Pharmaceutical Sciences,17th ed.,Mack PublishingCo.,Easton,Pa.,1990”。
本发明的疫苗组合物可以与用于冠状病毒的治疗剂或对症治疗剂被合并施用,且可以与其他疫苗、病毒治疗剂、免疫佐剂、症状缓解剂等被施用。
本发明的疫苗组合物可以被制备成单位剂型(unit dosage form),或可以根据可由本发明所属于领域中具有通常知识者能够轻易实施的方式,通过使用药学上可接受的载体和/或赋形剂被并入多剂量型容器(multi-dose container)。所述制剂可以根据传统方法制备并以口服制剂的形式使用,例如粉末、颗粒、药片、胶囊、悬浮液、乳化剂、糖浆和喷雾剂、外用制剂、栓剂和无菌注射溶液。本领域已知的合适制剂可以为揭露于参考文件(Remington's Pharmaceutical Science,Mack Publishing Company,Easton PA)中的制剂。口服的固态制剂包含药片、药丸、粉末、颗粒、胶囊等。这些固态制剂通过混合至少一赋形剂(如淀粉、碳酸钙、蔗糖、乳糖、明胶等)而被制备。除了简单的赋形剂,例如硬脂酸镁和滑石粉的润滑剂可以被使用。用于口服的液态制剂包含悬浮液、口服液体及溶液、乳化剂、糖浆等。除了为简单且常用的稀释剂的水及液态石蜡,例如为润湿剂、甜味剂、香料、防腐剂等的各种赋形剂可以被包含。肠胃外给药的制剂包括无菌水溶液、非水溶液、悬浮液、乳化剂、冻干制剂及栓剂。栓剂基质的实例包含Witepsol、聚乙烯二醇(macrogol)、Tween 61、可可脂、月桂酸酯、甘油明胶等。
本发明的疫苗组合物可以为口服或肠胃外给药。根据本发明的组合物的给药途径为,例如,肺部内、静脉内、皮下、肌肉内、动脉内、髓内、鞘内、心脏内、经皮(transdermal)、腹膜内、肠、舌下、口服或局部给药。根据本发明的组合物的剂量根据病人的体重、年龄、性别、健康状况、饮食、给药时间、给药方法、排泄率或疾病的严重程度而变化,并且本领域中具有通常知识者可以容易地判定。此外,通过使用临床施用的已知技术,本发明的组合物可以制备为合适的制剂。
在另一方面,本发明涉及融合蛋白在制备用于预防冠状病毒感染的疫苗组合物的用途。
在另一方面,本发明涉及融合蛋白在制备用于预防或治疗冠状病毒感染的疫苗组合物的用途。
在另一方面,本发明涉及用于对抗冠状病毒感染的疫苗接种的方法,所述方法包含施用融合蛋白和/或疫苗组合物予受试者。
在本发明的一实施方案中,使用了SARS-CoV-2衍生受体结合域,但是例如SARS-CoV-1的病毒也可以用于预防或治疗所有的冠状病毒感染,因为它通过类似的机制通过ACE2与具有保守序列(RBM)的棘状蛋白的结合进入细胞,并展现为疾病。
在另一方面,本发明涉及用于预防或治疗冠状病毒感染的药物组合物,包含以融合蛋白作为活性物质。
如本文所用,术语“预防”是指通过施用根据本发明的药物物组合物以致使目标疾病抑制或延迟的任何作用。
如本文所用,术语“治疗”是指通过施用根据本发明的药物物组合物以致使目标疾病中的症状减缓或症状有益改变的任何作用。
根据本发明的药物物组合物可以进一步包含通常用于药物组合物的适当的载体、赋形剂或稀释剂。
具体地,可以包含于药物组合物的载体、赋形剂或稀释剂可以包含乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶(acacia rubber)、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素(microcrystallinecellulose)、聚乙烯吡咯烷酮(polyvinylpyrrolidone)、水、甲基羟基苯甲酸酯(methylhydroxybenzoate)、丙基羟基苯甲酸酯(propylhydroxybenzoate)、滑石粉、硬脂酸镁及矿物油。所述的组合物可以通过使用常用的稀释剂或赋形剂而配制,例如填充剂、增量剂、黏合剂、湿润剂、崩解剂(disintegrant)或表面活性剂。
根据传统方法,根据本发明的药物组合物可以以各种制剂使用。合适的制剂包括口服制剂,例如药片、药丸、药粉、颗粒、糖衣药片、硬或软的胶囊、溶液、悬浮液或乳化剂、注射剂及喷雾剂、外用制备、栓剂及无菌注射溶液,但不限于此。
根据本发明的药物组合物可以使用药学上惰性的有机或无机载体以合适的制剂制备。亦即,当制剂是药片、膜衣片、糖衣药丸或硬胶囊时,它可以包含乳糖、蔗糖、淀粉或其衍生物、滑石、碳酸钙、明胶、硬脂酸或其盐。此外,当制剂为软胶囊时,其可以包含植物油、蜡、脂肪或半固体或半液体的多元醇(polyol)。此外,当制剂为溶液或糖浆时,其可以包含水、多元醇、甘油、植物油等。
除了载体之外,根据本发明的药物组合物可以进一步包含防腐剂、稳定剂、润湿剂、乳化剂、助溶剂、甜味剂、着色剂、渗透压调节剂、抗氧化剂等。
本发明的药物组合物可以以药学上的有效量施用,并且术语“药学上的有效量”是指足以以适用于所有治疗的合理的益处/风险比来治疗疾病的量,且有效量水平可以根据多种因素而变化,所述因素包含患者的疾病的类型和严重性、药物的活性、患者对药物的敏感性、给药时间、给药途径及根据本发明的组合物的排泄率、治疗时间及与的同时使用的药物,以及在制药领域常规的其他因素。本发明的药物组合物可以作为单一治疗剂或与其他治疗剂被合并施用、可以与传统治疗剂依序地或同时地施用,并且可以单剂量或多剂量施用。考虑到这些因素,重要的是施用足以实现最大功效而无副作用的最小量,并且所述量可以由本领域中具有通常知识者容易地判定。
根据本发明的药物组合物可以为口服或肠胃外给药。肠胃外施用可以是静脉注射、皮下注射、肌肉注射、腹膜内注射、内皮给药,局部给药、鼻腔给药、肺部给药、直肠给药等。口服给药时,由于蛋白或肽被消化,因此口服组合物可以用活性药物包覆或配制以保护它们在胃中不降解。另外,可以使用能够将活性物质递送至靶细胞的任何装置来施用组合物。
根据制剂,可以容易地选择根据本发明的药物组合物的给药方法,并且可以口服或肠胃外给药。剂量可以根据患者的年龄、性别、体重、疾病的严重程度及给药途径而变化。
在本发明中,冠状病毒感染最优选为SARS-CoV-2(COVID-19)。
在本发明中,药物组合物可以与其他用于治疗冠状病毒感染的组合物或方法被一起使用。
在另一方面,本发明涉及用于制备用于预防或治疗冠状病毒感染的药物组合物的融合蛋白的用途。
在另一方面,本发明涉及用于预防或治疗冠状病毒感染的方法,所述方法包含施用融合蛋白、疫苗组合物和/或药物组合物至受试者。
在另一方面,本发明涉及融合蛋白、疫苗组合物和/或药物组合物的用途,用于预防或治疗冠状病毒感染。
在另一方面,本发明涉及核酸,其编码融合蛋白。
本文所用的核酸可以存在于细胞中、存在于细胞溶解产物(cell lysate)中或以部分纯化或实质上纯化的形式存在。当已经通过标准技术从其他细胞成分或其他污染物纯化出核酸(例如其他核酸或蛋白)时,核酸可以是“被分离”或“被实质上纯化”,所述标准技术例如包含碱/SDS处理、CsCl显带(banding)、管柱色谱法、琼脂糖凝胶电泳(agarose gelelectrophoresis)和其他本领域熟知的方法。本发明的核酸可以为DNA或RNA。
在另一方面,本发明涉及重组载体(recombinant vector),包含根据本发明的核酸。
任何本领域常规的载体可以被本领域中具有通常知识者适当地选择出并作为重组载体使用而不受限制,只要其能够诱导被融合蛋白编码的蛋白的表达。例如,当使用大肠杆菌(E.coli)作为宿主时,包含T7系列(T7A1、T7A2、T7A3等)、lac、lacUV5、温度相依性(λphoA)、phoB、rmB、tac、trc、trp、trp或1PL启动子的载体可以被使用。当使用酵母作为宿主时,可以使用包含ADH1、AOX1、GAL1、GAL10、PGK或TDH3启动子的载体,而当使用芽孢杆菌(Bacillus)作为宿主时,可以使用包含P2启动子的载体。这些仅作为表示性的实施方案而提供,除了包含启动子的载体以外,本领域中具有通常知识者可以不受限制地从本领域已知的各种载体中适当选择任何载体,只要其适合作为宿主即可,其中所述载体包含用于诱导根据本发明的融合蛋白表达的启动子。
如本文所用,术语“载体”是指一种DNA产物,包含DNA序列有效连接(operativelylinked)至合适的调节序列,其中合适的调节序列能够表达合适宿主中的DNA。载体可以为质体(plasmid)、噬菌体颗粒(phage particle)或单纯系潜在的基因插入(genomicinsert)。当转换成合适的宿主时,载体可以被复制或执行独立于宿主基因组的功能,或部分的载体可以与基因组整合。质体目前为最常被使用的载体形式,并因此术语“质体”及“载体”经常可以交换使用。然而,本发明涵盖了其他形式的载体,且所述载体为本领域常规或具有与本领域常规的载体相同的功能。用于大肠杆菌的蛋白表达载体包含:来自Novagen,Inc(美国)的pET家族载体;来自Invitrogen Corp.(美国)的pBAD家族载体;来自TakaraBio Inc.(日本)的PHCE或pCOLD载体;及来自GenoFocus Inc.(韩国)的家族载体。在枯草杆菌(Bacillus subtilis)中,目标基因可以被插入基因组的特定部分以实现蛋白表达,或MoBiTech(德国)的pHT家族载体可以被使用。甚至在真菌及酵母菌中,也可以使用基因组插入或自我复制载体表达蛋白。使用T-DNA系统的植物蛋白表达载体(如根癌农杆菌(Agrobacterium tumefaciens)或苹果毛根病细菌(Agrobacterium rhizogenes))可以被使用。在哺乳动物细胞培养物中表达的典型表达载体是基于例如pRK5(EP 307,247)、pSV16B 5(WO 91/08291)及pVL1392(Pharmingen)。
如本文所用,术语“表达控制序列”是指对于表达有效连接至特定宿主有机体的编码序列必须的DNA序列。如此的控制序列包含用于进行转录的启动子、用于控制转录的运算符序列、用于编码合适mRNA的核糖体结合位点(ribosome-binding site)及用于控制转录及翻译的终止的序列。例如,适合用于原核生物的控制序列包含启动子、可选的运算符序列和核糖体结合位点。适合用于真核细胞的控制序列包含启动子、多腺核甘酸(polyadenylation)信号及加强子(enhancer)。对于质体中基因的表达水平具有最大影响的因子为启动子。SRα启动子、巨细胞病毒衍生的启动子等优选作为高表达的启动子。
各种表达控制序列中的任一种可以作为载体以表达本发明的DNA序列。有用的表达控制序列包含,例如,SV40或腺病毒的早期和晚期启动子、lac系统、trp系统、TAC或TRC系统、T3及T7启动子、噬菌体λ的主要运算符和启动子区域、fd代码蛋白的控制区域、3-磷酸甘油酸激酶或其他乙二醇裂解酶的启动子、磷酸酶的启动子(例如Pho5)、酵母α-交配系统的启动子以及其他具有已知能控制原核或真核细胞或病毒基因表达的配置和诱导活性的序列及上述的各种组合。T7 RNA的聚合酶启动子φ对于大肠杆菌中表达蛋白可以是有用的。
当核酸序列与另一个核酸序列具有功能关系时,所述核酸序列被“有效连接”。这可以是以此方式连接的基因和控制序列,使得当合适的分子(例如,转录活化蛋白(transcriptional activator protein))与控制序列连接时能够表达基因。例如,当表达为涉及多肽分泌的前蛋白(pre-protein)时,用于前序列(pre-sequence)或分泌前导(secretory leader)的DNA有效连接至用于多肽的DNA;当启动子或增强子影响序列的转录时,有效地与编码序列连接;当核糖体结合位点影响序列的转录时,它有效地连接至编码序列;或当核糖体结合位点被设置以促进翻译时,核糖体结合位点有效地连接至编码序列。通常,术语“有效连接”是指连接的DNA序列与其接触,且分泌前导与其接触并存在于读框(reading frame)中。然而,增强子不需与其接触。这些序列的连接是通过在方便的限制性酶切位点的接合(连接)来进行的。当没有这样的切位点存在时,根据传统方法的合成寡核甘酸(oligonucleotide)衔接子(adapter)或接头被使用。
如本文所用,术语“表达载体”通常是指重组载体,且其中插入有异源(heterologous)的DNA片段,且通常是指双股DNA的片段。于此,“异源DNA”是指在宿主细胞中非天然发现的异生(xenogenous)DNA。一旦宿主细胞中存在表达载体,其可以独立地复制宿主染色体DNA,且载体的数个复制(copy)及插入其的(异源)DNA可以被制备。
如本领域常规的,为了增加重组细胞中转染(transfected)基因的表达程度,基因应所述有效连接至在所选的表达宿主中运作的转录或翻译表达控制序列。优选地,表达控制序列及对应的基因包含在单个表达载体中,其中所述单个表达载体包含细菌筛选标记(selection marker)及复制起点(replication origin)。当表达宿主为真核细胞时,表达载体需进一步包含在真核表达宿主中有用的表达标记。
在另一方面,本发明涉及宿主细胞,其中的核酸编码融合蛋白,或重组载体被引入。
如本文所用,术语“宿主细胞”是指被引入基因或重组载体以制备蛋白等的表达细胞。宿主细胞可以不受限制地被使用,只要其为能够表达本发明的融合蛋白的细胞,且宿主细胞优选为真核细胞,更优选为酵母、昆虫细胞或动物细胞,最优选为动物细胞。举例来说,宿主细胞系主要用于表达融合蛋白的中国仓鼠卵巢细胞株(CHO cell line)或人类胚胎肾脏细胞株(HEK cell line),但不限于此。
