CN116963769A - 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 - Google Patents
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 Download PDFInfo
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Abstract
揭露的为新颖的具有降低的血管紧张素转化酶2的结合亲和力的冠状病毒衍生的受体结合域变体、包含其的融合蛋白及其用途。有机会克服使用冠状病毒棘状蛋白或其受体结合域的传统疫苗的缺点。尤其,藉结合冠状病毒受体结合域与Fc域所建构的融合蛋白附有显著增进的体内半衰期,且藉与冠状病毒衍生的域(例如N蛋白、M蛋白、ORF蛋白等)更进一步的结合,并通过额外的修饰,而具有优选的效能,并因此高度适用于多价免疫原组合物。因此,本发明的冠状病毒受体结合域变体能够用于预防及治疗包含COVID‑19的冠状病毒感染。
Description
技术领域
本发明涉及一种新颖的冠状病毒衍生的受体结合域变体、包含其的融合蛋白及其用途,其中冠状病毒衍生的受体结合域变体具有降低的血管紧张素转化酶2(ACE2)的结合亲和力(binding affinity)。
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)命名由严重急性呼吸系统综合症相关冠状病毒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)的仪表板。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到14天后发展。
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个地点发生,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,通过形成抗棘状蛋白或受体结合域(receptor-binding domain,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,尤其是与ACE2结合的受体结合域。
尤其,受体结合域为与ACE2结合的特定序列的氨基酸,其包含于棘状蛋白(S蛋白)中,且SARS-CoV-2的野生型氨基酸序列(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)。
然而先前对于具有通过与ACE2结合的细胞进入(cell entry)机制的SARS-CoV-1的研究(如SARS-CoV-2)显示出当SARS-CoV-1的棘状蛋白与ACE2结合,在急性肺部衰竭通过负回馈执行保护机制ACE2的表达被抑制,并因此肺部疾病加剧(Keiji et al,NATUREMEDICINE,2005)。此外,源自SARS-CoV-2的死亡被提出主因为心脏衰竭及急性肾损伤,而ACE2阻断剂最近被发现具有预防由SARS-CoV引起的急性肺损伤的效果。基于此,ACE2阻断剂作为COVID-19的治疗剂的临床试验正在进行中。因此,可以理解的是,除了冠状病毒进入细胞(感染)之外,棘状蛋白与ACE2的交互作用通过降低的ACE2表达而影响了疾病在肺部及心脏中的表达及恶化(Grifoni et al,Cell,2020)。
基于这些报告,施用使用棘状蛋白或SARS-CoV-2的受体结合域作为免疫原的疫苗至人体诱导了SARS-CoV中和抗体,及导致棘状蛋白或受体结合域与ACE2的结合,且如上所述,通过如ACE2的表达下降的病理机制,可能导致例如为肺部及心脏的急性损伤及衰竭的副作用。不利地,这些副作用可能导致ACE2的表达下降及致命的副作用,尤其当使用棘状蛋白或SARS-CoV-2的受体结合域作为免疫原的疫苗被施用至有潜在肺部及心脏疾病的病人身上。
在此背景技术下,作为发展用于预防或治疗冠状病毒感染疫苗的广泛研究成果,其中发展的疫苗可以克服冠状病毒衍生的棘状蛋白受体结合域与ACE2的结合所引起的肺部和心脏副作用,本案发明人发现具有受体结合域的氨基酸序列的一个或多个取代(substitution)展现出较野生型受体结合域更低的亲和力,并避免ACE2表达的下降,且当作为小鼠与猴子动物模型中的免疫原时,相较于包含野生型受体结合域的融合蛋白,包含变体及Fc域蛋白的融合蛋白和/或其他冠状病毒衍生的域展现了显著高的特定中和抗体形成的受体结合域的力价(titer),及展现了高冠状病毒中和能力。基于此发现,本发明已被完成。
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中具有通常知识者而言显而易见的现有技术的讯息。
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降低的ACE2结合亲和力的冠状病毒衍生受体结合域变体的融合蛋白及其用途。
本发明的另一目的是提供包含所述受体结合域变体的融合蛋白及其用途。
本发明的另一目的是提供作为活性成分(active ingredient)的单价或多价免疫原组合物,其包括所述受体结合域变体或包含其的融合蛋白。
本发明的另一目的是提供用于预防或治疗冠状病毒的组合物。
本发明的另一目的是提供用于预防或治疗冠状病毒的疫苗接种方法。
本发明的另一目的是提供用于预防或治疗冠状病毒感染的方法。
本发明的另一目的是提供核酸,所述核酸编码所述受体结合域变体或包含其的融合蛋白。
本发明的另一目的是提供包含所述核酸的重组载体。
本发明的另一目的是提供宿主细胞,其中被引入所述核酸或该重组载体。
本发明的另一目的是提供方法,其用于制备所述受体结合域变体或包含其的融合蛋白。
根据本发明的一个方面,上述及其他目的可以通过提供对ACE2受体具有降低的结合亲和力的冠状病毒衍生的受体结合域(RBD)变体。
根据另一方面,本发明提供一种包含所述受体结合域变体的融合蛋白。
根据另一方面,本发明提供一种包含该受体结合域(RBD)变体和/或所述融合蛋白的疫苗组合物。
根据另一方面,本发明提供该受体结合域(RBD)变体和/或所述融合蛋白在制备疫苗组合物中的用途。
根据另一方面,本发明提供用于对抗冠状病毒感染的疫苗接种的方法,该方法包含施用该受体结合域(RBD)变体、所述融合蛋白和/或该疫苗组合物至受试者。
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药物组合物,所述药物组合物包含以该受体结合域(RBD)变体和/或所述融合蛋白作为活性成分。
根据另一方面,本发明提供所述药物组合物的用途,其系用于制备预防或治疗冠状病毒感染的药物,其中该用途包含施用该疫苗组合物至受试者。
根据另一方面,本发明提供该受体结合域(RBD)变体和/或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,本发明提供用于预防或治疗冠状病毒感染的方法,该方法包含施用该受体结合域(RBD)变体、所述融合蛋白和/或所述药物组合物至受试者。
根据另一方面,本发明提供该受体结合域(RBD)变体和/或所述融合蛋白用于预防或治疗冠状病毒感染的用途。
根据另一方面,本发明提供编码(encode)该受体结合域(RBD)变体或所述融合蛋白的核酸。
根据另一方面,本发明提供包含所述核酸的重组载体。
根据另一方面,本发明提供宿主细胞,其中所述核酸或该重组载体被引入。
据另一方面,本发明提供制备受体结合域(RBD)变体或包含其的融合蛋白的方法,该方法包含培养该宿主细胞。
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SARS-CoV-2衍生野生型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(MHCI)及第二型主要组织兼容性复合体(MHC II)的抗原决定位(epitope),红色氨基酸表示在本发明的实施例中的筛选突变位;
图3为示出在实施例中制备的包含野生型RBD或变体RBD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RBDwt-Fc的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图6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RBDm(Q175A,N183A)-Fc的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图9为RBDm(G164A,V165A,Q175A,S176A,N183A)-Fc的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图10为Fc-RBDm(L137A,F168A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图11为RBDm(L137A,F168A)-Fc的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图12为RBDm(L137A,G164A,V165A,F168A,Q175A,S176A,N183A)-Fc的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图13为GIC-1114的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图14为GIC-1114m(L137A,F168A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图15为GIC-1114m(L137A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图16为GIC-1114m(F168A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图17为GIC-1114m(G184D)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图18为Fc-RBDm(L137A,G164A,V165A,F168A,Q175A,S176A,N183A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图19为示出GIC-1114N的示意图;
图20为GIC-1114m(L137A,F168A)的示意图;
图21为示出GIC-1114m(L137A,G164A,V165A,F168A,Q175A,S176A,N183A)的示意图;
图22为示出GIC-1151的示意图;
图23为GIC-1151m(L137A,F168A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图24为GIC-1132m(L137A,F168A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图25为GIC-1133m(L137A,F168A)的示意图(左),及示出SDS-PAGE对产物的分析结果(右);
图26为示出了不同浓度的所示融合蛋白与ACE2受体的结合亲和力随时间变化的曲线图(各项目的顶部),以及该结合亲和力的定量值;
图27为示出了单一浓度的所示融合蛋白与ACE2受体的结合亲和力随时间变化的曲线图;
图28示出了所示融合蛋白与hACE2受体的结合效率;
图29示出了当以所示融合蛋白处理时,HEK293细胞中hACE2表达量下降(调降(down-regulation));
图30为示出以本发明的融合蛋白对小鼠动物模型进行疫苗接种的示意图;
图31示出被以单独融合蛋白GIC-1114或GIC-1114m或与佐剂一起进行疫苗接种小鼠动物模型中RBD特定中和抗体形成的力价。其中GIC-1114包含野生型RBD、Fc域及SARS-CoV-2衍生的N蛋白,而GIC-1114m包含变体RBD(L137A,F168A)、Fc域及SARS-CoV-2衍生的N蛋白;
图32示出从使用AddaVax作为佐剂以GIC-1151m(L137A,F168A)接种后四周的小鼠取得的血清中,SARS-CoV2 RBD特定中和抗体形成的力价;
图33示意性地示出使用本发明的融合蛋白对猴子动物模型进行疫苗接种;
图34示出被以与佐剂(AddaVax)合并GIC-1114或GIC-1114m(L137A,F168A)进行疫苗接种的猴子动物模型中,SARS-CoV-2棘状蛋白特定中和抗体形成的力价,其中虚线显示了由USFDA(2880力价)鉴定的显著SARS-CoV-2棘状蛋白目标抗体力价(USFDA,Recommendations for Investigational COVID-19convalescent plasma);
图35示出确认在以与佐剂(AddaVax)合并GIC-1114或GIC-1114m(L137A,F168A)进行疫苗接种后四周收集的猴子血清的SARS-CoV-2中和能力sVNT的结果;以及
图36示出确认在以与佐剂(AddaVax)合并GIC-1114或GIC-1114m(L137A,F168A)进行疫苗接种后八周收集的猴子血清的SARS-CoV-2中和能力sVNT的结果。
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’到3’及N末端到C末端的从左到右的顺序撰写。本文所列的数值范围包含定义该范围的数值,及包含在该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1亿,数百万人死亡。尽管存在这些状况,但证实对于SARS-CoV-2有效的治疗剂及疫苗仍然严重缺乏,许多研究人员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的症状表达及感染(细胞进入)机制扮演着最重要的脚色。然而,根据对具有非常相似于SARS-CoV-2机制的SARS-CoV-1的报告及近期对SARS-CoV-2与ACE2的角色的研究,当棘状蛋白结合至ACE2时,ACE2的表达可能下降,且在肺部及心脏中下降的ACE2表达可能使疾病加剧(Keiji et al,NATURE MEDICINE,2005;Grifoni et al,Cell,2020)。因此,使用棘状蛋白或其片段作为免疫原的疫苗组合物具有很高的可能性在肺部或心脏造成副作用,且尤其,当施用至具有潜在疾病的病人时会有致命的缺点。
在本发明的一个实施方案中,为了克服使用这样的棘状蛋白或其片段作为免疫原的疫苗的缺点,基于SARS-CoV-2衍生的棘状蛋白受体结合域与ACE2之间的结合结构的分析,SARS-CoV-2受体结合域变体藉诱导受体结合基序氨基酸中的突变而被制备,且由于负回馈,相较于野生型受体结合域,受体结合域变体被发现有较低的与ACE2结合的能力及降低的ACE2表达。
在本发明的另一实施方案中,各种包含本发明的受体结合域变体的Fc融合蛋白被制备,且哺乳动物的动物模型(小鼠、猴子)被以其进行疫苗接种。结果显示Fc融合蛋白展现了显著高的中和抗体形成及诱发的T细胞免疫反应,并因此展现了对冠状病毒感染有绝佳的预防及治疗效果。
因此,在一方面,本发明涉及冠状病毒衍生的受体结合域(RBD)变体,其对ACE2受体具有降低的结合亲和力。
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,从SARS-CoV-2衍生的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SARS-CoV-2衍生的,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。
根据本发明的受体结合域被解读为包含变体或其片段,其中在特定氨基酸残基位置的氨基酸残基为被保守地取代。
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。
如本文所用,术语“受体结合域变体”旨在涵盖野生型受体结合域序列中至少一氨基酸残基的突变,优选为取代(substitution)、删除(deletion)、插入(insertion)等,及在N末端或C末端的至少一氨基酸残基的切割(cleavage)。因此,在本发明中,受体结合域变体被广义地使用,包含“受体结合域变体的片段”。
在本发明中,受体结合域变体可以包含受体结合基序的氨基酸序列中的突变。
在本发明中,受体结合域变体优选包含自由SEQ ID NO:1的氨基酸序列中L137、G164、V165、F168、Q175、S176、N183及G184组成的群组选择的至少一氨基酸中的突变,优选选自氨基酸L137、F168及G184中的至少一种的突变,更优选选自氨基酸L137及F168组成的群组选择中的至少一种的突变及氨基酸G184的突变,且最优选系氨基酸L137及F168的突变,但不限于此。
在本发明中,最广义而言,突变是指在包含所有氨基酸突变,如取代、删除及插入、氨基酸的糖化(glycosylation)、其侧链的取代等。
在本发明中,突变可以为氨基酸的取代。
在本发明中,突变可以为被丙氨酸(alanine)以及任何具有类似于丙氨酸的侧链的氨基酸残基或其他氨基酸残基取代,只要其能够降低与ACE2受体结合的能力即可。举例而言,突变可以为以赖氨酸、酪氨酸、苏氨酸、天冬酰胺、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸等,但不限于此。
在本发明中,受体结合域变体优选包含自SEQ ID NO:1的氨基酸序列中L137A、G164A、V165A、F168A、Q175A、S176A、N183A及G184D选择的至少一氨基酸残基的取代。
在本发明中,受体结合域变体更优选包含自由氨基酸L137A及F168A组成的群组选择的至少一取代;以及SEQ ID NO:1的氨基酸序列中氨基酸G184D的取代,且优选可以包含氨基酸L137A及F168A的取代,但不限于此。
在本发明中,当受体结合域具有与SEQ ID NO:1不同的氨基酸序列或其片段时(例如,在棘状蛋白中具有突变的变体冠状病毒的受体结合域),本领域中具有通常知识者可以通过比对及分析容易地得到对应上述氨基酸的氨基酸。在这个情况下,显然地,本发明的受体结合域变体可以包含对应上述氨基酸的至少一氨基酸的突变。
在本发明中,受体结合域可以与其他成分融合,例如多肽、蛋白或糖及PEG,以调节生物特性或物理/化学特性。
在本发明中,具有氨基酸残基码的一个字母与数字(n个)的形式的描述,例如“L137”,是指在各氨基酸序列中第n个位置的氨基酸残基的名称及类型。
例如,“L137”是指在SEQ ID NO:1的氨基酸序列中第137个位置的氨基酸残基为天冬酰胺。数字后面的氨基酸残基名称,例如“L137A”,是指氨基酸的取代,且“L137A”是指在SEQ ID NO:1的第137个位置的亮氨酸(Leu,L)被丙氨酸(Ala,A)取代。
在本发明的一个实施方案中,融合蛋白藉融合受体结合域变体与免疫球蛋白的Fc域而被制备。融合蛋白可以展现加强的生物特性,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。
在另一方面,本发明涉及包含本发明的受体结合域(RBD)变体的融合蛋白。
在本发明中,除了受体结合域变体外,融合蛋白可以进一步包含其他物质。举例而言,融合蛋白可以包含Fc域、冠状病毒衍生的物质(优选为SARS-CoV-2衍生的物质)、接头、佐剂、抗原、抗体等,但不限于此。
在本发明中,冠状病毒衍生的物质是指任何冠状病毒衍生的物质,例如冠状病毒衍生的蛋白、核酸(优选为RNA)或多糖。
在本发明中,冠状病毒衍生的物质可以为冠状病毒衍生的蛋白或其片段,优选为冠状病毒衍生的N蛋白或M蛋白,且更优选为冠状病毒衍生的N蛋白或其RNA结合域。
在本发明中,除了受体结合域变体外,冠状病毒衍生的物质可以包含两个或多个物质,且可以包含两个或多个相同的受体结合域变体或两个或多个其他物质。
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。
在本发明的一个实施方案中,与SARS-CoV-2衍生的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结合进入及扩散进宿主细胞,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SARS-CoV-2衍生的受体结合域及RNA结合域。
在本发明中,冠状病毒衍生的物质可以为从SARS-CoV-2取得。举例而言,冠状病毒衍生的物质可以为N蛋白、M蛋白、开放阅读框(open reading frame,ORF)蛋白等。优选地,本发明的融合蛋白更可以包含N蛋白和/或M蛋白,但不限于此。
在本发明中,融合蛋白可以具有其中受体结合域变体连接至冠状病毒衍生的物质的结构。
在本发明中,更优选地,融合蛋白可以具有其中受体结合域变体连接至SARS-CoV-2衍生的N蛋白的结构,最优选为连接至N蛋白的RNA结合域。
在本发明的一实施方案中,其中两个受体结合域变体及两个N蛋白RNA结合域通过接头融合的融合蛋白被制备(见图22及23),且其免疫原性(immunogenicity)被检测,但本发明不限于此。
在本发明中,融合蛋白可以有其中RNA受体结合域变体、N蛋白(或其RNA结合域)、N蛋白(或其RNA结合域)及RNA受体结合域变体以此顺序连接的结构。
在本发明中,受体结合域变体可以通过共价链直接地连接至N蛋白及M蛋白的至少一种,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其。
如本文所用,术语“接头”是指连接融合蛋白的域的分子,如受体结合域变体、Fc域、冠状病毒衍生的物质(例如N蛋白、M蛋白等)等。
