CN116348605A - 包含IgE Fc受体α亚基胞外结构域和抗IL-4R抗体的融合蛋白及其应用 - Google Patents
包含IgE Fc受体α亚基胞外结构域和抗IL-4R抗体的融合蛋白及其应用 Download PDFInfo
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- CN116348605A CN116348605A CN202180056780.XA CN202180056780A CN116348605A CN 116348605 A CN116348605 A CN 116348605A CN 202180056780 A CN202180056780 A CN 202180056780A CN 116348605 A CN116348605 A CN 116348605A
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Abstract
本发明涉及一种包含IgE Fc受体α亚基胞外结构域(FcεRIα‑ECD)和抗IL‑4R抗体的片段的融合蛋白二聚体;和一种包含相同融合蛋白二聚体的用于治疗过敏性疾病的组合物。本发明的融合蛋白二聚体展现出优异的IgE结合能力和优异的血清IgE水平降低效果。此外,本发明引发了IgE的超免疫反应,并因此具有优异的抑制IL‑4和IL‑13等诱导过敏性疾病的细胞因子活性的效果,并因此可用作治疗或预防IgE介导的过敏性疾病的药物。
Description
技术领域
本发明涉及一种包含IgE Fc受体α亚基胞外结构域(FcεRIα-ECD)和抗IL-4R抗体的片段的融合蛋白二聚体;以及一种包含相同融合蛋白二聚体的用于治疗过敏性疾病的组合物。
背景技术
过敏性疾病,例如过敏性鼻炎、特应性皮炎和包括哮喘在内的食物过敏在工业化和西方化的现代社会迅速增加,过敏性反应这种严重的过敏性疾病的发生也在增加。这些慢性免疫疾病严重危害个人的生活质量,社会经济成本也相应地飙升。因此,迫切需要采取措施来克服这些疾病。
大多数过敏性疾病是由免疫球蛋白E(IgE)的过度免疫反应引起的。IgE是正常情况下以极低浓度存在于血清中的抗体。IgE也通常由无害抗原产生。有一种情况是在没有任何特定刺激时,IgE的数量增加。这种情况可能导致过敏性疾病。异常增加的IgE可与肥大细胞、嗜碱性粒细胞等表面表达的高亲和力IgE Fc受体(FcεRI)结合。这种结合导致肥大细胞或嗜碱性粒细胞释放组胺、白三烯、前列腺素、缓激肽和血小板活化因子等化学介质。这些化学介质的释放导致过敏性症状。特别是,过敏性疾病可能由于IgE和FcεRI之间的结合而表现出恶化的症状。
目前,多种治疗过敏性疾病的方法被提出,例如过敏原回避、抗过敏药物的施用、体内IgE合成的调节和抗IgE抗体的开发等。然而,迄今为止已知的治疗方法有许多缺点,例如无法治愈过敏的根本原因、药物效力不足和出现严重副作用。
另一方面,炎性细胞因子IL-4的生物学活性是由细胞表面的特异性IL-4受体(白细胞介素-4受体,IL-4R)介导的。IL-4受体有两种类型:1型,IL-4受体α链与γc链复合;2型,IL-4受体α链与IL-13受体α1链复合。在这个方面,已经证明抗IL-4Rα链的人单克隆抗体在临床上有效减轻和治疗哮喘、湿疹和特应性皮炎等症状。
至今为止,由再生元制药公司(Regeneron Pharmaceuticals Inc.)开发的抗hIL-4Rα抗体,度普利尤单抗(dupilumab),已于2017年获得FDA批准,并用于治疗过敏性疾病(美国专利号7,605,237)。度普利尤单抗以外的抗hIL-4Rα抗体尚未获得批准。
发明内容
技术问题