各种表达宿主/载体组核可以用于表达本发明的融合蛋白。用于真核宿主的合适的表达载体包含,例如但不限于从SV40、牛乳图突病毒(cow papillomavirus)、腺病毒、腺相关病毒、巨细胞病毒及反转录病毒衍生的表达控制序列。可以用于细菌宿主的表达载体包含从大肠杆菌(E.coli)取得的细菌质体(例如pBluescript、pGEX2T、pUC载体、col E1、pCR1、pBR322、pMB9及其衍生物)、具有能被多种类型的噬菌体λ衍生物(例如λNM989)示例的广泛宿主类型的质体(例如RP4、噬菌体DNA),及其他DNA噬菌体(例如M13及丝状单股DNA噬菌体)。对于酵母细胞有用的表达载体包含2μ质体及其衍生物。对于昆虫细胞有用的载体为pVL 941。
重组载体可以通过转染或转换(transformation)被引入宿主细胞。如本文所用,术语“转染”是指将DNA引入宿主且通过使用染色体外因素(extrachromosomal factor)或染色体整合(chromosomal integration)使DNA能够被复制。如本文所用,术语“转换”是指不论任何编码序列是否确实被表达,表达载体被宿主细胞容纳。
应理解的是,并不是所有的载体在表达本发明的DNA序列时都以相同的方式运作。相似地,对于相同的表达系统,并非所有宿主都以相同的方式运作。然而,本领域中具有通常知识者将能够从各种载体、表达控制序列及宿主中做出适当的选择而无须过度实验且不背离本发明的范围。例如,载体的选择应考虑宿主,因载体在其中复制。载体的复制数量、控制复制数量的能力及被对应载体编码的其他蛋白的表达(例如抗体标记的表达)应被考虑。在选择表达控制序列时,应当考虑多种因素。例如,相对于本发明的DNA序列的序列强度、相对于本发明的DNA序列的控制度及与本发明的DNA序列的兼容度应被考虑,特别是关于可能的二级结构(secondary structure)。可以考虑以下因素来选择单细胞宿主,例如选择的载体、由本发明的DNA序列编码的产物的毒性、分泌特征、准确折叠蛋白的能力、培养及发酵因素,以及纯化由根据本发明的DNA序列编码的产物的容易度。在这些因素的范围内,本领域中具有通常知识者可以选择各种能够在发酵或大型动物培养基中表达本发明的DNA序列的载体/表达控制序列/宿主的组合。作为用于通过表达克隆(clone)克隆蛋白的cDNA的筛选方法,结合方法、重复筛选(panning)方法、胶片乳化(film emulsion)方法等可以被应用。
基因及重组载体可以通过各种常规方法被引入宿主细胞。编码核酸(所述核酸编码本发明的融合蛋白)的基因可以被直接引入宿主细胞的基因组且可以染色体上的因子的方式存在。对本领域中具有通常知识者显而易见的是,本发明涉及即使将基因插入宿主细胞的基因染色体,其也会具有与当重组载体被引入宿主细胞时的相同效果。
在另一方面,本发明涉及用于制备融合蛋白的方法,包含培养宿主细胞。
当能够表达融合蛋白的重组表达载体被引入哺乳动物宿主细胞时,融合蛋白可以通过培养宿主细胞一段足够让融合蛋白在宿主细胞中表达的时间而被制备,且优选地,培养宿主细胞一段足够让融合蛋白被分泌入培养基的时间。
在一些情况中,表达的融合蛋白可以被从宿主细胞分离且纯化至同质(homogeneity)。所述融合蛋白的分离或纯化可以通过使用用于传统蛋白的分离及纯化方法而实行,例如色谱法(chromatography)。色谱法例如可以包含从亲合色谱法(affinitychromatography)、离子交换色谱法及疏水色谱法选择的一个或多个的组合,但不限于此。色谱法与过滤、超滤、盐析、透析等的组合可以被使用。
虽然特定氨基酸序列及核苷酸序列在本发明中被说明,对本领域中具有通常知识者显而易见的是,实质上相同于欲实现于本发明中的酶及编码其的核苷酸序列的氨基酸序列落于本发明的范围内。术语“实质上相同”包含氨基酸或核苷酸序列高度同源的情况,以及具有与序列的同源性无关的结构特征或与本发明中使用的功能相同的蛋白质的情况。本发明可以包含酶,所述酶中构成本发明核心的序列以外的序列的一部分已被删除,或编码本发明核心的的核苷酸序列的片段,且可以包含所有具有用于本发明的氨基酸或核苷酸序列相同功能的氨基酸或核苷酸序列而不论片段的长度。
实施例
在下文中,将参考以下实施方案更详细地描述本发明。然而,提供这些实施方案仅用于示例说明本发明,而不应解释为限制本发明的范围。
实施例1:融合蛋白的制备
如图3所示,控制组及实验组被设置,而融合蛋白(图4至9)被制备以评估包含受体结合域(RBD)、核壳蛋白及Fc域的融合蛋白的ACE2结合能力及免疫原性(immunogenicity)。为了制备融合蛋白,包含编码融合蛋白的碱基序列(base sequence)的核苷酸通过使用Integrated DNA Technologies的gBlockTM基因片段被合成,并加载pcDNA3.4载体,其中融合蛋白包含如表1所示的野生型RBD蛋白、核壳蛋白(N蛋白)RNA结合域、IgG1 Fc域、接头及信号序列。
表1:每个元素的氨基酸序列
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表2:每个元素的DNA序列
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制备出的载体被引入CHO细胞(Expi-CHOTM)以表达各融合蛋白。在引入载体后,以5% CO2环境在37℃下及125RPM对细胞进行培养7天,培养液被收集,且融合蛋白被纯化。
各融合蛋白通过使用Mabselect Xtra树脂执行管柱色谱法而被纯化。由ThermoFisher Scientific Inc.制备的蛋白A缓冲液被使用以执行平衡。接着,将通过0.22μm过滤器过滤的上清液装载到柱上,并使用蛋白质A结合缓冲剂以对应于树脂体积的10倍的体积冲洗柱。接着,由Thermo Fisher Scientific Inc.制备的IgG洗脱缓冲剂被使用以执行洗脱(elution)。融合蛋白被收集至收集管内,所述收集管包含pH 9的20%1M Tris-HCl。接着,用于所收集到的融合蛋白的缓冲剂通过透析被以PBS取代。
接着,TSKgel G3000SWXL管柱(TOSOH Bioscience)被使用以执行尺寸排阻色谱法(size exclusion chromatography),且吸亮度在波长214nm被测量以取得高浓度的融合蛋白。此时,在以考马斯蓝(Coomassie Blue)染色后,分离且纯化的融合蛋白的组成(formation)通过在还原(R)或非还原(NR)的情况下执行SDS-PAGE而被辨识出。
制备出的融合蛋白的氨基酸序列及编码其的氨基酸序列示出于下表3及4中。
表3
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表4
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实施例2:以本发明的融合蛋白对小鼠接种疫苗后的免疫反应评估
实施例4-1:小鼠的准备及疫苗接种
用于动物实验以评估在实施例1中制备的融合蛋白的免疫原性的小鼠及融合蛋白示出于下表5。
表5
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考虑到各融合蛋白的分子量(IgG1 Fc:54kDa,GIC-1114(N-Fc-RBDwt:140kDa,Fc-RBDwt:105.5kDa,N-Fc:87.7kDa),剂量被控制为具有相同摩尔数。融合蛋白通过股骨肌(femoral muscle)内注射给药,且在初次接种的两周后,以融合蛋白额外(第二次)接种。在给药四周后,血液通过每个受试对象的腹静脉被收集,且血清被分离并储存于低温冰箱中。此外,每个受试对象的脾脏在第四周被收集并与RPMI1640培养液+10% FBS混合,而混合物被装入15mL锥形管中以制备冰冷状态的血清。
实施例4-2:中和抗体的测量
在实施例4-1血清中搜集的小鼠中和抗体形成的力价通过ELISA分析。具体地,SARS-CoV-2(COVID-19)蛋白RBD(ACRO biosystem,SPD-C53H3)或人类重组IgG1蛋白(Sinobiologics,10702-HNAH)在1X PBS(10X PBS(Welgene,ML 008-02)以1:10稀释)中被稀释,且被以100μl(500ng/孔)装载入96孔盘(BioLegend,423501),被以黏着胶覆盖并在4℃下将其培养过夜。
1X ELISA测定稀释剂(5X ELISA测定稀释剂(BioLegend,421203)1X PBS稀释剂)被以100μl的量加入所述盘的每个孔并将其保存在室温下2小时并同时以100rpm摇晃。上清液被从每个孔移除,而每个孔被以200μL的冲洗缓冲剂(0.05%的Tween20(Sigma,P7949)在1X PBS中)冲洗两次。在初始的稀释(1:128)被执行后,254μL的1X ELISA测定稀释剂被加入从每只小鼠收集到的2μL的血清。接着,连续稀释至1:2、1:4、1:8、1:16、1:32、1:64及1:128更被执行,且100μl的被稀释样本被加入每个孔,接着将其保存在室温下2小时并同时以100rpm的速度摇晃。稀释后的样品被移除并以200μL的冲洗缓冲剂冲洗三次。100μL的羊抗鼠IgG(H+L)Ab(Invitrogen,31430)稀释剂(1X ELISA测定稀释剂,1:10000)被加入每个孔,并在暗室以室温培养90分钟并同时以100rpm摇晃。在上清液被移除后,剩余的样品被以200μL的冲洗缓冲剂冲洗五次。100μL的TMB溶液(BioLegend,421101)被加入每个孔,并让其在室温下反应1分钟,100μL的停止溶液(stop solution)(BioLegend,77316)被加入每个孔以停止反应。每个样本的OD值被以450nm使用ELISA读取器(Molecular device,SpectraMaxiD3)测量,且中和抗体形成的力价被测量。
从图11可以看到,当以不含佐剂的融合蛋白进行疫苗接种时,高抗体RBD特定IgG力价仅在包含野生型RBD、核酸蛋白壳(nucleocapsid)及Fc蛋白的融合蛋白(GIC-1114)被施用时被取得。当仅使用IgG1 Fc或Fc-RBDwt融合蛋白而不含佐剂进行疫苗接种时,未形成显著水平的中和抗体。
此外,当佐剂被一并施用以促进免疫反应时,每个中和抗体形成的力价被增进。当佐剂被一并施用时,对于RBD的中和抗体被从Fc-RBDwt融合蛋白形成,而当以GIC-1114融合蛋白处理时,中和抗体形成的力价为显著地高。
上述的结果表示根据本发明的包含RBD、N蛋白及Fc域的融合蛋白(GIC-1114)可以展现显著高于仅包含RBD及Fc域的融合蛋白的免疫原性。
实施例4-3:T细胞免疫反应评估
细胞过滤器(cell strainer)被放置于50mL的锥形管,且5mL的1X PBS(Welgene,ML 008-02)被倒入其中以充分地润湿细胞过滤器。从小鼠取得的脾脏被至于细胞过滤器中并通过使用5mL活塞式注射器的橡胶包装件将其压碎直到肉眼看不到各别的脾脏块,接着20mL的1X PBS被缓慢倒入细胞过滤器以获取细胞过滤器中剩余的所有细胞。50mL锥形管中获取的细胞被以1500rpm在4℃下离心5分钟,上清液被移除,锥形管被轻柔拍打以释放结块的细胞,且细胞在室温下与1mL的ACK裂解缓冲剂反应5分钟。反应产物在4mL的1X PBS以1500rpm在4℃下离心5分钟。上清液被移除且细胞被散入(suspend)6mL的R10培养液(RPMI1640(Welgene,目录号LM011-01)与10% FBS(Hyclone,目录号SY30208.02)、1%抗生素(Corning,目录号30-004-CI)及10IU的IL-2(Novartis,Proleukin)),接着细胞的数量被以ADAM细胞计数器(目录号ADAM-MC2)计算。细胞在96孔盘上被以1x106个细胞/孔的密度散入R10培养液,且100nM/mL的T细胞刺激抗原(Fc、N-Fc)被加入每个孔以将每个孔的体积调整至200uL。细胞在培养箱中以37℃及5% CO2的环境下培养72小时,接着被以1500rpm在4℃下离心5分钟,上清液被取得并储存于-80℃或更低温的环境下。
来自小鼠Th1/Th2/Th17细胞激素试剂盒(BD,目录号560485)的小鼠Th1/Th2/Th17细胞激素捕获珠(capture bead)被涡旋3至5秒。所需的样本量被计算,七种小鼠Th1/Th2/Th17细胞激素捕获珠被混和,且其20μL被等分至96孔盘的每个测定孔中。混和的捕获珠被涡旋并以20μL装载到96孔盘的每个测定孔中。标准稀释剂(小鼠Th1/Th2/Th17细胞激素试剂盒(BD,目录号560485),1:2、1:4、1:8、1:16、1:32、1:64、1:128、1:256)及负控制溶液各被以20μL装载到96孔盘中,且从储存于-80℃或更低温的环境下取得的小鼠脾脏细胞上清液的样品被以20μL装载到各个孔中。20μL的Th1/Th2/Th17的PE检测试剂被加入并让其在暗室中在室温下反应2小时。两小时后,200μL的冲洗缓冲剂被加入每个孔,且离心被以1500rpm在4℃下执行5分钟,上清液被移除,珠粒(bead pellet)被散入100μL的冲洗缓冲,而细胞激素分泌能力通过使用流式细胞测量术(flow cytometry)(FACS)被测量。