在本发明中,接头可以优选为甘氨酸–丝氨酸接头(glycine-serine linker,GSlinker)。甘氨酸–丝氨酸接头可以为,例如,G2S、G3S或G4S接头,但不限于此。
在本发明中,接头可以更优选包含自由SEQ ID NO:6至SEQ ID NO:11的氨基酸序列组成的群组选择的氨基酸序列。
在本发明中,融合蛋白可以具有受体结合域变体(RBD)–GS接头–N或M蛋白、RBD–GS接头–N蛋白–GS接头–M蛋白或RBD–GS接头–M蛋白–GS接头–N蛋白依序连接的结构,但不限于此。
在本发明中,融合蛋白可以具有由SEQ ID NO:60表示的序列。
在本发明中,融合蛋白可以包含受体结合域变体及Fc域。
如本文所用,术语“Fc域”是指抗体的尾部区域(tail region),且该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-chainconstant domain)CH2及CH3,且更可以包含重链稳定域的枢纽区(hinge region)。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,融合蛋白被以同型二聚体(homodimer)的形式产生,其中两个相同的Fc域与受体结合域变体和/或冠状病毒衍生的物质通过双硫键(disulfide bond)相连。
在本发明中,融合蛋白可以包含两个或多个Fc域及受体结合域变体。
在本发明中,融合蛋白可以为包含受体结合域变体及Fc域的蛋白的二聚体。
在本发明中,融合蛋白可以为包含受体结合域变体、Fc域及至少一冠状病毒衍生的物质的蛋白的二聚体。
举例而言,在本发明中,二聚体可以通过每个Fc域的至少一半胱氨酸(cysteine)残基的双硫键形成,但不限于此。
在本发明中,融合蛋白可以为包含受体结合域变体及Fc域的蛋白的异型二聚体(heterodimer)或同型二聚体(homodimer)。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。
在本发明中,Fc域可以为哺乳动物的免疫球蛋白Fc域,优选为老鼠、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,其为从有机体取得的同型(isotype)IgG。
在本发明中,Fc域最优选由SEQ ID NO:2的序列表示,或包含该序列,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,受体结合域变体可以连接至Fc域的N末端和/或C末端,且优选为连接至其C末端。
在本发明中,受体结合域变体可以连接至Fc域的N末端或C末端,而冠状病毒衍生的物质可以更连接至剩余者。
本发明的特征在于冠状病毒的ORF蛋白、N蛋白和/或M蛋白的RNA结合域,优选为N蛋白,更优选为N蛋白的RNA结合域与Fc域的另一端连接。
在本发明中,例如为受体结合域变体、Fc域及SARS-CoV-2衍生的物质(优选为N蛋白和/或M蛋白)的包含在融合蛋白中的成分直接通过共价键连接,或可以通过接头间接地连接。在本发明的一实施方案中,融合蛋白是通过使用由SEQ ID NO:6至SEQ ID NO:11表示的接头,连接受体结合域(或其变体)或SARS-CoV-2衍生的N蛋白至Fc域的C末端和/或N末端制备而成,但本发明不限于此。
在本发明中,融合蛋白优选具有受体结合域变体、Fc域及核壳蛋白以此顺序连接的结构,或核壳蛋白、Fc域及受体结合域变体以此顺序连接的结构,或为其二聚体,且M蛋白可以更连接至核壳蛋白,但本发明不限于此。
在本发明中,当N蛋白连接至另一端时,其作为抗原并诱发毒杀型淋巴细胞(cytotoxic lymphocyte,CTL)的表达以杀死病毒。
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。
如本文所用,术语“M蛋白”是指细胞膜蛋白。
在本发明中,冠状病毒衍生的物质如N蛋白及M蛋白旨在涵盖不只整个蛋白,更涵盖蛋白的片段。举例而言,N蛋白旨在涵盖不只整个N蛋白,而是更涵盖N蛋白的特定域或片段,且优选包含N蛋白的RNA结合域或包含其的片段。N蛋白及M蛋白具有高的免疫原性且促进毒杀型淋巴细胞的分化。
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。
在本发明中,融合蛋白可以由自SEQ ID NO:43至48组成的群组选择的任一氨基酸序列表示,或可以包含其。
在本发明中,融合蛋白可以由自SEQ ID NO:50至54及SEQ ID NO:56至58组成的群组选择的任一氨基酸序列表示,或可以包含其。
在本发明的一个实施方案中,发现的是,藉连接受体结合域变体至Fc域的一端(N末端或C末端)及连接N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冠状病毒RBD特定中和抗体形成及T细胞免疫反应诱发能力。
本发明的受体结合域变体和/或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,本发明的受体结合域变体和/或融合蛋白可以诱导与野生型受体结合域及包含其的融合蛋白相当或更优选的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受体结合域变体和/或融合蛋白。
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该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,当该受试者被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、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,以在受施用免疫原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、咪唑并喹啉、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、明矾、MPLA及其组合组成的群组选择,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,该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。
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)。该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'sPharmaceutical 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,本发明涉及受体结合域变体和/或融合蛋白在制备用于预防冠状病毒感染的疫苗组合物中的用途。
在另一方面,本发明涉及受体结合域变体、融合蛋白和/或疫苗组合物的用途,用于对抗冠状病毒感染,其中该用途包含一方法,该方法包含施用受体结合域变体、融合蛋白和/或疫苗组合物至受试者。
在本发明一实施方案中,使用了SARS-CoV-2衍生的受体结合域,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藉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,包含以受体结合域变体和/或融合蛋白作为活性物质。
在本发明中,药物组合物可以为治疗疫苗组合物用于疫苗疗法。
如本文所用,术语“预防”是指通过施用根据本发明的医药物组合物以致使目标疾病的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医药物组合物以致使目标疾病中的症状减缓或症状的有益改变的任何作用。
根据本发明的医药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、糖衣药丸及硬胶囊时,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,且有效剂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,并且该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受体结合域变体和/或融合蛋白的用途。
在另一方面,本发明涉及用于预防或治疗冠状病毒感染的受体结合域变体、融合蛋白和/或药物组合物的用途,其中该方法包含施用受体结合域变体、融合蛋白和/或药物组合物至受试者的方法。
在另一方面,本发明涉及受体结合域变体和/或融合蛋白的用途,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,其编码受体结合域变体和/或融合蛋白。
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)、管柱层析法、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)或单纯为潜在的基因插入(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,且该些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、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、从巨细胞病毒取得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,基因应该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,其中的核酸编码受体结合域变体或融合蛋白和/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受体结合域变体和/或融合蛋白的细胞,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,宿主细胞为主要用于表达融合蛋白的中国仓鼠卵巢细胞株(CHOcell 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受体结合域变体和/或融合蛋白。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(cowpapillomavirus)、腺病毒、腺相关病毒、巨细胞病毒及反转录病毒取得的表达控制序列。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 vectors、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受体结合域变体和/或融合蛋白)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受体结合域变体和/或包含其的融合蛋白的方法,该方法包含培养宿主细胞。
当能够表达受体结合域变体和/或包含其的融合蛋白的重组表达载体被引入哺乳动物宿主细胞时,受体结合域变体和/或包含其的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受体结合域变体和/或包含其的融合蛋白被分泌入培养基的时间。
在一些情况中,表达的受体结合域变体和/或包含其的融合蛋白可以被从宿主细胞分离且纯化至同质(homogeneity)。所述受体结合域变体和/或包含其的融合蛋白的分离或纯化可以藉使用用于传统蛋白的分离及纯化方法而实行,例如层析法(chromatography)。层析法例如可以包含从亲合层析法(affinity chromatography)、离子交换层析法及疏水层析法选择的一个或多个的组合,但不限于此。层析法与过滤、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,该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:包含野生型受体结合域或变体的融合蛋白的制备
如图3所示,控制组及实验组被设置,而融合蛋白(图4到25)被制备以评估受体结合域(RBD)变体的ACE2结合亲和力及免疫原性(immunogenicity)。为了制备融合蛋白,下表1所示的野生型RBD、变体RBD、IgG1 Fc域及核壳蛋白(N蛋白)RNA结合域被连接以设计融合蛋白及包含编码融合蛋白的碱基序列(base sequence)的核苷酸通过使用Integrated DNATechnologies的gBlockTM基因片段被合成,并加载pcDNA3.4载体。
表1
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表2: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树脂执行管柱层析法而被纯化。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层析法(size exclusion chromatography),且吸亮度在波长214nm被量测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。
GIC-1151及GIC-1151m通过使用阳离子交换树脂(Capto S,GE)的层析法被纯化。50mM Tris-HCl(pH 8.0)缓冲剂被使用以执行平衡。接着,将通过0.22μm过滤器过滤的上清液装载到柱上,且柱被以50mM Tris-HCl(pH8.0)缓冲剂对应于树脂体积的10倍的体积冲洗。接着,使用50mM Tris-HCl(pH 8.0)缓冲剂及1M NaCl(梯度)缓冲剂按照5mL的分液进行洗脱。SDS-PAGE及以考马斯蓝染色被依序执行,且为预期大小的切片融合蛋白被收集,尺寸排阻层析法藉使用尺寸排阻树脂(superdex 75pg 16/600,GE)而被执行,且吸亮度在波长214nm被量测以取得高浓度的融合蛋白。此时,在以考马斯蓝染色后,分离且纯化的融合蛋白的组成(formation)藉在还原(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核酸序列如下表3及4所示。
表3
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表4
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实施例2:以融合蛋白与ACE2之间的结合亲和力的评估
AHC生物传感器(Anti-hIgG Fccapture,ForteBio,18-5060)预先在96孔微量盘(96-well microplate)上被润湿(hydrated)(Greiner Bio-One,目录号:655209),其每个孔含200μl的1X动力缓冲剂(kinetic buffer)(10X Kinetics buffer,ForteBio,18-1042)。待附接至生物传感器的配位子(融合蛋白)被以1X Ni-NTA动力缓冲剂稀释至浓度10μg/ml。待附接至配位子的hACE2(His-Tag,Acro,AC2-H52H8)被以1X动力缓冲剂稀释至浓度500nM、250nM、125nM、62.5nM、31.2nM、15.6nM、7.8nM或60nM(单一浓度)。200μl的各试剂被加入96孔微量盘的各个孔中Greiner Bio-One,目录号#655209,并设定程序。
在实施例1中制备的多个融合蛋白中,包含野生型RBD(RBDwt)或变体RBD(RBDm)且连接至Fc域的C末端的融合蛋白对ACE2的结合亲和力被侦测(在每个受体浓度下确认)。如图26所示,结果显示包含野生型RBD的融合蛋白对ACE2受体展现高结合亲和力(低KD值),而包含RBD变体(RBDm(L137A,F168A))的融合蛋白对ACE2受体展现低结合亲和力(高KD值)。同时,包含具有L137A或F168A突变的RBD变体的融合蛋白在结合后表达出低解离度(dissociation),但是包含具有L137A及F168A突变的RBD变体的融合蛋白在结合后表达出高解离度(图26)。具有G184D的单个突变的RBD变体(RBDm(G184D))根本未与ACE2结合。每个融合蛋白的结合亲和力如下表5所示。
表5:融合蛋白对ACE2的结合亲和力
此外,在实施例1中制备的多个融合蛋白中,包含野生型RBD(RBDwt)或变体RBD(RBDm)且连接至Fc域的N末端的融合蛋白对ACE2的结合亲和力对ACE2的结合亲和力被侦测(单一浓度)。如图27所示,包含野生型RBD或变体RBD的融合蛋白无论对Fc域的N末端或C末端的连接位置为何,皆展现了同样的结果。这些结果表示其中特定氨基酸已被突变的变体RBD本身影响了对ACE2的结合亲和力,不论Fc域或RBD的结合位置。此外,除了L137A及F168A,在存在更多氨基酸取代(G164A、V165A、F168A、Q175A、S176A、N183A)的情况中,结合亲和力下降,但在L137A及F168A不存在的情况下G164A、V165A、F168A、Q175A、S176A及N183A变体),结合亲和力则维持住。
整体而言,发现的是相较于包含野生型RBD的融合蛋白,本发明包含变体RBD的融合蛋白的结合力(binding force)降低了10到100倍或更多,且结果表示当i)L137A及F168A突变,或ii)G184D突变存在,则RBD对ACE2受体的结合亲和力被显著地降低。
实施例3:确认融合蛋白的hACE2结合效率及hACE2调降
表达hACE2的HEK293T细胞(HEK293T/hACE2,Genecopoeia,目录号##SL221)充分地成长且以浓度3x105细胞/100μl FACS缓冲剂(5%(v/v)FBS在PBS)种在每个FACS管中。下表6所示的蛋白被混合进各管中,并接着让其在4℃反应1小时。
表6
产物 | 量 |
Fc控制(IgG1) | 0.4ug/ml |
GIC-1114 | 1ug/ml |
GIC-1114m(L137A,F168A) | 1ug/ml |
GIC-1114m(G184D) | 1ug/ml |
接着,每个样品在4℃下被以300xg离心5分钟以移除上清液,而颗粒(pellet)悬浮(suspended)于1ml的FACS缓冲剂中。在重复离心及悬浮程序两次后,抗人IgG(anti-humanIgG)(H+L)抗体(FITC;Invitrogen,目录号#31259)被以FACS缓冲剂稀释至1:500,而样品被以100μl的稀释液处理并在4℃下反应30分钟。接着,每个样品在4℃下被以300xg离心5分钟以移除上清液,而颗粒悬浮于1ml的FACS缓冲剂中。在重复离心及悬浮程序两次以移除未结合的抗体后,每个样品悬浮于500μl的FACS缓冲剂中,且荧光异硫氰酸盐(fluoresceinisothiocyanate,FITC)强度被以使用流式细胞仪(flow cytometer)量测(BDFACSCelestaTM,BD,CA,USA)以判定每个融合蛋白对hACE2的结合效率。
如图28所示,结果显示相较于包含野生型RBD的融合蛋白(GIC-1114),包含RBD变体的融合蛋白(GIC-1114m(L137A,F168A)及GIC-1114m(G184D))展现了显著较低的hACE2结合效率。
所辨识的包含每个受体结合域变体的融合蛋白的降低的结合效率是否导致抑制hACE2表达抑制被确定。具体而言,表达hACE2的HEK293T细胞(HEK293T/hACE2,Genecopoeia,目录号#SL221)充分生长,并以3x105细胞/100μl的FACS缓冲剂(PBS中5%(v/v)FBS)的浓度种于FACS管子中。上表6所示的蛋白被混合进各管中,并接着让其在37℃反应1小时。接着,每个样品在4℃下被以300xg离心5分钟以移除上清液,而颗粒悬浮于1ml的FACS缓冲剂中。在重复离心及悬浮程序两次后,羊抗人(goat anti-human)AEC2胞外(ectodomain)抗体(R&D系统,AF933)被以FACS缓冲剂稀释至2μg/ml的最终浓度,而样品被以100μl的稀释液处理并在4℃下反应1小时。接着,每个样品在4℃下被以300xg离心5分钟以移除上清液,而颗粒悬浮于1ml的FACS缓冲剂中。在重复离心及悬浮程序两次以移除未结合的抗体后,兔抗羊(rabbit anti-goat)IgG(H+L)交叉吸附二级抗体(cross-adsorbedsecondary antibody)(DyLight 650;Invitrogen,SA5-10081)被以FACS缓冲剂稀释至1:1000,而样品被以100μl的稀释液处理并在4℃下反应30分钟。接着,每个样品在4℃下被以300xg离心5分钟以移除上清液,而颗粒悬浮于1ml的FACS缓冲剂中。在重复离心及悬浮程序两次后,每个样品悬浮于500μl的FACS缓冲剂中,且FITC强度被以使用流式细胞仪量测(BDFACSCelestaTM,BD,CA,USA)以判定hACE2的降低(调降)表达量。
如图29所示,以包含野生型RBD的融合蛋白(GIC-1114)进行的处理调降了hACE2的表达,但以包含RBD变体的融合蛋白(GIC-1114m(L137A,F168A)及GIC-1114m(G184D))进行的处理展现了HEK293中hACE2表达显著降低的效果。
因此,不同于野生型RBD,本发明的RBD变体对hACE2展现了低结合亲和力及结合效率,且不会造成hACE2表达的降低,由于传统疫苗因由野生型RBD导致的hACE2的降低的表达量造成的副作用的风险是很低的,因此本发明的RBD变体对用于冠状病毒的疫苗是有用的,即使当本发明的RBD变体作为疫苗的免疫原(抗原)时。