因此,本发明人研究开发了一种新的融合蛋白的组合,用于有效治疗和预防过敏性疾病。结果证实,包含IgE Fc受体α亚基胞外结构域(FcεRIα-ECD)和抗IL-4R抗体的片段的融合蛋白二聚体表现出优异的IgE结合能力和优异的血清IgE水平降低效果。此外,结果证实,IL-4和IL-13等引发IgE超免疫反应从而诱导过敏性疾病的细胞因子的活性以浓度依赖的方式被抑制。基于以上,本发明通过鉴定融合蛋白二聚体可有用地用作哮喘和特应性皮炎等过敏性疾病的治疗剂而完成。
问题的解决方法
为了实现上述目的,本发明在一方面提供了一种包含IgE Fc受体α亚基胞外结构域(FcεRIα-ECD)和抗IL-4R抗体的片段的融合蛋白二聚体。
本发明在另一方面提供了一种编码所述融合蛋白的多核苷酸、一种包含所述多核苷酸的表达载体和一种导入所述表达载体的转化细胞。
本发明在另一方面提供了一种生产融合蛋白二聚体的方法,包含:培养所述转化细胞;和回收融合蛋白二聚体。
本发明在另一方面提供了一种用于预防或治疗过敏性疾病的药物组合物,包含所述融合蛋白二聚体。
本发明在另一方面提供了一种用于改善或减轻过敏性症状的食品组合物,包含所述融合蛋白二聚体。
本发明在另一方面提供了包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体在制备治疗或预防过敏性疾病的药物中的应用。
本发明在另一方面提供了包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体在治疗或预防过敏性疾病中的应用。
本发明在另一方面提供了一种治疗或预防过敏性疾病的方法,包含给受试者施用包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体。
发明效果
本发明的融合蛋白二聚体包含IgE Fc受体α亚基胞外结构域(FcεRIα-ECD)和抗IL-4R抗体的片段,表现出优异的IgE结合能力和优异的血清IgE水平降低效果。此外,它还能引发IgE的超免疫反应,并因此具有优异的抑制IL-4和IL-13等诱导过敏性疾病的细胞因子活性的效果。此外,在功能方面,所述融合蛋白二聚体复杂地作为IgE陷阱和抗IL-4R抗体,因此它可有用地用作一种用于治疗过敏性疾病的新的药物组合物,可替代传统的抗IgE抗体和抗IL-4R抗体的单独治疗剂。
附图说明
图1说明了本发明的融合蛋白GI-305(FcεRIαECD-Fc-抗IL-4R scFv)的结构。
图2说明了通过SDS-PAGE鉴定所得融合蛋白GI-305所获得的结果。
图3说明了通过蛋白Western blot鉴定所得融合蛋白GI-305所获得的结果。
图4为展示了通过测量本发明的融合蛋白GI-305与人IgE的结合能力所获得的结果的图。
图5为展示了通过鉴定本发明的融合蛋白GI-305作为抗IL-4R抗体的效力所获得的结果的图。
图6和图7为展示了通过鉴定本发明的融合蛋白GI-305的血清IgE水平降低作用所获得的结果的图。
本发明最佳实施方式
包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白
在本发明的一方面提供了一种包含IgE Fc受体α亚基胞外结构域(FcεRIα-ECD)和抗IL-4R抗体的片段的融合蛋白。
如本文所使用,术语“IgE”意为已知是免疫球蛋白E的抗体蛋白。IgE对血液中的肥大细胞、嗜碱性粒细胞等具有亲和力。此外,IgE抗体与其相应的抗原(过敏原)的反应引起炎症反应。此外,IgE被认为是引起过敏反应的抗体,过敏反应的发生是由于肥大细胞或嗜碱性粒细胞的突然分泌。