可以从图12看到,被以GIC-1114进行疫苗接种的小鼠脾脏的T细胞在以N蛋白(N-Fc)刺激时展现高的IFN-γ水平,其中N蛋白是自SARS-CoV-2衍生。尤其,当使用佐剂时,相较于当以具有免疫促进反应的其他融合蛋白(Fc-RBD或N-Fc)处理时,被以GIC-1114进行疫苗接种的小鼠脾脏的T细胞展现显著增进的IFN-γ水平。这表示根据本发明的包含RBD、Fc及N蛋白的融合蛋白可以活化冠状病毒特定胞毒T细胞。
尽管已经详细描述了本发明的具体配置,但是本领域中具有通常知识者将理解的是,提供所述描述是为了说明性目的而提出优选实施方案,并不应解释为限制本发明的范围。因此,本发明的实质范围由所附权利要求书及其均等范围限定。
产业可利用性
与仅包含受体结合域的免疫原组合物相比,本发明的包含冠状病毒衍生的受体结合域的融合蛋白及核壳蛋白高度适用于具有明显改善的体内半衰期并且具有显著优越的功效的多价疫苗组合物。特别地,本发明的融合蛋白可以显著地改善冠状病毒特定抗体形成的力价及T细胞免疫反应,因此可用于预防及治疗包含SARS-CoV-2的冠状病毒。
文本文件
参见所附序列表。
<110> 吉爱希公司
<120> 包含冠状病毒衍生的受体结合域及核壳蛋白的融合蛋白及其用途
<130> PP-B2551
<150> KR 2020-0113989
<151> 2020-09-07
<160> 26
<170> KoPatentIn 3.0
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Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp
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Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln
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Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr
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Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly
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Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys
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Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr
145 150 155 160
Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val
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Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly
195 200 205
Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys
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Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
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Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
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Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
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Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
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Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr
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Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg
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Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn
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Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu
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Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro
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Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr
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Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp
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Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp
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His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln
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Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser
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Ser Ser Arg Asn Ser Thr Pro Gly Ser Ser Arg Gly Thr Ser Pro Ala
195 200 205
Arg Met Ala Gly Asn Gly Gly Asp Ala Ala Leu Ala Leu Leu Leu Leu
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Asp Arg Leu Asn Gln Leu Glu Ser Lys Met Ser Gly Lys Gly Gln Gln
225 230 235 240
Gln Gln Gly Gln Thr Val Thr Lys Lys Ser Ala Ala Glu Ala Ser Lys
245 250 255
Lys Pro Arg Gln Lys Arg Thr Ala Thr Lys Ala Tyr Asn Val Thr Gln
260 265 270
Ala Phe Gly Arg Arg Gly Pro Glu Gln Thr Gln Gly Asn Phe Gly Asp
275 280 285
Gln Glu Leu Ile Arg Gln Gly Thr Asp Tyr Lys His Trp Pro Gln Ile
290 295 300
Ala Gln Phe Ala Pro Ser Ala Ser Ala Phe Phe Gly Met Ser Arg Ile
305 310 315 320
Gly Met Glu Val Thr Pro Ser Gly Thr Trp Leu Thr Tyr Thr Gly Ala
325 330 335
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340 345 350
Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro
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Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln
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Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu Lys Phe Pro
20 25 30
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Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp His Ile Gly
100 105 110
Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln Leu Pro Gln
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
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agagttcagc ctaccgagtc catcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
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gccgactaca attacaagct gcccgacgac ttcaccggct gcgtgatcgc ttggaactcc 360
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tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgtcgaggg cttcaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
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gaacctaagt cctccgacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 60
ggcggacctt ccgtgtttct gttcccacct aagccaaagg acaccctgat gatcagcaga 120
acccctgaag tgacctgcgt ggtggtggat gtgtctcacg aggaccccga agtgaagttc 180
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 240
tacaactcca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 300
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgaaaagacc 360
atctccaagg ccaagggcca gcctagggaa ccccaggttt acacactgcc tccatctcgg 420
gacgagctga ccaagaatca ggtgtccctg acctgtctgg tcaagggctt ctacccttcc 480
gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 540
cctgtgctgg actccgacgg ctcattcttc ctgtatagca agctgacagt ggacaagtcc 600
cggtggcagc agggcaacgt gttctcctgt tctgtgatgc acgaggccct gcacaaccac 660
tacacccaga agagtctgtc cttgagcccg ggc 693
<210> 10