实施例4:以本发明的融合蛋白对小鼠进行疫苗接种后的免疫反应的评估
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7。
表7
考虑到各融合蛋白的分子量(GIC-1114(N-Fc-RBDwt):140kDa,GIC-1114m(N-Fc-RBDmt_L137A,F168A):140kDa,GIC-1151m(RBDmt_L137A,F168A-N-N-RBDmt_L137A,F168A):85kDa),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,以融合蛋白再次接种。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移除并与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(图30)。
实施例4-2:中和抗体的评估
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被分析。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孔微量盘(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的量加入该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,且被以200μL的冲洗缓冲剂(0.05%的Tween20(Sigma,P7949)在1X PBS中)冲洗两次。254μL的1X ELISA测定稀释剂被加入从每只小鼠收集到的2μL的血清以执行初始的稀释(1:128)。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的稀释血清被加入每个孔,接着将其保存在室温下2小时并同时以100rpm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,SpectraMax iD3)量测,且中和抗体形成的力价被量测。
从图31可以看到,在使用不含佐剂的融合蛋白进行疫苗接种的状况中,当包含变体RBD的融合蛋白(GIC-1114m(L137A,F168A))被施用时,相较于当包含野生型RBD的融合蛋白(GIC-1114)被施用时,RBD特定中和抗体的显著高的力价被取得。
此外,当佐剂被一并施用以促进免疫反应时,每个抗体的力价被增进。当GIC-1114或GIC-1114m(L137A,F168A)被使用时,中和抗体力价相近。
在融合蛋白不包含Fc域的融合蛋白的GIC-1151m(L137A,F168A)状况中,在以Addavax作为佐剂对小鼠接种后四周取得的血清中,SARS-CoV2的RBD特定中和抗体力价被判定。如图32所示,GIC-1151m(L137A,F168A)展现与GIC-1114及GIC-1114m(L137A,F168A)相近程度的RBD特定中和抗体力价。
以上的结果显示尽管基因突变及ACE2结合亲和力下降,变体RBD及包含其的融合蛋白不影响SARS-CoV2的RBD特定抗体的力价,因而展现与包含野生型RBD的疫苗组合物相近或更优选的免疫原性,同时降低副作用。
实施例5:以包含RBD变体的融合蛋白对猴子模型进行疫苗接种后的免疫反应的评估
实施例5-1:猴子的疫苗准备及接种
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猴子及融合蛋白示出于下表8。
表8
融合蛋白被以25μg的恒定量通过股骨肌的肌肉注射施用至猴子模型,且血液在接种后以7天的间隔(8周共8次)被从股静脉收集,以量测抗体的力价,且无病毒中和性抗体检测(SARS-CoV-2surrogate virus neutralization test,sVNT)在接种后28及56天被执行。
收集到的血液被转移到血清分离管(SST tube)中,让其处在室温下30分钟,并在4℃以300rpm离心10分钟以取得血清,所取得的血清被储存在1.7mL的微量离心管(Axygen,USA)中(图33)。
实施例5-2:中和抗体力价的评估
从猴子模型收集到的血清中所含的中和抗体力价通过使用如实施例4-2中所描述的方法被侦测。如图34所示,在接种后一周的GIC-1114展现RBD特定中和抗体形成的高的力价,但未达根据USFDA标准表示有显著疫苗能力的参考力价(2880),且在2周后超过参考力价水平,且相较于被施用包含野生型RBD的GIC-1114的猴子,被施用包含RBD变体的GIC-1114m(L137A,F168A)的猴子的血液展现了较高力价的中和抗体形成。在3到4周之间的抗体的力价为最高,且高的抗体力价被维持直到8周而无显著的下降,这表示即使当本发明的RBD变体及融合蛋白仅被施用一次,长期的免疫可以被维持住而不产生额外的免疫增强(immune boosting)。
实施例5-3:融合蛋白的无病毒中和性抗体检测(sVNT)
无病毒中和性抗体检测(sVNT)被执行以判断从以本发明的融合蛋白接种的猴子模型收集到的血液的抗体是否可以有效地中和SARS-CoV-2。
具体地,ELISA藉使用ACE2:SARS-CoV-2棘状蛋白抑制剂筛选检测试剂(ACE2:SARS-CoV-2spike inhibitor screening assay kit)(BPS Bioscience,目录号#79936)。检测试剂中的ACE2-His(目录号#11003)被以PBS稀释至最终浓度1μg/ml,且50μl的被稀释的溶液被植入孔盘中并附接于其1小时。在附接后,上清液被移除,且每个孔被以100μl的1X免疫缓冲剂1(Immuno Buffer 1)冲洗三次,并以100μl的阻断缓冲剂2(Blocking Buffer2)阻断10分钟,接着上清液被移除。
猴子模型的10μl的血清样本稀释液(最终稀释至1:64)及20μl的1X免疫缓冲剂1被植入制备的盘中的每个孔,且抑制剂缓冲剂(PBS)以10μl/孔被植入以作为阳性对照组及空白组。20μl的SARS-CoV-2棘状蛋白(被稀释至1ng/μl的最终浓度)被植入标为阳性对照组及测试抑制剂的每个孔,且20μl的抑制剂缓冲剂(PBS)被植入标为空白组的孔,并接着让其在室温下反应1小时。每个盘被以100μl的1X免疫缓冲剂1冲洗三次,并接着被以100μl的阻断缓冲剂2阻断10分钟。二级HRP标记抗体1(目录号#52130H)被以阻断缓冲剂2稀释至1000X,并接着以100μl/孔被植入及在室温下反应1小时。每个盘被以100μl的1X免疫缓冲剂1冲洗三次,并接着被以100μl的阻断缓冲剂2阻断10分钟。ELISA增强化学发光(enhancedchemiluminescence,ECL)基质A(substrate)及ELISA增强化学发光基质B被以1比1的比例混合,所产生的混合物以100μl/孔被植入,且样本的冷光(luminescence)值藉使用微量盘分析仪(Discover Microplate Reader(Promega))而被量测。
如图35及36所示,从猴子模型收集到的血清的sVNT测试结果显示,相较于被施用包含野生型RBD的GIC-1114的猴子,在本发明的多个融合蛋白中,包含在被施用包含RBD变体的GIC-1114m(L137A,F168A)猴子血清内的SARS-CoV-2抗体展现了显著较高的SARS-CoV-2中和能力。
整体而言,以上的结果显示具有高力价及中和能力的抗体可以在本发明的RBD变体及包含其的融合蛋白的施用后形成。
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,提供该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
冠状病毒衍生的本发明的受体结合域变体对ACE2具有显著降低结合力,并因此可以克服使用冠状病毒棘状蛋白或其受体结合域的传统疫苗的缺点,其中因与ACE2结合及负回馈而降低的ACE2表达可能导致肺部及心脏的副作用,且尤其,对于肺部及心脏有潜在疾病的病人可能是致命的。尤其,藉结合冠状病毒受体结合域与Fc域所建构的本发明的融合蛋白附有显著增进的体内半衰期,且藉与冠状病毒衍生的域(例如N蛋白、M蛋白、ORF蛋白等)更进一步的结合,并通过额外的修饰,而具有优选的效能,并因此高度适用于多价免疫原组合物。因此,本发明的冠状病毒受体结合域变体能够用于预防及治疗包含COVID-19的冠状病毒感染。
文本文件
参见所附序列表。
<110> 吉爱希公司
<120> 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
<130> PP-B2552
<150> KR 2020-0113989
<151> 2020-09-07
<160> 82
<170> KoPatentIn 3.0
<210> 1
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> Wild type RBD
<400> 1
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
210 215
<210> 2
<211> 231
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG1 Fc domain
<400> 2
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly
225 230
<210> 3
<211> 419
<212> PRT
<213> Artificial Sequence
<220>
<223> N protein_full
<400> 3
Met Ser Asp Asn Gly Pro Gln Asn Gln Arg Asn Ala Pro Arg Ile Thr
1 5 10 15
Phe Gly Gly Pro Ser Asp Ser Thr Gly Ser Asn Gln Asn Gly Glu Arg
20 25 30
Ser Gly Ala Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn Asn
35 40 45
Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp Leu
50 55 60
Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser Pro
65 70 75 80
Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg Gly
85 90 95
Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr
100 105 110
Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys Asp
115 120 125
Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys Asp
130 135 140
His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu Gln
145 150 155 160
Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly Ser
165 170 175
Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg Asn
180 185 190
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
210 215 220
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
Ile Lys Leu Asp Asp Lys Asp Pro Asn Phe Lys Asp Gln Val Ile Leu
340 345 350
Leu Asn Lys His Ile Asp Ala Tyr Lys Thr Phe Pro Pro Thr Glu Pro
355 360 365
Lys Lys Asp Lys Lys Lys Lys Ala Asp Glu Thr Gln Ala Leu Pro Gln
370 375 380
Arg Gln Lys Lys Gln Gln Thr Val Thr Leu Leu Pro Ala Ala Asp Leu
385 390 395 400
Asp Asp Phe Ser Lys Gln Leu Gln Gln Ser Met Ser Ser Ala Asp Ser
405 410 415
Thr Gln Ala
<210> 4
<211> 156
<212> PRT
<213> Artificial Sequence
<220>
<223> N protein_RNA binding domain
<400> 4
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
145 150 155
<210> 5
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> M protein
<400> 5
Arg Leu Phe Ala Arg Thr Arg Ser Met Trp Ser Phe Asn Pro Glu Thr
1 5 10 15
Asn Ile Leu Leu Asn Val Pro Leu His Gly Thr Ile Leu Thr Arg Pro
20 25 30
Leu Leu Glu Ser Glu Leu Val Ile Gly Ala Val Ile Leu Arg Gly His
35 40 45
Leu Arg Ile Ala Gly His His Leu Gly Arg Cys Asp Ile Lys Asp Leu
50 55 60
Pro Lys Glu Ile Thr Val Ala Thr Ser Arg Thr Leu Ser Tyr Tyr Lys
65 70 75 80
Leu Gly Ala Ser Gln Arg Val Ala Gly Asp Ser Gly Phe Ala Ala Tyr
85 90 95
Ser Arg Tyr Arg Ile Gly Asn Tyr Lys Leu Asn Thr Asp His Ser Ser
100 105 110
Ser Ser Asp Asn Ile Ala Leu Leu Val Gln
115 120
<210> 6
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker1
<400> 6
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 7
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker2
<400> 7
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 8
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker3
<400> 8
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 9
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker4
<400> 9
Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5
<210> 10
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker5
<400> 10
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10
<210> 11
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker6
<400> 11
Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5
<210> 12
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Signal peptide
<400> 12
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser
<210> 13
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> RBDm(Q175A, N183A)
<400> 13
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 Ala Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Ala 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
210 215
<210> 14
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> RBDm(G164A, V165A, Q175A, S176A, N183A)
<400> 14
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 Ala Ala Glu Gly Phe Asn Cys Tyr Phe Pro Leu Ala Ala
165 170 175
Tyr Gly Phe Gln Pro Thr Ala 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
210 215
<210> 15
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> RBDm(L137A, G164A, V165A, F168A, Q175A, S176A, N183A)
<400> 15
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 Ala 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 Ala Ala Glu Gly Ala Asn Cys Tyr Phe Pro Leu Ala Ala
165 170 175
Tyr Gly Phe Gln Pro Thr Ala 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
210 215
<210> 16
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> RBDm(L137A, F168A)
<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 Ala 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 Ala 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
210 215
<210> 17
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> RBDm(L137A)
<400> 17
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 Ala 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
210 215
<210> 18
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> RBDm(F168A)
<400> 18
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 Ala 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
210 215
<210> 19
<211> 219
<212> PRT
<213> Artificial Sequence
<220>
<223> RBDm(G184D)
<400> 19
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 Asp 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
210 215
<210> 20
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Wild type RBD_DNA sequence
<400> 20
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 gaacaag 657
<210> 21
<211> 693
<212> DNA
<213> Artificial Sequence
<220>
<223> IgG1 Fc domain-DNA sequence