如本文所使用,术语“IgE Fc受体”也被称为Fcε受体,与IgE的Fc部分结合。受体有两种类型。与IgE Fc具有高亲和力的受体被称为Fcε受体I(FcεRI)。与IgE Fc具有低亲和力的受体称为Fcε受体Ⅱ(FcεRⅡ)。FcεRI在肥大细胞和嗜碱性粒细胞中表达。在与FcεRI结合的IgE抗体被多价抗原交联的情况下,肥大细胞或嗜碱性粒细胞发生脱粒,从而释放包括组胺的各种化学递质。这种释放会导致立即过敏性反应。
FcεRI是由一条α链、一条β链和两条γ链通过二硫键连接而成的膜蛋白。在这些链中,IgE结合的部分是α链(FcεRIα),FcεRIα具有约60kDa的大小,由存在于细胞膜内部的疏水结构域和存在于细胞膜外部的亲水结构域组成。特别是,IgE与α链的胞外结构域结合。“FcεRIα”可与“IgE Fc受体α亚基”互换使用。
具体来说,IgE Fc受体的α亚基可具有NP_001992.1中所提出的氨基酸序列。此外,IgE Fc受体的α亚基的胞外结构域(FcεRIα-ECD)可具有SEQ ID NO:2的氨基酸序列。在本说明书中,IgE Fc受体α亚基的胞外结构域可为IgE Fc受体α亚基的胞外结构域的片段或变体,只要该片段或变体能与IgE结合。
变体可通过在野生型FcεRIα-ECD(胞外结构域)中取代、缺失或添加一个或多个蛋白质的方法来制备,只要该方法不改变FcεRI的α链的功能。这些不同的蛋白质或肽段可与SEQ ID NO:2的氨基酸序列有90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高的同一性。此外,SEQ ID NO:2的FcεRIαECD可由具有SEQ ID NO:11序列的多核苷酸来编码。
如本文所使用,术语“IL-4R(白细胞介素-4受体)”或“白细胞介素-4受体”是白细胞介素-4(IL-4)特异性结合的细胞因子受体,以1型IL-4受体和2型IL-4受体的形式存在。1型IL-4受体是包含IL-4Rα链和γc链的二聚体受体,2型IL-4受体是包含IL-4Rα链和IL-13Rα1链的二聚体受体。1型IL-4受体与IL-4相互作用并受IL-4刺激,2型IL-4受体与IL-4和IL-13相互作用并受IL-4和IL-13刺激。
Th2细胞因子,IL-4和IL-13,被认为在哮喘、特应性皮炎、过敏性鼻炎等过敏性疾病中发挥重要作用,并参与T淋巴细胞的生长、分化为Th2细胞以及B淋巴细胞产物转化为IgE。此外,IL-4和IL-13共享IL-4受体α(IL-4Rα,IL-4受体α),具有相似的生物学特性。具体来说,IL-4对B淋巴细胞产物转化为IgE至关重要,并促进嗜酸性粒细胞的趋化和黏附。此外,IL-13作为IgE产生和维持的重要中介体。因此,IL-4和IL-13引发IgE的超免疫反应,从而诱导过敏性疾病。
此处,抗IL-4R抗体可为与IL-4受体特异性结合的抗体。具体来说,它可为与2型IL-4受体特异性结合的抗体。此外,抗体的片段可以任何形式被使用,只要它包含能与IL-4受体特异性结合的抗原结合结构域。此外,抗IL-4R抗体的片段可以scFv的形式存在。如本文所使用,术语“scFv”是单链可变片段的缩写,是指重链可变区和轻链可变区通过肽连接子结合的形式。
本发明实施方案中所使用的抗IL-4R抗体的scFv的重链可变区可具有SEQ ID NO:7或26的氨基酸序列。具体来说,重链可变区的HCDR1、HCDR2和HCDR3可分别为SEQ ID NO:20、21和22。此外,抗IL-4R抗体的scFv的轻链可变区可具有SEQ ID NO:8或27的氨基酸序列。具体而言,轻链可变区的LCDR1、LCDR2和LCDR3可分别为SEQ ID NO:23、24和25。此外,在实施方案中,连接重链可变区和轻链可变区的肽连接子可具有SEQ ID NO:9的氨基酸序列。此外,本发明实施方案中所使用的抗IL-4R抗体的scFv可具有SEQ ID NO:6的氨基酸序列。