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<212> DNA
<213> Artificial Sequence
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<223> N protein_Full DNA sequence
<400> 10
atgtctgata atggacccca aaatcagcga aatgcacccc gcattacgtt tggtggaccc 60
tcagattcaa ctggcagtaa ccagaatgga gaacgcagtg gggcgcgatc aaaacaacgt 120
cggccccaag gtttacccaa taatactgcg tcttggttca ccgctctcac tcaacatggc 180
aaggaagacc ttaaattccc tcgaggacaa ggcgttccaa ttaacaccaa tagcagtcca 240
gatgaccaaa ttggctacta ccgaagagct accagacgaa ttcgtggtgg tgacggtaaa 300
atgaaagatc tcagtccaag atggtatttc tactacctag gaactgggcc agaagctgga 360
cttccctatg gtgctaacaa agacggcatc atatgggttg caactgaggg agccttgaat 420
acaccaaaag atcacattgg cacccgcaat cctgctaaca atgctgcaat cgtgctacaa 480
cttcctcaag gaacaacatt gccaaaaggc ttctacgcag aagggagcag aggcggcagt 540
caagcctctt ctcgttcctc atcacgtagt cgcaacagtt caagaaattc aactccaggc 600
agcagtaggg gaacttctcc tgctagaatg gctggcaatg gcggtgatgc tgctcttgct 660
ttgctgctgc ttgacagatt gaaccagctt gagagcaaaa tgtctggtaa aggccaacaa 720
caacaaggcc aaactgtcac taagaaatct gctgctgagg cttctaagaa gcctcggcaa 780
aaacgtactg ccactaaagc atacaatgta acacaagctt tcggcagacg tggtccagaa 840
caaacccaag gaaattttgg ggaccaggaa ctaatcagac aaggaactga ttacaaacat 900
tggccgcaaa ttgcacaatt tgcccccagc gcttcagcgt tcttcggaat gtcgcgcatt 960
ggcatggaag tcacaccttc gggaacgtgg ttgacctaca caggtgccat caaattggat 1020
gacaaagatc caaatttcaa agatcaagtc attttgctga ataagcatat tgacgcatac 1080
aaaacattcc caccaacaga gcctaaaaag gacaaaaaga agaaggctga tgaaactcaa 1140
gccttaccgc agagacagaa gaaacagcaa actgtgactc ttcttcctgc tgcagatttg 1200
gatgatttct ccaaacaatt gcaacaatcc atgagcagtg ctgactcaac tcaggcctaa 1260
1260
<210> 11
<211> 468
<212> DNA
<213> Artificial Sequence
<220>
<223> N protein_RNA binding domain_DNA sequence
<400> 11
cggtctaagc agagaaggcc tcagggcctg cctaacaata ccgcctcctg gtttaccgct 60
ctgacccagc acggcaaaga ggacctgaag ttccctagag gacagggcgt gcccatcaac 120
accaactcta gccctgacga ccagatcggc tactacagac gggccaccag aagaatcaga 180
ggcggcgacg gcaagatgaa ggacctgtct cctcggtggt acttctacta cctcggcacc 240
ggaccagagg ctggattgcc ttatggcgcc aacaaggacg gcatcatctg ggttgcaaca 300
gagggcgctc tgaacacccc taaggaccac atcggcaccc ggaatcctgc caacaatgct 360
gccattgtgc tgcagctgcc acagggcaca acactgccta agggctttta cgccgagggc 420
tctagaggcg gctctcaggc ctcttccaga tcctccagta gatcacgt 468
<210> 12
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker1_DNA sequence
<400> 12
ggcggcggag gatccggcgg tggtggttcc ggcggaggcg gttct 45
<210> 13
<211> 60
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker2_DNA sequence
<400> 13
ggtggcggcg gttcaggcgg cggtggaagt ggcggtggcg gatctggcgg aggtggtagt 60
60
<210> 14
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal peptide_DNA sequence
<400> 14
atgaaatggg tcacctttat ctccctgctg ttcctgttct cctccgccta ctct 54
<210> 15
<211> 246
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_IgG1 Fc
<400> 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
20 25 30
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
35 40 45
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
50 55 60
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
65 70 75 80
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
85 90 95
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
100 105 110
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
115 120 125
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
130 135 140
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
145 150 155 160
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
165 170 175
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
180 185 190
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
195 200 205
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
210 215 220
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
225 230 235 240
Leu Ser Leu Ser Pro Gly
245
<210> 16
<211> 465
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_RBDwt-Fc
<400> 16
Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn
1 5 10 15
Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val
20 25 30
Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser
35 40 45
Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val
50 55 60
Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp
65 70 75 80
Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln
85 90 95
Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr
100 105 110
Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly
115 120 125
Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys
130 135 140
Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr
145 150 155 160
Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val
180 185 190
Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly
195 200 205
Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Gly Gly Gly Gly Ser
210 215 220
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly
465
<210> 17
<211> 485
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_Fc-RBDwt
<400> 17
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
1 5 10 15
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
20 25 30
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
35 40 45
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
50 55 60
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
65 70 75 80
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
85 90 95
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
100 105 110
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
115 120 125
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
130 135 140
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
145 150 155 160
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
165 170 175
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
180 185 190
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