<400> 21
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> 22
<211> 1260
<212> DNA
<213> Artificial Sequence
<220>
<223> N protein_full DNA sequence
<400> 22
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> 23
<211> 468
<212> DNA
<213> Artificial Sequence
<220>
<223> N protein_RNA binding domain_DNA sequence
<400> 23
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> 24
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> M protein_DNA sequence
<400> 24
cggctgttcg cccggaccag atctatgtgg tctttcaacc ccgagacaaa catcctgctg 60
aacgtgccac tgcacggcac catcctgacc agacctctgc tggaatccga gctggtcatc 120
ggcgctgtga tcctgagagg ccacctgaga atcgctggcc accatctggg cagatgcgac 180
atcaaggacc tgcctaaaga gatcaccgtc gccacctctc ggaccctgag ctactataag 240
ctgggcgcct ctcagagagt ggctggcgat tctggctttg ccgcctactc cagataccgg 300
atcggcaact acaagctgaa caccgaccac tcctccagct ccgacaatat cgctctgctg 360
gtgcag 366
<210> 25
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker1_DNA sequence
<400> 25
ggcggcggag gatccggcgg tggtggttcc ggcggaggcg gttct 45
<210> 26
<211> 60
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker2_DNA sequence
<400> 26
ggtggcggcg gttcaggcgg cggtggaagt ggcggtggcg gatctggcgg aggtggtagt 60
60
<210> 27
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker3_DNA sequence
<400> 27
ggcggaggcg gatctggtgg cggaggatct 30
<210> 28
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker4_DNA sequence
<400> 28
ggtggcagtg gtggctctgg cggatct 27
<210> 29
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker5_DNA sequence
<400> 29
ggcggatccg gaggatcagg tggaagcgga ggttca 36
<210> 30
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Linker6_DNA sequence
<400> 30
ggtggtagtg gcggaagcgg cggctcc 27
<210> 31
<211> 54
<212> DNA
<213> Artificial Sequence
<220>
<223> Signal peptide_DNA sequence
<400> 31
atgaaatggg tcacctttat ctccctgctg ttcctgttct cctccgccta ctct 54
<210> 32
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> RBDm(Q175A, N183A)_DNA sequece
<400> 32
agagtgcagc ctaccgagtc tatcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactccg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcagaggcga cgaagtgcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca actacaagct gcccgacgac ttcaccggct gtgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaattacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgtaatg gcgtggaagg cttcaactgc tacttccctc tggcctccta cggcttccaa 540
cctacagctg gcgtgggcta ccagccttac agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctaccgtgtg cggccctaag aaatctacca acctggtcaa gaacaag 657
<210> 33
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> RBDm(G164A, V165A, Q175A, S176A, N183A)_DNA sequece
<400> 33
agagtgcagc ctaccgagtc tatcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactccg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcagaggcga cgaagtgcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca actacaagct gcccgacgac ttcaccggct gtgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaattacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgtaatg ccgccgaggg cttcaactgc tactttcctc tggccgccta cggcttccaa 540
cctacagctg gcgttggcta ccagccttac agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctaccgtgtg cggccctaag aaatctacca acctggtcaa gaacaag 657
<210> 34
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> RBDm(L137A, G164A, V165A, F168A, Q175A, S176A, N183A)_DNA sequece
<400> 34
agagtgcagc ctaccgagtc tatcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactccg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcagaggcga cgaagtgcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca actacaagct gcccgacgac ttcaccggct gtgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaattacc tgtaccgggc cttccgcaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgtaatg ctgccgaagg cgccaactgc tactttcctc tggccgccta tggcttccag 540
cctacagctg gcgttggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctaccgtgtg cggccctaag aaatctacca acctggtcaa gaacaaa 657
<210> 35
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> RBDm(L137A, F168A)_DNA sequece
<400> 35
agagtgcagc 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 tgtaccgggc cttcagaaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgttgaagg cgccaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctacagtgtg cggccccaag aaatctacca acctggtcaa gaacaag 657
<210> 36
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> RBDm(L137A)_DNA sequece
<400> 36
agagtgcagc 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 tgtaccgggc cttcagaaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgttgaagg cttcaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctacagtgtg cggccccaag aaatctacca acctggtcaa gaacaag 657
<210> 37
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> RBDm(F168A)_DNA sequece
<400> 37
agagtgcagc 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 gttcagaaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgttgaagg cgccaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctacagtgtg cggccccaag aaatctacca acctggtcaa gaacaag 657
<210> 38
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> RBDm(G184D)_DNA sequence
<400> 38
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 acgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctaccgtgtg cggccctaag aaatctacca acctggtcaa gaacaag 657
<210> 39
<211> 246
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_IgG1 Fc
<400> 39
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> 40
<211> 465
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_RBDwt-Fc
<400> 40
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> 41
<211> 485
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_Fc-RBDwt
<400> 41
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> 42
<211> 402
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_N-Fc
<400> 42
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> 43
<211> 465
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_RBDm(Q175A, N183A)-Fc
<400> 43
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 Ala Ser
165 170 175
Tyr Gly Phe Gln Pro Thr Ala 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> 44
<211> 465
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_RBDm(G164A, V165A, Q175A, S176A, N183A)-Fc
<400> 44
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 Ala Ala Glu Gly Phe Asn Cys Tyr Phe Pro Leu Ala Ala
165 170 175
Tyr Gly Phe Gln Pro Thr Ala 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> 45
<211> 485
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_Fc-RBDm(L137A, F168A)
<400> 45
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 Ala 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 Ala 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> 46
<211> 485
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_Fc-RBDm(L137A, G164A, V165A, F168A, Q175A, S176A,
N183A)
<400> 46
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 Ala 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 Ala Ala Glu
420 425 430
Gly Ala Asn Cys Tyr Phe Pro Leu Ala Ala Tyr Gly Phe Gln Pro Thr
435 440 445
Ala 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> 47
<211> 465
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_RBDm(L137A, F168A)-Fc
<400> 47
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 Ala 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 Ala 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> 48
<211> 465
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_RBDm(L137A, G164A, V165A, F168A, Q175A, S176A,
N183A)-Fc
<400> 48
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 Ala 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 Ala Ala Glu Gly Ala Asn Cys Tyr Phe Pro Leu Ala Ala
165 170 175
Tyr Gly Phe Gln Pro Thr Ala 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> 49
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114
<400> 49
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> 50
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114m(L137A, F168A)
<400> 50
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 Ala 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 Ala 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> 51
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114m(L137A)
<400> 51
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 Ala 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> 52
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114m(F168A)
<400> 52
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 Ala 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> 53
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114m(G184D)
<400> 53
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 Asp 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> 54
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114m(L137A, G164A, V165A, F168A, Q175A,
S176A, N183A)
<400> 54
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 Ala 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 Ala Ala Glu Gly Ala Asn Cys
580 585 590
Tyr Phe Pro Leu Ala Ala Tyr Gly Phe Gln Pro Thr Ala 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> 55
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114N
<400> 55
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> 56
<211> 641
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114Nm(L137A, F168A)
<400> 56
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 Ala 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 Ala 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> 57
<211> 773
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1132m(L137A, F168A)
<400> 57
Arg Leu Phe Ala Arg Thr Arg Ser Met Trp Ser Phe Asn Pro Glu Thr
1 5 10 15
Asn Ile Leu Leu Asn Val Pro Leu His Gly Thr Ile Leu Thr Arg Pro
20 25 30
Leu Leu Glu Ser Glu Leu Val Ile Gly Ala Val Ile Leu Arg Gly His
35 40 45
Leu Arg Ile Ala Gly His His Leu Gly Arg Cys Asp Ile Lys Asp Leu
50 55 60
Pro Lys Glu Ile Thr Val Ala Thr Ser Arg Thr Leu Ser Tyr Tyr Lys
65 70 75 80
Leu Gly Ala Ser Gln Arg Val Ala Gly Asp Ser Gly Phe Ala Ala Tyr
85 90 95
Ser Arg Tyr Arg Ile Gly Asn Tyr Lys Leu Asn Thr Asp His Ser Ser
100 105 110
Ser Ser Asp Asn Ile Ala Leu Leu Val Gln Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn
130 135 140
Asn Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp
145 150 155 160
Leu Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser
165 170 175
Pro Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg
180 185 190
Gly Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr
195 200 205
Tyr Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys
210 215 220
Asp Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys
225 230 235 240
Asp His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu
245 250 255
Gln Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly
260 265 270
Ser Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg
275 280 285
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
290 295 300
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
305 310 315 320
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
325 330 335
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
340 345 350
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
355 360 365
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
370 375 380
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
385 390 395 400
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
405 410 415
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
420 425 430
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
435 440 445
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
450 455 460
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
465 470 475 480
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
485 490 495
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
500 505 510
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
515 520 525
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
530 535 540
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Gln Pro Thr Glu
545 550 555 560
Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
565 570 575
Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
580 585 590
Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
595 600 605
Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
610 615 620
Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
625 630 635 640
Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
645 650 655
Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
660 665 670
Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
675 680 685
Tyr Arg Ala Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
690 695 700
Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
705 710 715 720
Gly Ala Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
725 730 735
Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
740 745 750
Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn
755 760 765
Leu Val Lys Asn Lys
770
<210> 58
<211> 773
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1114Nm(L137A, F168A)
<400> 58
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 Arg Leu Phe Ala Arg Thr Arg Ser Met Trp
165 170 175
Ser Phe Asn Pro Glu Thr Asn Ile Leu Leu Asn Val Pro Leu His Gly
180 185 190
Thr Ile Leu Thr Arg Pro Leu Leu Glu Ser Glu Leu Val Ile Gly Ala
195 200 205
Val Ile Leu Arg Gly His Leu Arg Ile Ala Gly His His Leu Gly Arg
210 215 220
Cys Asp Ile Lys Asp Leu Pro Lys Glu Ile Thr Val Ala Thr Ser Arg
225 230 235 240
Thr Leu Ser Tyr Tyr Lys Leu Gly Ala Ser Gln Arg Val Ala Gly Asp
245 250 255
Ser Gly Phe Ala Ala Tyr Ser Arg Tyr Arg Ile Gly Asn Tyr Lys Leu
260 265 270
Asn Thr Asp His Ser Ser Ser Ser Asp Asn Ile Ala Leu Leu Val Gln
275 280 285
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
290 295 300
Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
305 310 315 320
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
325 330 335
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
340 345 350
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
355 360 365
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
370 375 380
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
385 390 395 400
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
405 410 415
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
420 425 430
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
435 440 445
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
450 455 460
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
465 470 475 480
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
485 490 495
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
500 505 510
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
515 520 525
Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
530 535 540
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Gln Pro Thr Glu
545 550 555 560
Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu
565 570 575
Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys
580 585 590
Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala
595 600 605
Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn
610 615 620
Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly
625 630 635 640
Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp
645 650 655
Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp
660 665 670
Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu
675 680 685
Tyr Arg Ala Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile
690 695 700
Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu
705 710 715 720
Gly Ala Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr
725 730 735
Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu
740 745 750
Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr Asn
755 760 765
Leu Val Lys Asn Lys
770
<210> 59
<211> 780
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1151
<400> 59
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 Ser Gly Gly
210 215 220
Ser Gly Gly Ser Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn
225 230 235 240
Asn Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp
245 250 255
Leu Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser
260 265 270
Pro Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg
275 280 285
Gly Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr
290 295 300
Tyr Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys
305 310 315 320
Asp Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys
325 330 335
Asp His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu
340 345 350
Gln Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly
355 360 365
Ser Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg
370 375 380
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Arg Ser Lys Gln
385 390 395 400
Arg Arg Pro Gln Gly Leu Pro Asn Asn Thr Ala Ser Trp Phe Thr Ala
405 410 415
Leu Thr Gln His Gly Lys Glu Asp Leu Lys Phe Pro Arg Gly Gln Gly
420 425 430
Val Pro Ile Asn Thr Asn Ser Ser Pro Asp Asp Gln Ile Gly Tyr Tyr
435 440 445
Arg Arg Ala Thr Arg Arg Ile Arg Gly Gly Asp Gly Lys Met Lys Asp
450 455 460
Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr Leu Gly Thr Gly Pro Glu Ala
465 470 475 480
Gly Leu Pro Tyr Gly Ala Asn Lys Asp Gly Ile Ile Trp Val Ala Thr
485 490 495
Glu Gly Ala Leu Asn Thr Pro Lys Asp His Ile Gly Thr Arg Asn Pro
500 505 510
Ala Asn Asn Ala Ala Ile Val Leu Gln Leu Pro Gln Gly Thr Thr Leu
515 520 525
Pro Lys Gly Phe Tyr Ala Glu Gly Ser Arg Gly Gly Ser Gln Ala Ser
530 535 540
Ser Arg Ser Ser Ser Arg Ser Arg Gly Gly Ser Gly Gly Ser Gly Gly
545 550 555 560
Ser Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr
565 570 575
Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser
580 585 590
Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr
595 600 605
Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly
610 615 620
Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala
625 630 635 640
Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly
645 650 655
Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe
660 665 670
Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val
675 680 685
Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu
690 695 700
Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser
705 710 715 720
Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln
725 730 735
Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg
740 745 750
Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys
755 760 765
Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys
770 775 780
<210> 60
<211> 780
<212> PRT
<213> Artificial Sequence
<220>
<223> Fusion protein_GIC-1151m(L137A, F168A)
<400> 60
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 Ala 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 Ala 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 Ser Gly Gly
210 215 220
Ser Gly Gly Ser Arg Ser Lys Gln Arg Arg Pro Gln Gly Leu Pro Asn
225 230 235 240
Asn Thr Ala Ser Trp Phe Thr Ala Leu Thr Gln His Gly Lys Glu Asp
245 250 255