195 200 205
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
210 215 220
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
225 230 235 240
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Gln Pro Thr Glu
260 265 270
Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
275 280 285
Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
290 295 300
Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
305 310 315 320
Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
325 330 335
Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
340 345 350
Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
355 360 365
Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
370 375 380
Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
385 390 395 400
Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
405 410 415
Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
420 425 430
Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
435 440 445
Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
450 455 460
Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn
465 470 475 480
Leu Val Lys Asn Lys
485
<210> 18
<211> 402
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_N-Fc
<400> 18
Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn Thr Ala Ser
1 5 10 15
Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu Lys Phe Pro
20 25 30
Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro Asp Asp Gln
35 40 45
Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly Gly Asp Gly
50 55 60
Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr Leu Gly Thr
65 70 75 80
Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp Gly Ile Ile
85 90 95
Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp His Ile Gly
100 105 110
Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln Leu Pro Gln
115 120 125
Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser Arg Gly Gly
130 135 140
Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
165 170 175
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
180 185 190
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
195 200 205
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
210 215 220
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
225 230 235 240
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
245 250 255
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
260 265 270
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
275 280 285
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
290 295 300
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
305 310 315 320
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
325 330 335
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
340 345 350
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
355 360 365
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
370 375 380
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
385 390 395 400
Pro Gly
<210> 19
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114
<400> 19
Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn Thr Ala Ser
1 5 10 15
Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu Lys Phe Pro
20 25 30
Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro Asp Asp Gln
35 40 45
Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly Gly Asp Gly
50 55 60
Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr Leu Gly Thr
65 70 75 80
Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp Gly Ile Ile
85 90 95
Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp His Ile Gly
100 105 110
Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln Leu Pro Gln
115 120 125
Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser Arg Gly Gly
130 135 140
Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Gly Gly Gly Gly
145 150 155 160
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser
165 170 175
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
180 185 190
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
195 200 205
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
210 215 220
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
225 230 235 240
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
245 250 255
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
260 265 270
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
275 280 285
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
290 295 300
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
305 310 315 320
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
325 330 335
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
340 345 350
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
355 360 365
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
370 375 380
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
385 390 395 400
Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
405 410 415
Ser Gly Gly Gly Gly Ser Arg Val Gln Pro Thr Glu Ser Ile Val Arg
420 425 430
Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala
435 440 445
Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn
450 455 460
Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr
465 470 475 480
Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe
485 490 495
Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg
500 505 510
Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys
515 520 525
Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn
530 535 540
Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe
545 550 555 560
Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile
565 570 575
Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys
580 585 590
Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly
595 600 605
Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala
610 615 620
Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn
625 630 635 640
Lys
<210> 20
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114N
<400> 20
Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn
1 5 10 15
Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val
20 25 30
Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser
35 40 45
Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val
50 55 60
Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp
65 70 75 80
Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln
85 90 95
Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr
100 105 110
Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly
115 120 125
Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys
130 135 140
Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr
145 150 155 160
Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val
180 185 190
Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly
195 200 205
Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Gly Gly Gly Gly Ser
210 215 220
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp
225 230 235 240
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Gly Gly Gly Gly Ser Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro
485 490 495
Asn Asn Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu
500 505 510
Asp Leu Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser
515 520 525
Ser Pro Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile
530 535 540
Arg Gly Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe
545 550 555 560
Tyr Tyr Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn
565 570 575
Lys Asp Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro
580 585 590
Lys Asp His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val
595 600 605
Leu Gln Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu
610 615 620
Gly Ser Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser
625 630 635 640
Arg
<210> 21
<211> 738
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_IgG1 Fc
<400> 21
ggcggcggag gatccggcgg tggtggttcc ggcggaggcg gttctgaacc taagtcctcc 60
gacaagaccc acacctgtcc tccatgtcct gctccagaac tgctcggcgg accttccgtg 120
tttctgttcc cacctaagcc aaaggacacc ctgatgatca gcagaacccc tgaagtgacc 180
tgcgtggtgg tggatgtgtc tcacgaggac cccgaagtga agttcaattg gtacgtggac 240
ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagtacaa ctccacctac 300
agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agagtacaag 360
tgcaaggtgt ccaacaaggc cctgcctgct cctatcgaaa agaccatctc caaggccaag 420
ggccagccta gggaacccca ggtttacaca ctgcctccat ctcgggacga gctgaccaag 480
aatcaggtgt ccctgacctg tctggtcaag ggcttctacc cttccgatat cgccgtggaa 540
tgggagagca atggccagcc tgagaacaac tacaagacaa cccctcctgt gctggactcc 600
gacggctcat tcttcctgta tagcaagctg acagtggaca agtcccggtg gcagcagggc 660
aacgtgttct cctgttctgt gatgcacgag gccctgcaca accactacac ccagaagagt 720
ctgtccttga gcccgggc 738
<210> 22
<211> 1395
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_RBDwt-Fc
<400> 22
agagttcagc ctaccgagtc catcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgctac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactctg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcaggggcga cgaagttcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca attacaagct gcccgacgac ttcaccggct gcgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaactacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgtcgaggg cttcaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctaccgtgtg cggccctaag aaatctacca acctggtcaa gaacaagggc 660
ggcggaggat ccggcggtgg tggttccggc ggaggcggtt ctgaacctaa gtcctccgac 720
aagacccaca cctgtcctcc atgtcctgct ccagaactgc tcggcggacc ttccgtgttt 780
ctgttcccac ctaagccaaa ggacaccctg atgatcagca gaacccctga agtgacctgc 840
gtggtggtgg atgtgtctca cgaggacccc gaagtgaagt tcaattggta cgtggacggc 900
gtggaagtgc acaacgccaa gaccaagcct agagaggaac agtacaactc cacctacaga 960
gtggtgtccg tgctgaccgt gctgcaccag gattggctga acggcaaaga gtacaagtgc 1020
aaggtgtcca acaaggccct gcctgctcct atcgaaaaga ccatctccaa ggccaagggc 1080
cagcctaggg aaccccaggt ttacacactg cctccatctc gggacgagct gaccaagaat 1140
caggtgtccc tgacctgtct ggtcaagggc ttctaccctt ccgatatcgc cgtggaatgg 1200
gagagcaatg gccagcctga gaacaactac aagacaaccc ctcctgtgct ggactccgac 1260
ggctcattct tcctgtatag caagctgaca gtggacaagt cccggtggca gcagggcaac 1320
gtgttctcct gttctgtgat gcacgaggcc ctgcacaacc actacaccca gaagagtctg 1380
tccttgagcc cgggc 1395
<210> 23
<211> 1455
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_Fc-RBDwt
<400> 23
ggcggcggag gatccggcgg tggtggttcc ggcggaggcg gttctgaacc taagtcctcc 60
gacaagaccc acacctgtcc tccatgtcct gctccagaac tgctcggcgg accttccgtg 120
tttctgttcc cacctaagcc aaaggacacc ctgatgatca gcagaacccc tgaagtgacc 180
tgcgtggtgg tggatgtgtc tcacgaggac cccgaagtga agttcaattg gtacgtggac 240
ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagtacaa ctccacctac 300
agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agagtacaag 360
tgcaaggtgt ccaacaaggc cctgcctgct cctatcgaaa agaccatctc caaggccaag 420
ggccagccta gggaacccca ggtttacaca ctgcctccat ctcgggacga gctgaccaag 480
aatcaggtgt ccctgacctg tctggtcaag ggcttctacc cttccgatat cgccgtggaa 540
tgggagagca atggccagcc tgagaacaac tacaagacaa cccctcctgt gctggactcc 600
gacggctcat tcttcctgta tagcaagctg acagtggaca agtcccggtg gcagcagggc 660
aacgtgttct cctgttctgt gatgcacgag gccctgcaca accactacac ccagaagagt 720
ctgtccttga gcccgggcgg tggcggcggt tcaggcggcg gtggaagtgg cggtggcgga 780
tctggcggag gtggtagtag agttcagcct accgagtcca tcgtgcggtt ccccaacatc 840
accaacctgt gtcctttcgg cgaggtgttc aacgctacca gattcgcctc tgtgtacgcc 900
tggaaccgga agcggatctc taactgcgtg gccgactact ccgtgctgta caactctgcc 960
tccttcagca ccttcaagtg ctacggcgtg tcccctacca agctgaacga cctgtgcttc 1020
accaacgtgt acgccgactc cttcgtgatc aggggcgacg aagttcggca gatcgctcct 1080