Leu Lys Phe Pro Arg Gly Gln Gly Val Pro Ile Asn Thr Asn Ser Ser
260 265 270
Pro Asp Asp Gln Ile Gly Tyr Tyr Arg Arg Ala Thr Arg Arg Ile Arg
275 280 285
Gly Gly Asp Gly Lys Met Lys Asp Leu Ser Pro Arg Trp Tyr Phe Tyr
290 295 300
Tyr Leu Gly Thr Gly Pro Glu Ala Gly Leu Pro Tyr Gly Ala Asn Lys
305 310 315 320
Asp Gly Ile Ile Trp Val Ala Thr Glu Gly Ala Leu Asn Thr Pro Lys
325 330 335
Asp His Ile Gly Thr Arg Asn Pro Ala Asn Asn Ala Ala Ile Val Leu
340 345 350
Gln Leu Pro Gln Gly Thr Thr Leu Pro Lys Gly Phe Tyr Ala Glu Gly
355 360 365
Ser Arg Gly Gly Ser Gln Ala Ser Ser Arg Ser Ser Ser Arg Ser Arg
370 375 380
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Arg Ser Lys Gln
385 390 395 400
Arg Arg Pro Gln Gly Leu Pro Asn Asn Thr Ala Ser Trp Phe Thr Ala
405 410 415
Leu Thr Gln His Gly Lys Glu Asp Leu Lys Phe Pro Arg Gly Gln Gly
420 425 430
Val Pro Ile Asn Thr Asn Ser Ser Pro Asp Asp Gln Ile Gly Tyr Tyr
435 440 445
Arg Arg Ala Thr Arg Arg Ile Arg Gly Gly Asp Gly Lys Met Lys Asp
450 455 460
Leu Ser Pro Arg Trp Tyr Phe Tyr Tyr Leu Gly Thr Gly Pro Glu Ala
465 470 475 480
Gly Leu Pro Tyr Gly Ala Asn Lys Asp Gly Ile Ile Trp Val Ala Thr
485 490 495
Glu Gly Ala Leu Asn Thr Pro Lys Asp His Ile Gly Thr Arg Asn Pro
500 505 510
Ala Asn Asn Ala Ala Ile Val Leu Gln Leu Pro Gln Gly Thr Thr Leu
515 520 525
Pro Lys Gly Phe Tyr Ala Glu Gly Ser Arg Gly Gly Ser Gln Ala Ser
530 535 540
Ser Arg Ser Ser Ser Arg Ser Arg Gly Gly Ser Gly Gly Ser Gly Gly
545 550 555 560
Ser Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr
565 570 575
Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser
580 585 590
Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr
595 600 605
Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly
610 615 620
Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala
625 630 635 640
Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly
645 650 655
Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe
660 665 670
Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val
675 680 685
Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Ala Phe Arg Lys Ser Asn Leu
690 695 700
Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser
705 710 715 720
Thr Pro Cys Asn Gly Val Glu Gly Ala Asn Cys Tyr Phe Pro Leu Gln
725 730 735
Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg
740 745 750
Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys
755 760 765
Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys
770 775 780
<210> 61
<211> 738
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_IgG1 Fc
<400> 61
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> 62
<211> 1395
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_RBDwt-Fc
<400> 62
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> 63
<211> 1455
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_Fc-RBDwt
<400> 63
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> 64
<211> 1206
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_N-Fc
<400> 64
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> 65
<211> 1395
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_RBDm(Q175A, N183A)-Fc
<400> 65
agagtgcagc ctaccgagtc tatcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactccg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcagaggcga cgaagtgcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca actacaagct gcccgacgac ttcaccggct gtgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaattacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgtaatg gcgtggaagg cttcaactgc tacttccctc tggcctccta cggcttccaa 540
cctacagctg gcgtgggcta ccagccttac 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> 66
<211> 1395
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_RBDm(G164A, V165A, Q175A, S176A,
N183A)-Fc
<400> 66
agagtgcagc ctaccgagtc tatcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactccg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcagaggcga cgaagtgcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca actacaagct gcccgacgac ttcaccggct gtgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaattacc tgtaccggct gttccggaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgtaatg ccgccgaggg cttcaactgc tactttcctc tggccgccta cggcttccaa 540
cctacagctg gcgttggcta ccagccttac 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> 67
<211> 1455
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_Fc-RBDm(L137A, F168A)
<400> 67
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 agtgcagcct 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
taccgggcct tcagaaagtc caacctgaag cctttcgagc gggacatctc caccgagatc 1260
taccaggctg gcagcacccc ttgcaatggc gttgaaggcg ccaactgcta cttcccactg 1320
cagtcctacg gcttccagcc taccaatggc gtgggctacc agccttatag agtggtggtg 1380
ctgtccttcg agctgctgca tgctcctgct acagtgtgcg gccccaagaa atctaccaac 1440
ctggtcaaga acaag 1455
<210> 68
<211> 1455
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_Fc-RBDm(L137A, G164A, V165A, F168A,
Q175A, S176A, N183A)
<400> 68
ggcggcggag gatccggcgg tggtggttcc ggcggaggcg gttctgaacc taagtcctcc 60
gacaagaccc acacctgtcc tccatgtcct gctccagaac tgctcggcgg accttccgtg 120
tttctgttcc ctccaaagcc taaggacacc ctgatgatct ctcggacccc tgaagtgacc 180
tgcgtggtgg tcgatgtgtc tcacgaggac ccagaagtga agttcaattg gtacgtggac 240
ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagtacaa ctccacctac 300
agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaatggcaa agagtacaag 360
tgcaaggtgt ccaacaaggc cctgcctgct cctatcgaaa agaccatctc caaggccaag 420
ggccagccta gggaacccca ggtttacacc ttgcctccat ctcgggacga gctgaccaag 480
aaccaggtgt ccctgacctg tctggtcaag ggcttctacc cctccgatat cgccgtggaa 540
tgggagtcta atggccagcc tgagaacaac tacaagacaa cccctcctgt gctggactcc 600
gacggctcat tcttcctgta ctccaagctg acagtggaca agtccagatg gcagcagggc 660
aacgtgttct cctgctccgt gatgcacgag gccctgcaca atcactacac acagaagtcc 720
ctgtctctgt cccctggtgg tggcggcggt tcaggcggcg gtggaagtgg cggtggcgga 780
tctggcggag gtggtagtag agtgcagcct accgagtcta tcgtgcggtt ccccaacatc 840
accaacctgt gtcctttcgg cgaggtgttc aacgccacca gattcgcctc tgtgtacgcc 900
tggaaccgga agcggatctc taactgcgtg gccgactact ccgtgctgta caactccgcc 960
tccttcagca ccttcaagtg ctacggcgtg tcccctacca agctgaacga cctgtgcttc 1020
accaacgtgt acgccgactc cttcgtgatc agaggcgacg aagtgcggca gatcgctcct 1080
ggacagaccg gcaagatcgc cgactacaac tacaagctgc ccgacgactt caccggctgt 1140
gtgatcgctt ggaactccaa caacctggac tccaaagtcg gcggcaacta caattacctg 1200
taccgggcct tccgcaagtc caacctgaag cctttcgagc gggacatctc caccgagatc 1260
taccaggctg gcagcacccc ttgtaatgct gccgaaggcg ccaactgcta ctttcctctg 1320
gccgcctatg gcttccagcc tacagctggc gttggctacc agccttatag agtggtggtg 1380
ctgtccttcg agctgctgca tgctcctgct accgtgtgcg gccctaagaa atctaccaac 1440
ctggtcaaga acaaa 1455
<210> 69
<211> 1395
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_RBDm(L137A, F168A)-Fc
<400> 69
agagtgcagc 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 tgtaccgggc cttcagaaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgttgaagg cgccaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctacagtgtg cggccccaag 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> 70
<211> 1395
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_RBDm(L137A, G164A, V165A, F168A,
Q175A, S176A, N183A)-Fc
<400> 70
agagtgcagc ctaccgagtc tatcgtgcgg ttccccaaca tcaccaacct gtgtcctttc 60
ggcgaggtgt tcaacgccac cagattcgcc tctgtgtacg cctggaaccg gaagcggatc 120
tctaactgcg tggccgacta ctccgtgctg tacaactccg cctccttcag caccttcaag 180
tgctacggcg tgtcccctac caagctgaac gacctgtgct tcaccaacgt gtacgccgac 240
tccttcgtga tcagaggcga cgaagtgcgg cagatcgctc ctggacagac cggcaagatc 300
gccgactaca actacaagct gcccgacgac ttcaccggct gtgtgatcgc ttggaactcc 360
aacaacctgg actccaaagt cggcggcaac tacaattacc tgtaccgggc cttccgcaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgtaatg ctgccgaagg cgccaactgc tactttcctc tggccgccta tggcttccag 540
cctacagctg gcgttggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctaccgtgtg cggccctaag aaatctacca acctggtcaa gaacaaaggc 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> 71
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114
<400> 71
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> 72
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114m(L137A, F168A)
<400> 72
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 tctgttccct 600
ccaaagccta aggacaccct gatgatctct cggacccctg aagtgacctg cgtggtggtc 660
gatgtgtctc acgaggaccc agaagtgaag ttcaattggt acgtggacgg cgtggaagtg 720
cacaacgcca agaccaagcc tagagaggaa cagtacaact ccacctacag agtggtgtcc 780
gtgctgaccg tgctgcacca ggattggctg aatggcaaag agtacaagtg caaggtgtcc 840
aacaaggccc tgcctgctcc tatcgaaaag accatctcca aggccaaggg ccagcctagg 900
gaaccccagg tttacacctt gcctccatct cgggacgagc tgaccaagaa ccaggtgtcc 960
ctgacctgtc tggtcaaggg cttctacccc tccgatatcg ccgtggaatg ggagtctaat 1020
ggccagcctg agaacaacta caagacaacc cctcctgtgc tggactccga cggctcattc 1080
ttcctgtact ccaagctgac agtggacaag tccagatggc agcagggcaa cgtgttctcc 1140
tgctccgtga tgcacgaggc cctgcacaat cactacacac agaagtccct gtctctgtcc 1200
cctggtggtg gcggcggttc aggcggcggt ggaagtggcg gtggcggatc tggcggaggt 1260
ggtagtagag tgcagcctac 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 ccgggccttc 1680
agaaagtcca acctgaagcc tttcgagcgg gacatctcca ccgagatcta ccaggctggc 1740
agcacccctt gcaatggcgt tgaaggcgcc aactgctact tcccactgca gtcctacggc 1800
ttccagccta ccaatggcgt gggctaccag ccttatagag tggtggtgct gtccttcgag 1860
ctgctgcatg ctcctgctac agtgtgcggc cccaagaaat ctaccaacct ggtcaagaac 1920
aag 1923
<210> 73
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114m(L137A)
<400> 73
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 tctgttccct 600
ccaaagccta aggacaccct gatgatctct cggacccctg aagtgacctg cgtggtggtc 660
gatgtgtctc acgaggaccc agaagtgaag ttcaattggt acgtggacgg cgtggaagtg 720
cacaacgcca agaccaagcc tagagaggaa cagtacaact ccacctacag agtggtgtcc 780
gtgctgaccg tgctgcacca ggattggctg aatggcaaag agtacaagtg caaggtgtcc 840
aacaaggccc tgcctgctcc tatcgaaaag accatctcca aggccaaggg ccagcctagg 900
gaaccccagg tttacacctt gcctccatct cgggacgagc tgaccaagaa ccaggtgtcc 960
ctgacctgtc tggtcaaggg cttctacccc tccgatatcg ccgtggaatg ggagtctaat 1020
ggccagcctg agaacaacta caagacaacc cctcctgtgc tggactccga cggctcattc 1080
ttcctgtact ccaagctgac agtggacaag tccagatggc agcagggcaa cgtgttctcc 1140
tgctccgtga tgcacgaggc cctgcacaat cactacacac agaagtccct gtctctgtcc 1200
cctggtggtg gcggcggttc aggcggcggt ggaagtggcg gtggcggatc tggcggaggt 1260
ggtagtagag tgcagcctac 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 ccgggccttc 1680
agaaagtcca acctgaagcc tttcgagcgg gacatctcca ccgagatcta ccaggctggc 1740
agcacccctt gcaatggcgt tgaaggcttc aactgctact tcccactgca gtcctacggc 1800
ttccagccta ccaatggcgt gggctaccag ccttatagag tggtggtgct gtccttcgag 1860
ctgctgcatg ctcctgctac agtgtgcggc cccaagaaat ctaccaacct ggtcaagaac 1920
aag 1923
<210> 74
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114m(F168A)
<400> 74
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 tctgttccct 600
ccaaagccta aggacaccct gatgatctct cggacccctg aagtgacctg cgtggtggtc 660
gatgtgtctc acgaggaccc agaagtgaag ttcaattggt acgtggacgg cgtggaagtg 720
cacaacgcca agaccaagcc tagagaggaa cagtacaact ccacctacag agtggtgtcc 780
gtgctgaccg tgctgcacca ggattggctg aatggcaaag agtacaagtg caaggtgtcc 840
aacaaggccc tgcctgctcc tatcgaaaag accatctcca aggccaaggg ccagcctagg 900
gaaccccagg tttacacctt gcctccatct cgggacgagc tgaccaagaa ccaggtgtcc 960
ctgacctgtc tggtcaaggg cttctacccc tccgatatcg ccgtggaatg ggagtctaat 1020
ggccagcctg agaacaacta caagacaacc cctcctgtgc tggactccga cggctcattc 1080
ttcctgtact ccaagctgac agtggacaag tccagatggc agcagggcaa cgtgttctcc 1140
tgctccgtga tgcacgaggc cctgcacaat cactacacac agaagtccct gtctctgtcc 1200
cctggtggtg gcggcggttc aggcggcggt ggaagtggcg gtggcggatc tggcggaggt 1260
ggtagtagag tgcagcctac 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
agaaagtcca acctgaagcc tttcgagcgg gacatctcca ccgagatcta ccaggctggc 1740
agcacccctt gcaatggcgt tgaaggcgcc aactgctact tcccactgca gtcctacggc 1800
ttccagccta ccaatggcgt gggctaccag ccttatagag tggtggtgct gtccttcgag 1860
ctgctgcatg ctcctgctac agtgtgcggc cccaagaaat ctaccaacct ggtcaagaac 1920
aag 1923
<210> 75
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114m(G184D)
<400> 75
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 tctgttccct 600
ccaaagccta aggacaccct gatgatctct cggacccctg aagtgacctg cgtggtggtc 660
gatgtgtctc acgaggaccc agaagtgaag ttcaattggt acgtggacgg cgtggaagtg 720
cacaacgcca agaccaagcc tagagaggaa cagtacaact ccacctacag agtggtgtcc 780
gtgctgaccg tgctgcacca ggattggctg aatggcaaag agtacaagtg caaggtgtcc 840
aacaaggccc tgcctgctcc tatcgaaaag accatctcca aggccaaggg ccagcctagg 900
gaaccccagg tttacacctt gcctccatct cgggacgagc tgaccaagaa ccaggtgtcc 960
ctgacctgtc tggtcaaggg cttctacccc tccgatatcg ccgtggaatg ggagtctaat 1020
ggccagcctg agaacaacta caagacaacc cctcctgtgc tggactccga cggctcattc 1080
ttcctgtact ccaagctgac agtggacaag tccagatggc agcagggcaa cgtgttctcc 1140
tgctccgtga tgcacgaggc cctgcacaat cactacacac agaagtccct gtctctgtcc 1200
cctggtggtg gcggcggttc aggcggcggt ggaagtggcg gtggcggatc tggcggaggt 1260
ggtagtagag 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 ccaatgacgt gggctaccag ccttatagag tggtggtgct gtccttcgag 1860
ctgctgcatg ctcctgctac cgtgtgcggc cctaagaaat ctaccaacct ggtcaagaac 1920
aag 1923
<210> 76
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114m(L137A, G164A, V165A, F168A,
Q175A, S176A, N183A)
<400> 76
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 tctgttccct 600
ccaaagccta aggacaccct gatgatctct cggacccctg aagtgacctg cgtggtggtc 660
gatgtgtctc acgaggaccc agaagtgaag ttcaattggt acgtggacgg cgtggaagtg 720
cacaacgcca agaccaagcc tagagaggaa cagtacaact ccacctacag agtggtgtcc 780
gtgctgaccg tgctgcacca ggattggctg aatggcaaag agtacaagtg caaggtgtcc 840
aacaaggccc tgcctgctcc tatcgaaaag accatctcca aggccaaggg ccagcctagg 900
gaaccccagg tttacacctt gcctccatct cgggacgagc tgaccaagaa ccaggtgtcc 960
ctgacctgtc tggtcaaggg cttctacccc tccgatatcg ccgtggaatg ggagtctaat 1020
ggccagcctg agaacaacta caagacaacc cctcctgtgc tggactccga cggctcattc 1080
ttcctgtact ccaagctgac agtggacaag tccagatggc agcagggcaa cgtgttctcc 1140
tgctccgtga tgcacgaggc cctgcacaat cactacacac agaagtccct gtctctgtcc 1200
cctggtggtg gcggcggttc aggcggcggt ggaagtggcg gtggcggatc tggcggaggt 1260
ggtagtagag tgcagcctac cgagtctatc gtgcggttcc ccaacatcac caacctgtgt 1320
cctttcggcg aggtgttcaa cgccaccaga ttcgcctctg tgtacgcctg gaaccggaag 1380
cggatctcta actgcgtggc cgactactcc gtgctgtaca actccgcctc cttcagcacc 1440
ttcaagtgct acggcgtgtc ccctaccaag ctgaacgacc tgtgcttcac caacgtgtac 1500
gccgactcct tcgtgatcag aggcgacgaa gtgcggcaga tcgctcctgg acagaccggc 1560
aagatcgccg actacaacta caagctgccc gacgacttca ccggctgtgt gatcgcttgg 1620
aactccaaca acctggactc caaagtcggc ggcaactaca attacctgta ccgggccttc 1680
cgcaagtcca acctgaagcc tttcgagcgg gacatctcca ccgagatcta ccaggctggc 1740
agcacccctt gtaatgctgc cgaaggcgcc aactgctact ttcctctggc cgcctatggc 1800
ttccagccta cagctggcgt tggctaccag ccttatagag tggtggtgct gtccttcgag 1860
ctgctgcatg ctcctgctac cgtgtgcggc cctaagaaat ctaccaacct ggtcaagaac 1920
aaa 1923
<210> 77
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114N
<400> 77
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
<210> 78
<211> 1923
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1114Nm(L137A, F168A)
<400> 78
agagtgcagc 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 tgtaccgggc cttcagaaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgttgaagg cgccaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctacagtgtg cggccccaag aaatctacca acctggtcaa gaacaagggc 660
ggcggaggat ccggtggtgg tggatctggt ggcggaggct ctgaacctaa gtcctccgac 720
aagacccaca cctgtcctcc atgtcctgct ccagaactgc tcggcggacc ttccgtgttt 780
ctgttccctc caaagcctaa ggacaccctg atgatctctc ggacccctga agtgacctgc 840
gtggtggtcg atgtgtctca cgaggaccca gaagtgaagt tcaattggta cgtggacggc 900
gtggaagtgc acaacgccaa gaccaagcct agagaggaac agtacaactc cacctacaga 960
gtggtgtccg tgctgaccgt gctgcaccag gattggctga atggcaaaga gtacaagtgc 1020
aaggtgtcca acaaggccct gcctgctcct atcgaaaaga ccatctccaa ggccaagggc 1080
cagcctaggg aaccccaggt ttacaccttg cctccatctc gggacgagct gaccaagaac 1140
caggtgtccc tgacctgtct ggtcaagggc ttctacccct ccgatatcgc cgtggaatgg 1200
gagtctaatg gccagcctga gaacaactac aagacaaccc ctcctgtgct ggactccgac 1260
ggctcattct tcctgtactc caagctgaca gtggacaagt ccagatggca gcagggcaac 1320
gtgttctcct gctccgtgat gcacgaggcc ctgcacaatc actacacaca gaagtccctg 1380
tctctgtccc ctggtggtgg cggcggttca ggcggcggtg gaagtggcgg tggcggatct 1440
ggcggaggtg gtagtcggtc 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
<210> 79
<211> 2319
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1132m(L137A, F168A)
<400> 79
cggctgttcg cccggaccag atctatgtgg tctttcaacc ccgagacaaa catcctgctg 60
aacgtgccac tgcacggcac catcctgacc agacctctgc tggaatccga gctggtcatc 120
ggcgctgtga tcctgagagg ccacctgaga atcgctggcc accatctggg cagatgcgac 180
atcaaggacc tgcctaaaga gatcaccgtc gccacctctc ggaccctgag ctactataag 240
ctgggcgcct ctcagagagt ggctggcgat tctggctttg ccgcctactc cagataccgg 300
atcggcaact acaagctgaa caccgaccac tcctccagct ccgacaatat cgctctgctg 360
gtgcagggcg gaggcggatc tggtggcgga ggatctcggt ctaagcagag aaggcctcag 420
ggcctgccta acaataccgc ctcctggttt accgctctga cccagcacgg caaagaggac 480
ctgaagttcc ctagaggaca gggcgtgccc atcaacacca actctagccc tgacgaccag 540
atcggctact acagacgggc caccagaaga atcagaggcg gcgacggcaa gatgaaggac 600
ctgtctcctc ggtggtactt ctactacctc ggcaccggac cagaggctgg attgccttat 660
ggcgccaaca aggacggcat catctgggtt gcaacagagg gcgctctgaa cacccctaag 720
gaccacatcg gcacccggaa tcctgccaac aatgctgcca ttgtgctgca gctgccacag 780
ggcacaacac tgcctaaggg cttttacgcc gagggctcta gaggcggctc tcaggcctct 840
tccagatcct ccagtagatc acgtggcggc ggaggatccg gtggtggtgg atctggtggc 900
ggaggctctg aacctaagtc ctccgacaag acccacacct gtcctccatg tcctgctcca 960
gaactgctcg gcggaccttc cgtgtttctg ttccctccaa agcctaagga caccctgatg 1020
atctctcgga cccctgaagt gacctgcgtg gtggtcgatg tgtctcacga ggacccagaa 1080
gtgaagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcctaga 1140
gaggaacagt acaactccac ctacagagtg gtgtccgtgc tgaccgtgct gcaccaggat 1200
tggctgaatg gcaaagagta caagtgcaag gtgtccaaca aggccctgcc tgctcctatc 1260
gaaaagacca tctccaaggc caagggccag cctagggaac cccaggttta caccttgcct 1320
ccatctcggg acgagctgac caagaaccag gtgtccctga cctgtctggt caagggcttc 1380
tacccctccg atatcgccgt ggaatgggag tctaatggcc agcctgagaa caactacaag 1440
acaacccctc ctgtgctgga ctccgacggc tcattcttcc tgtactccaa gctgacagtg 1500
gacaagtcca gatggcagca gggcaacgtg ttctcctgct ccgtgatgca cgaggccctg 1560
cacaatcact acacacagaa gtccctgtct ctgtcccctg gtggtggcgg cggttcaggc 1620
ggcggtggaa gtggcggtgg cggatctggc ggaggtggta gtagagtgca gcctaccgag 1680
tccatcgtgc ggttccccaa catcaccaac ctgtgtcctt tcggcgaggt gttcaacgct 1740
accagattcg cctctgtgta cgcctggaac cggaagcgga tctctaactg cgtggccgac 1800
tactccgtgc tgtacaactc tgcctccttc agcaccttca agtgctacgg cgtgtcccct 1860
accaagctga acgacctgtg cttcaccaac gtgtacgccg actccttcgt gatcaggggc 1920
gacgaagttc ggcagatcgc tcctggacag accggcaaga tcgccgacta caattacaag 1980
ctgcccgacg acttcaccgg ctgcgtgatc gcttggaact ccaacaacct ggactccaaa 2040
gtcggcggca actacaacta cctgtaccgg gccttcagaa agtccaacct gaagcctttc 2100