ggacagaccg gcaagatcgc cgactacaat tacaagctgc ccgacgactt caccggctgc 1140
gtgatcgctt ggaactccaa caacctggac tccaaagtcg gcggcaacta caactacctg 1200
taccggctgt tccggaagtc caacctgaag cctttcgagc gggacatctc caccgagatc 1260
taccaggctg gcagcacccc ttgcaatggc gtcgagggct tcaactgcta cttcccactg 1320
cagtcctacg gcttccagcc taccaatggc gtgggctacc agccttatag agtggtggtg 1380
ctgtccttcg agctgctgca tgctcctgct accgtgtgcg gccctaagaa atctaccaac 1440
ctggtcaaga acaag 1455
<210> 24
<211> 1206
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_N-Fc
<400> 24
cggtctaagc agagaaggcc tcagggcctg cctaacaata ccgcctcctg gtttaccgct 60
ctgacccagc acggcaaaga ggacctgaag ttccctagag gacagggcgt gcccatcaac 120
accaactcta gccctgacga ccagatcggc tactacagac gggccaccag aagaatcaga 180
ggcggcgacg gcaagatgaa ggacctgtct cctcggtggt acttctacta cctcggcacc 240
ggaccagagg ctggattgcc ttatggcgcc aacaaggacg gcatcatctg ggttgcaaca 300
gagggcgctc tgaacacccc taaggaccac atcggcaccc ggaatcctgc caacaatgct 360
gccattgtgc tgcagctgcc acagggcaca acactgccta agggctttta cgccgagggc 420
tctagaggcg gctctcaggc ctcttccaga tcctccagta gatcacgtgg cggcggagga 480
tccggtggtg gtggatctgg tggcggaggc tctgaaccta agtcctccga caagacccac 540
acctgtcctc catgtcctgc tccagaactg ctcggcggac cttccgtgtt tctgttccca 600
cctaagccaa aggacaccct gatgatcagc agaacccctg aagtgacctg cgtggtggtg 660
gatgtgtctc acgaggaccc cgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 720
cacaacgcca agaccaagcc tagagaggaa cagtacaact ccacctacag agtggtgtcc 780
gtgctgaccg tgctgcacca ggattggctg aacggcaaag agtacaagtg caaggtgtcc 840
aacaaggccc tgcctgctcc tatcgaaaag accatctcca aggccaaggg ccagcctagg 900
gaaccccagg tttacacact gcctccatct cgggacgagc tgaccaagaa tcaggtgtcc 960
ctgacctgtc tggtcaaggg cttctaccct tccgatatcg ccgtggaatg ggagagcaat 1020
ggccagcctg agaacaacta caagacaacc cctcctgtgc tggactccga cggctcattc 1080
ttcctgtata gcaagctgac agtggacaag tcccggtggc agcagggcaa cgtgttctcc 1140
tgttctgtga tgcacgaggc cctgcacaac cactacaccc agaagagtct gtccttgagc 1200
ccgggc 1206
<210> 25
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114
<400> 25
cggtctaagc agagaaggcc tcagggcctg cctaacaata ccgcctcctg gtttaccgct 60
ctgacccagc acggcaaaga ggacctgaag ttccctagag gacagggcgt gcccatcaac 120
accaactcta gccctgacga ccagatcggc tactacagac gggccaccag aagaatcaga 180
ggcggcgacg gcaagatgaa ggacctgtct cctcggtggt acttctacta cctcggcacc 240
ggaccagagg ctggattgcc ttatggcgcc aacaaggacg gcatcatctg ggttgcaaca 300
gagggcgctc tgaacacccc taaggaccac atcggcaccc ggaatcctgc caacaatgct 360
gccattgtgc tgcagctgcc acagggcaca acactgccta agggctttta cgccgagggc 420
tctagaggcg gctctcaggc ctcttccaga tcctccagta gatcacgtgg cggcggagga 480
tccggcggtg gtggttccgg cggaggcggt tctgaaccta agtcctccga caagacccac 540
acctgtcctc catgtcctgc tccagaactg ctcggcggac cttccgtgtt tctgttccca 600
cctaagccaa aggacaccct gatgatcagc agaacccctg aagtgacctg cgtggtggtg 660
gatgtgtctc acgaggaccc cgaagtgaag ttcaattggt acgtggacgg cgtggaagtg 720
cacaacgcca agaccaagcc tagagaggaa cagtacaact ccacctacag agtggtgtcc 780
gtgctgaccg tgctgcacca ggattggctg aacggcaaag agtacaagtg caaggtgtcc 840
aacaaggccc tgcctgctcc tatcgaaaag accatctcca aggccaaggg ccagcctagg 900
gaaccccagg tttacacact gcctccatct cgggacgagc tgaccaagaa tcaggtgtcc 960
ctgacctgtc tggtcaaggg cttctaccct tccgatatcg ccgtggaatg ggagagcaat 1020
ggccagcctg agaacaacta caagacaacc cctcctgtgc tggactccga cggctcattc 1080
ttcctgtata gcaagctgac agtggacaag tcccggtggc agcagggcaa cgtgttctcc 1140
tgttctgtga tgcacgaggc cctgcacaac cactacaccc agaagagtct gtccttgagc 1200
ccgggcggtg gcggtggaag cggaggtggc ggatctggtg gcggaggtag tggcggaggc 1260
ggatctagag ttcagcctac cgagtccatc gtgcggttcc ccaacatcac caacctgtgt 1320
cctttcggcg aggtgttcaa cgctaccaga ttcgcctctg tgtacgcctg gaaccggaag 1380
cggatctcta actgcgtggc cgactactcc gtgctgtaca actctgcctc cttcagcacc 1440
ttcaagtgct acggcgtgtc ccctaccaag ctgaacgacc tgtgcttcac caacgtgtac 1500
gccgactcct tcgtgatcag gggcgacgaa gttcggcaga tcgctcctgg acagaccggc 1560
aagatcgccg actacaatta caagctgccc gacgacttca ccggctgcgt gatcgcttgg 1620
aactccaaca acctggactc caaagtcggc ggcaactaca actacctgta ccggctgttc 1680
cggaagtcca acctgaagcc tttcgagcgg gacatctcca ccgagatcta ccaggctggc 1740
agcacccctt gcaatggcgt cgagggcttc aactgctact tcccactgca gtcctacggc 1800
ttccagccta ccaatggcgt gggctaccag ccttatagag tggtggtgct gtccttcgag 1860
ctgctgcatg ctcctgctac cgtgtgcggc cctaagaaat ctaccaacct ggtcaagaac 1920
aag 1923
<210> 26
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114N
<400> 26
agagttcagc ctaccgagtc catcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgctac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactctg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcaggggcga cgaagttcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca attacaagct gcccgacgac ttcaccggct gcgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaactacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgtcgaggg cttcaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctaccgtgtg cggccctaag aaatctacca acctggtcaa gaacaagggc 660
ggcggaggat ccggcggtgg tggttccggc ggaggcggtt ctgaacctaa gtcctccgac 720
aagacccaca cctgtcctcc atgtcctgct ccagaactgc tcggcggacc ttccgtgttt 780
ctgttcccac ctaagccaaa ggacaccctg atgatcagca gaacccctga agtgacctgc 840
gtggtggtgg atgtgtctca cgaggacccc gaagtgaagt tcaattggta cgtggacggc 900
gtggaagtgc acaacgccaa gaccaagcct agagaggaac agtacaactc cacctacaga 960
gtggtgtccg tgctgaccgt gctgcaccag gattggctga acggcaaaga gtacaagtgc 1020
aaggtgtcca acaaggccct gcctgctcct atcgaaaaga ccatctccaa ggccaagggc 1080
cagcctaggg aaccccaggt ttacacactg cctccatctc gggacgagct gaccaagaat 1140
caggtgtccc tgacctgtct ggtcaagggc ttctaccctt ccgatatcgc cgtggaatgg 1200
gagagcaatg gccagcctga gaacaactac aagacaaccc ctcctgtgct ggactccgac 1260
ggctcattct tcctgtatag caagctgaca gtggacaagt cccggtggca gcagggcaac 1320
gtgttctcct gttctgtgat gcacgaggcc ctgcacaacc actacaccca gaagagtctg 1380