gagcgggaca tctccaccga gatctaccag gctggcagca ccccttgcaa tggcgttgaa 2160
ggcgccaact gctacttccc actgcagtcc tacggcttcc agcctaccaa tggcgtgggc 2220
taccagcctt atagagtggt ggtgctgtcc ttcgagctgc tgcatgctcc tgctacagtg 2280
tgcggcccca agaaatctac caacctggtc aagaacaag 2319
<210> 80
<211> 2319
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1133m(L137A, F168A)
<400> 80
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 cggaggcgga 480
tctggtggcg gaggatctcg gctgttcgcc cggaccagat ctatgtggtc tttcaacccc 540
gagacaaaca tcctgctgaa cgtgccactg cacggcacca tcctgaccag acctctgctg 600
gaatccgagc tggtcatcgg cgctgtgatc ctgagaggcc acctgagaat cgctggccac 660
catctgggca gatgcgacat caaggacctg cctaaagaga tcaccgtcgc cacctctcgg 720
accctgagct actataagct gggcgcctct cagagagtgg ctggcgattc tggctttgcc 780
gcctactcca gataccggat cggcaactac aagctgaaca ccgaccactc ctccagctcc 840
gacaatatcg ctctgctggt gcagggcggc ggaggatccg gtggtggtgg atctggtggc 900
ggaggctctg aacctaagtc ctccgacaag acccacacct gtcctccatg tcctgctcca 960
gaactgctcg gcggaccttc cgtgtttctg ttccctccaa agcctaagga caccctgatg 1020
atctctcgga cccctgaagt gacctgcgtg gtggtcgatg tgtctcacga ggacccagaa 1080
gtgaagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcctaga 1140
gaggaacagt acaactccac ctacagagtg gtgtccgtgc tgaccgtgct gcaccaggat 1200
tggctgaatg gcaaagagta caagtgcaag gtgtccaaca aggccctgcc tgctcctatc 1260
gaaaagacca tctccaaggc caagggccag cctagggaac cccaggttta caccttgcct 1320
ccatctcggg acgagctgac caagaaccag gtgtccctga cctgtctggt caagggcttc 1380
tacccctccg atatcgccgt ggaatgggag tctaatggcc agcctgagaa caactacaag 1440
acaacccctc ctgtgctgga ctccgacggc tcattcttcc tgtactccaa gctgacagtg 1500
gacaagtcca gatggcagca gggcaacgtg ttctcctgct ccgtgatgca cgaggccctg 1560
cacaatcact acacacagaa gtccctgtct ctgtcccctg gtggtggcgg cggttcaggc 1620
ggcggtggaa gtggcggtgg cggatctggc ggaggtggta gtagagtgca gcctaccgag 1680
tccatcgtgc ggttccccaa catcaccaac ctgtgtcctt tcggcgaggt gttcaacgct 1740
accagattcg cctctgtgta cgcctggaac cggaagcgga tctctaactg cgtggccgac 1800
tactccgtgc tgtacaactc tgcctccttc agcaccttca agtgctacgg cgtgtcccct 1860
accaagctga acgacctgtg cttcaccaac gtgtacgccg actccttcgt gatcaggggc 1920
gacgaagttc ggcagatcgc tcctggacag accggcaaga tcgccgacta caattacaag 1980
ctgcccgacg acttcaccgg ctgcgtgatc gcttggaact ccaacaacct ggactccaaa 2040
gtcggcggca actacaacta cctgtaccgg gccttcagaa agtccaacct gaagcctttc 2100
gagcgggaca tctccaccga gatctaccag gctggcagca ccccttgcaa tggcgttgaa 2160
ggcgccaact gctacttccc actgcagtcc tacggcttcc agcctaccaa tggcgtgggc 2220
taccagcctt atagagtggt ggtgctgtcc ttcgagctgc tgcatgctcc tgctacagtg 2280
tgcggcccca agaaatctac caacctggtc aagaacaag 2319
<210> 81
<211> 2340
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1151
<400> 81
agagtgcagc 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 gttcagaaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgttgaagg cttcaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctacagtgtg cggccccaag aaatctacca acctggtcaa gaacaagggt 660
ggcagtggtg gctctggcgg atctcggtct aagcagagaa ggcctcaggg cctgcctaac 720
aataccgcct cctggtttac cgctctgacc cagcacggca aagaggacct gaagttccct 780
agaggacagg gcgtgcccat caacaccaac tctagccctg acgaccagat cggctactac 840
agacgggcca ccagaagaat cagaggcggc gacggcaaga tgaaggacct gtctcctcgg 900
tggtacttct actacctcgg caccggacca gaggctggat tgccttatgg cgccaacaag 960
gacggcatca tctgggttgc aacagagggc gctctgaaca cccctaagga ccacatcggc 1020
acccggaatc ctgccaacaa tgctgccatt gtgctgcagc tgccacaggg cacaacactg 1080
cctaagggct tttacgccga gggctctaga ggcggctctc aggcctcttc cagatcctcc 1140
agtagatcac gtggcggatc cggaggatca ggtggaagcg gaggttcacg gtctaagcag 1200
agaaggcctc agggcctgcc taacaatacc gcctcctggt ttaccgctct gacccagcac 1260
ggcaaagagg acctgaagtt ccctagagga cagggcgtgc ccatcaacac caactctagc 1320
cctgacgacc agatcggcta ctacagacgg gccaccagaa gaatcagagg cggcgacggc 1380
aagatgaagg acctgtctcc tcggtggtac ttctactacc tcggcaccgg accagaggct 1440
ggattgcctt atggcgccaa caaggacggc atcatctggg ttgcaacaga gggcgctctg 1500
aacaccccta aggaccacat cggcacccgg aatcctgcca acaatgctgc cattgtgctg 1560
cagctgccac agggcacaac actgcctaag ggcttttacg ccgagggctc tagaggcggc 1620
tctcaggcct cttccagatc ctccagtaga tcacgtggtg gtagtggcgg aagcggcggc 1680
tccagagttc agcctaccga gtccatcgtg cggttcccca acatcaccaa cctgtgtcct 1740
ttcggcgagg tgttcaacgc taccagattc gcctctgtgt acgcctggaa ccggaagcgg 1800
atctctaact gcgtggccga ctactccgtg ctgtacaact ctgcctcctt cagcaccttc 1860
aagtgctacg gcgtgtcccc taccaagctg aacgacctgt gcttcaccaa cgtgtacgcc 1920
gactccttcg tgatcagggg cgacgaagtt cggcagatcg cacctggcca gaccggcaag 1980
atcgccgact ataactacaa gctgcccgac gacttcaccg gctgtgtgat cgcttggaac 2040
tccaacaacc tggactccaa agtcggcggc aactacaact acctgtaccg gctgttccgg 2100
aagtccaacc tgaagccttt cgagcgggac atctccaccg agatctacca ggctggctct 2160
accccttgca atggcgtcga gggcttcaac tgctacttcc cactgcagtc ctacggcttc 2220
cagcctacca atggcgtggg ctaccagcct tatagagtgg tggtgctgtc cttcgagctg 2280
ctgcatgctc ctgctaccgt gtgcggccct aagaaatcta ccaacctggt caagaacaag 2340
2340
<210> 82
<211> 2340
<212> DNA
<213> Artificial Sequence
<220>
<223> Fusion protein_DNA sequence_GIC-1151m(L137A, F168A)
<400> 82
agagtgcagc 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 tgtaccgggc cttcagaaag 420
tccaacctga agcctttcga gcgggacatc tccaccgaga tctaccaggc tggcagcacc 480
ccttgcaatg gcgttgaagg cgccaactgc tacttcccac tgcagtccta cggcttccag 540
cctaccaatg gcgtgggcta ccagccttat agagtggtgg tgctgtcctt cgagctgctg 600
catgctcctg ctacagtgtg cggccccaag aaatctacca acctggtcaa gaacaagggt 660
ggcagtggtg gctctggcgg atctcggtct aagcagagaa ggcctcaggg cctgcctaac 720
aataccgcct cctggtttac cgctctgacc cagcacggca aagaggacct gaagttccct 780
agaggacagg gcgtgcccat caacaccaac tctagccctg acgaccagat cggctactac 840
agacgggcca ccagaagaat cagaggcggc gacggcaaga tgaaggacct gtctcctcgg 900
tggtacttct actacctcgg caccggacca gaggctggat tgccttatgg cgccaacaag 960
gacggcatca tctgggttgc aacagagggc gctctgaaca cccctaagga ccacatcggc 1020
acccggaatc ctgccaacaa tgctgccatt gtgctgcagc tgccacaggg cacaacactg 1080
cctaagggct tttacgccga gggctctaga ggcggctctc aggcctcttc cagatcctcc 1140
agtagatcac gtggcggatc cggaggatca ggtggaagcg gaggttcacg gtctaagcag 1200
agaaggcctc agggcctgcc taacaatacc gcctcctggt ttaccgctct gacccagcac 1260
ggcaaagagg acctgaagtt ccctagagga cagggcgtgc ccatcaacac caactctagc 1320
cctgacgacc agatcggcta ctacagacgg gccaccagaa gaatcagagg cggcgacggc 1380
aagatgaagg acctgtctcc tcggtggtac ttctactacc tcggcaccgg accagaggct 1440
ggattgcctt atggcgccaa caaggacggc atcatctggg ttgcaacaga gggcgctctg 1500
aacaccccta aggaccacat cggcacccgg aatcctgcca acaatgctgc cattgtgctg 1560
cagctgccac agggcacaac actgcctaag ggcttttacg ccgagggctc tagaggcggc 1620
tctcaggcct cttccagatc ctccagtaga tcacgtggtg gtagtggcgg aagcggcggc 1680
tccagagtgc agcctaccga gtccatcgtg cggttcccca acatcaccaa cctgtgtcct 1740
ttcggcgagg tgttcaacgc taccagattc gcctctgtgt acgcctggaa ccggaagcgg 1800
atctctaact gcgtggccga ctactccgtg ctgtacaact ctgcctcctt cagcaccttc 1860
aagtgctacg gcgtgtcccc taccaagctg aacgacctgt gcttcaccaa cgtgtacgcc 1920
gactccttcg tgatcagggg cgacgaagtt cggcagatcg ctcctggaca gaccggcaag 1980
atcgccgact acaattacaa gctgcccgac gacttcaccg gctgcgtgat cgcttggaac 2040
tccaacaacc tggactccaa agtcggcggc aactacaact acctgtaccg ggccttcaga 2100
aagtccaacc tgaagccttt cgagcgggac atctccaccg agatctacca ggctggcagc 2160
accccttgca atggcgttga aggcgccaac tgctacttcc cactgcagtc ctacggcttc 2220
cagcctacca atggcgtggg ctaccagcct tatagagtgg tggtgctgtc cttcgagctg 2280
ctgcatgctc ctgctacagt gtgcggcccc aagaaatcta ccaacctggt caagaacaag 2340
2340
Claims (26)
1.一种冠状病毒衍生的受体结合域变体,其对血管紧张素转化酶2受体具有降低的结合亲和力。
2.如权利要求1所述的冠状病毒衍生的受体结合域变体,其中该冠受体结合域变体包含选自SEQ ID NO:1的氨基酸序列中的L137、G164、V165、F168、Q175、S176、N183和G184中的至少一个位置的突变。
3.如权利要求2所述的冠状病毒衍生的受体结合域变体,其中所述受体结合域变体包含选自氨基酸L137及F168的突变以及氨基酸G184的突变中的至少一个突变。
4.如权利要求2所述的冠状病毒衍生的受体结合域变体,其中该突变为取代。
5.如权利要求4所述的冠状病毒衍生的受体结合域变体,其中所述受体结合域变体包含选自氨基酸L137A及F168A的取代以及氨基酸G184D的取代中的至少一种。
6.如权利要求1所述的冠状病毒衍生的受体结合域变体,其中该冠状病毒为SARS-CoV-2。
7.一种融合蛋白,包含如权利要求1至6任一项所述的冠状病毒衍生的受体结合域变体。
8.如权利要求7所述的融合蛋白,进一步包含冠状病毒衍生的物质。
9.如权利要求8所述的融合蛋白,其中该冠状病毒衍生的物质包含选自SARS-CoV-2衍生的N蛋白及M蛋白中的至少一种。
10.如权利要求8所述的融合蛋白,其中所述受体结合域变体及SARS-CoV-2衍生的物质通过甘氨酸-丝氨酸接头连接。
11.如权利要求7所述的融合蛋白,进一步包含Fc域。
12.如权利要求11所述的融合蛋白,其中所述受体结合域变体连接至该Fc域的N末端及C末端中的至少一种。
13.如权利要求12所述的融合蛋白,其中所述受体结合域变体连接至该Fc域的该N末端及该C末端的一者,而至少一冠状病毒衍生的物质连接至剩余的另一者。
14.如权利要求11所述的融合蛋白,其中该Fc域为免疫球蛋白G的Fc域。
15.如权利要求11所述的融合蛋白,其中所述融合蛋白为包含受体结合域变体及Fc域的蛋白的二聚体。
16.如权利要求15所述的融合蛋白,其中所述融合蛋白为进一步包含至少一冠状病毒衍生的物质的蛋白的二聚体。
17.一种疫苗组合物,包含
如权利要求1至6任一项所述的冠状病毒衍生的受体结合域变体;或
包含该冠状病毒衍生的受体结合域变体的融合蛋白。
18.如权利要求17所述的疫苗组合物,进一步包含佐剂。
19.如权利要求18所述的疫苗组合物,其中该佐剂包含选自铝盐、角鲨烯、含角鲨烯的乳化剂、钙盐、双股核糖核酸类似物、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型凝集素配位子、CD1d配位子、清洁剂、脂质体、石碱、细胞激素及肽中的至少一种。
20.一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17至19所述的疫苗组合物施用至受试者。
21.一种药物组合物,用于预防或治疗冠状病毒感染,包含作为活性物质的如权利要求1至6中任一项所述的冠状病毒衍生的受体结合域变体,或包含以该冠状病毒衍生的受体结合域变体的融合蛋白。
22.如权利要求21所述的药物组合物,其中该冠状病毒感染为COVID-19。
23.一种预防或治疗冠状病毒感染的方法,所述方法包括施用权利要求21的药物组合物至受试者。
24.一种核酸,编码如权利要求1至6中任一项所述的冠状病毒衍生的受体结合域变体,或编码包含该冠状病毒衍生的受体结合域变体的融合蛋白。
25.一种重组载体,包含如权利要求24所述的核酸。
26.一种宿主细胞,其中被引入如权利要求24所述的核酸或如权利要求25所述的核酸重组载体。
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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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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 |
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US20230355745A1 (en) | 2023-11-09 |
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EP4212543A1 (en) | 2023-07-19 |
CN116801904A (zh) | 2023-09-22 |
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 |
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