tccttgagcc cgggcggtgg cggtggaagc ggaggtggcg gatctggtgg cggaggtagt 1440
ggcggaggcg gatctcggtc taagcagaga aggcctcagg gcctgcctaa caataccgcc 1500
tcctggttta ccgctctgac ccagcacggc aaagaggacc tgaagttccc tagaggacag 1560
ggcgtgccca tcaacaccaa ctctagccct gacgaccaga tcggctacta cagacgggcc 1620
accagaagaa tcagaggcgg cgacggcaag atgaaggacc tgtctcctcg gtggtacttc 1680
tactacctcg gcaccggacc agaggctgga ttgccttatg gcgccaacaa ggacggcatc 1740
atctgggttg caacagaggg cgctctgaac acccctaagg accacatcgg cacccggaat 1800
cctgccaaca atgctgccat tgtgctgcag ctgccacagg gcacaacact gcctaagggc 1860
ttttacgccg agggctctag aggcggctct caggcctctt ccagatcctc cagtagatca 1920
cgt 1923
Claims (22)
1.一种融合蛋白,包含:
冠状病毒衍生的受体结合域;
核壳蛋白;以及
Fc域。
2.如权利要求1所述的融合蛋白,其中所述受体结合域包含由SEQ ID NO:1表示的序列。
3.如权利要求1所述的融合蛋白,其中所述核壳蛋白包含由SEQ ID NO:4表示的序列。
4.如权利要求1所述的融合蛋白,其中所述Fc域为免疫球蛋白G的Fc域。
5.如权利要求1所述的融合蛋白,其中所述Fc域包含由SEQ ID NO:2表示的序列。
6.如权利要求1所述的融合蛋白,其中所述受体结合域连接至所述Fc域的N末端及C末端中的至少一者。
7.如权利要求6所述的融合蛋白,其中所述受体结合域连接至所述Fc域的N末端及C末端中的一者,而所述核壳蛋白连接至N末端及C末端中的剩余者。
8.如权利要求1所述的融合蛋白,其中所述融合蛋白为与核壳蛋白及所述受体结合域连接的Fc域的二聚体。
9.如权利要求1所述的融合蛋白,其中所述冠状病毒为严重急性呼吸系统综合征冠状病毒2型。
10.一种疫苗组合物,包含如权利要求1至9中任一项所述的融合蛋白。
11.如权利要求10所述的疫苗组合物,进一步包含佐剂。
12.如权利要求11所述的疫苗组合物,其中所述佐剂包含选自铝盐、含鲨烯的乳化剂、钙盐、dsRNA类似物、脂多糖、脂质A类似物、鞭毛蛋白、咪唑并喹啉、CpG寡脱氧核苷酸、矿物油、类Toll受体拮抗剂、C型凝集素配体、CD1d配体、清洁剂、脂质体、石碱、细胞激素和肽中的至少一种。
13.一种药物组合物,用于预防或治疗冠状病毒感染,其中所述药物组合物包含作为活性成分的如权利要求1至9中任一项所述的融合蛋白。
14.如权利要求13所述的药物组合物的用途,其中所述冠状病毒感染为COVID-19。
15.一种核酸,编码如权利要求1至9中任一项所述的融合蛋白。
16.一种重组载体,包含如权利要求15的核酸。
17.一种宿主细胞,其被引入有编码如权利要求1至9中任一项所述的融合蛋白的核酸或包含所述核酸的重组载体。
18.一种用于制备融合蛋白方法,包含:
培养如权利要求17所述的宿主细胞以制备融合蛋白;以及
获得所述制备的融合蛋白。
19.一种针对冠状病毒感染的疫苗接种的方法,所述方法包括将权利要求10所述的疫苗组合物施用至受试者。
20.一种预防或治疗冠状病毒感染的方法,所述方法包括将权利要求13的药物组合物施用至受试者。
21.一种如权利要求1至9中任一项所述的融合蛋白在制备疫苗组合物中的用途。
22.一种如权利要求1至9中任一项所述的融合蛋白在制备用于预防或治疗冠状病毒感染的药物组合物中的用途。
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KR10-2020-0113989 | 2020-09-07 | ||
KR20200113989 | 2020-09-07 | ||
PCT/KR2021/001245 WO2022050520A1 (ko) | 2020-09-07 | 2021-01-29 | 코로나바이러스 유래 수용체 결합 도메인 및 뉴클레오캡시드 단백질을 포함하는 융합단백질 및 이의 용도 |
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CN202180072523.5A Pending CN116801904A (zh) | 2020-09-07 | 2021-01-29 | 包含冠状病毒衍生的受体结合域及核壳蛋白的融合蛋白及其用途 |
CN202180072520.1A Pending CN116963769A (zh) | 2020-09-07 | 2021-01-29 | 具有降低的ace 2的结合亲和力的冠状病毒衍生的受体结合域变体及包含其的疫苗组合物 |
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US (2) | US20230355745A1 (zh) |
EP (2) | EP4212543A1 (zh) |
JP (2) | JP2023540778A (zh) |
KR (2) | KR102613962B1 (zh) |
CN (2) | CN116801904A (zh) |
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IL87737A (en) | 1987-09-11 | 1993-08-18 | Genentech Inc | Method for culturing polypeptide factor dependent vertebrate recombinant cells |
EP0502036B1 (en) | 1989-11-22 | 1995-12-20 | Genentech, Inc. | Latency associated peptide and uses therefor |
AU2005319716A1 (en) * | 2004-06-30 | 2006-06-29 | Id Biomedical Corporation Of Quebec | Vaccine compositions for treating coronavirus infection |
US20080044437A1 (en) | 2004-09-02 | 2008-02-21 | Qun Chen | Encapsidation System for Production of Recombinant Virus-Like Particles |
WO2014134439A1 (en) * | 2013-03-01 | 2014-09-04 | New York Blood Center, Inc. | Immunogenic composition for mers coronavirus infection |
KR20170140180A (ko) | 2015-02-24 | 2017-12-20 | 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 | 중동 호흡기 증후군 코로나 바이러스 면역원, 항체 및 그 용도 |
WO2017075615A1 (en) | 2015-10-29 | 2017-05-04 | Bullet Biotechnology, Inc. | Virus-like particle intermediates, agents attached thereto, methods for making and uses thereof |
KR20180058206A (ko) * | 2016-11-23 | 2018-05-31 | 에스케이케미칼 주식회사 | 중동호흡기증후군 코로나바이러스 s 단백질 면역원 조성물 및 이의 제작 방법 |
WO2019066389A1 (ko) * | 2017-09-26 | 2019-04-04 | 한국생명공학연구원 | 메르스 코로나바이러스의 뉴클레오캡시드 단백질의 n-말단 도메인 단편 및 c-말단 도메인 단편을 포함한 nc 융합 단백질 및 이를 이용한 메르스 코로나바이러스 감염 진단용 키트 |
CN111592602B (zh) * | 2020-02-10 | 2021-03-02 | 中国科学院微生物研究所 | 一种β冠状病毒抗原、其制备方法和应用 |
CN111088283B (zh) * | 2020-03-20 | 2020-06-23 | 苏州奥特铭医药科技有限公司 | mVSV病毒载体及其病毒载体疫苗、一种基于mVSV介导的新冠肺炎疫苗 |
CN111499765B (zh) * | 2020-04-08 | 2022-04-08 | 四川携光生物技术有限公司 | 一种冠状病毒融合蛋白及其制备方法与应用 |
CN111474350B (zh) | 2020-04-23 | 2023-07-07 | 中国林业科学研究院林业研究所 | 一种检测冠状病毒s1抗原的试剂盒及其非诊断目的的检测方法 |
-
2021
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- 2021-01-29 WO PCT/KR2021/001245 patent/WO2022050520A1/ko active Application Filing
- 2021-01-29 KR KR1020210013261A patent/KR102613962B1/ko active IP Right Grant
- 2021-01-29 US US18/044,365 patent/US20230355745A1/en active Pending
- 2021-01-29 CN CN202180072523.5A patent/CN116801904A/zh active Pending
- 2021-01-29 CN CN202180072520.1A patent/CN116963769A/zh active Pending
- 2021-01-29 KR KR1020210013262A patent/KR102613963B1/ko active IP Right Grant
- 2021-01-29 EP EP21864486.2A patent/EP4212543A1/en not_active Withdrawn
- 2021-01-29 US US18/044,245 patent/US20240082387A1/en active Pending
- 2021-01-29 WO PCT/KR2021/001246 patent/WO2022050521A1/ko active Application Filing
- 2021-01-29 JP JP2023515271A patent/JP2023540779A/ja not_active Abandoned
- 2021-01-29 EP EP21864487.0A patent/EP4212544A1/en not_active Withdrawn
- 2021-02-01 TW TW110103676A patent/TW202210500A/zh unknown
- 2021-02-01 TW TW110103677A patent/TW202210501A/zh unknown
Also Published As
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CN116963769A (zh) | 2023-10-27 |
WO2022050521A1 (ko) | 2022-03-10 |
US20230355745A1 (en) | 2023-11-09 |
KR20220033964A (ko) | 2022-03-17 |
TW202210500A (zh) | 2022-03-16 |
KR20220033963A (ko) | 2022-03-17 |
EP4212543A1 (en) | 2023-07-19 |
TW202210501A (zh) | 2022-03-16 |
US20240082387A1 (en) | 2024-03-14 |
WO2022050520A1 (ko) | 2022-03-10 |
KR102613963B1 (ko) | 2023-12-18 |
JP2023540778A (ja) | 2023-09-26 |
EP4212544A1 (en) | 2023-07-19 |
JP2023540779A (ja) | 2023-09-26 |
KR102613962B1 (ko) | 2023-12-18 |
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