另一方面,本发明实施方案中所使用的SEQ ID NO:7的抗IL-4R抗体的scFv的重链可变区可通过将度普利尤单抗scFv(SEQ ID NO:26)氨基酸序列中的第44位氨基酸由G突变为C来获得,从而形成二硫键来稳定scFv结构。此外,本发明实施方案中所使用的SEQ IDNO:8的抗IL-4R抗体的scFv的轻链可变区可通过将度普利尤单抗scFv(SEQ ID NO:27)氨基酸序列中的第105位氨基酸由Q突变为C来获得,从而形成二硫键来稳定scFv结构。
此处,融合蛋白可含有免疫球蛋白的Fc区。此处,免疫球蛋白的Fc结构域是指含有免疫球蛋白的重链恒定区2(CH2)和重链恒定区3(CH3),但不含有免疫球蛋白的重链和轻链可变区以及轻链恒定区(CL)的蛋白。免疫球蛋白可为IgG、IgA、IgE、IgD或IgM,优选为IgG4。
此外,免疫球蛋白的Fc结构域既可为野生型Fc结构域,也可为Fc结构域变体。此外,如本文所使用的,术语“Fc结构域变体”可指在糖基化模式上不同于野生型Fc结构域的形式,或者与野生型Fc结构域相比具有高糖基化,或者与野生型Fc结构域相比具有低糖基化,或者去糖基化形式。此外,糖基化的Fc结构域也包括在其中。通过宿主的培养条件或遗传操作,Fc结构域或其变体可适应具有调整数量的唾液酸、岩藻糖基化或糖基化。
此外,免疫球蛋白的Fc结构域的糖基化可通过化学方法、酶法和利用微生物的基因工程方法等常规方法进行修饰。此外,Fc结构域变体可为免疫球蛋白IgG、IgA、IgE、IgD或IgM各自的Fc区的混合形式。此外,Fc结构域变体可为Fc结构域的一些氨基酸被其他氨基酸取代的形式。
此外,修饰后的Fc区域可具有天然形式的糖基化或与天然形式相比具有高糖基化。免疫球蛋白的Fc结构域的糖基化可通过化学方法、酶法和利用微生物的基因工程方法等常规方法进行修饰。
在实施方案中,Fc结构域变体可具有SEQ ID NO:4的氨基酸序列。
具体来说,融合蛋白可由以下结构式(I)或(II)组成:
N’-X-连接子(1)-Fc区片段或其变体-连接子(2)-Y-C’(I)
N’-Y-连接子(1)-Fc区片段或其变体-连接子(2)-X-C’(II)
在所述结构式(I)和(II)中,
N’为所述融合蛋白的N端,
C’为所述融合蛋白的C端,
X为FcεRIα-ECD或其片段,
Y为抗IL-4R抗体的片段,和
所述连接子(1)和连接子(2)为肽连接子。
此处,FcεRIα-ECD或其片段与抗IL-4R抗体的片段如上所述。
此处,肽连接子(1)可由5至80个连续氨基酸、10至70个连续氨基酸、15至60个连续氨基酸、20至50个连续氨基酸、25至40个连续氨基酸或25至35个氨基酸组成。在实施方案中,肽连接子(1)可由30个氨基酸组成。此外,肽连接子(1)可包含至少一个半胱氨酸。具体来说,它可包含1个、2个或3个半胱氨酸。此外,肽连接子(1)可来源于免疫球蛋白的铰链。在实施方案中,肽连接子(1)可为由SEQ ID NO:3的氨基酸序列组成的肽连接子。
肽连接子(2)可由1至50个连续氨基酸、3至30个连续氨基酸或5至15个氨基酸组成。肽连接子(2)可包括(G4S)n(其中,n为1至10的整数),可进一步包括(G)n。此处,在(G4S)n和(G)n中,n可分别为1、2、3、4、5、6、7、8、9或10。肽连接子(2)可为由SEQ ID NO:5的氨基酸序列组成的肽连接子。
融合蛋白的各个氨基酸序列如下表1所示。此外,在实施方案中,GI-305(FcεRIαECD-Fc-抗IL-4R scFv)的氨基酸序列可具有SEQ ID NO:10的氨基酸序列。
表1
融合蛋白二聚体
在本发明的另一方面提供了一种融合蛋白二聚体,其中两个如上所述的融合蛋白结合。此处,融合蛋白可通过将FcεRIα-ECD或其片段与免疫球蛋白的Fc区连接的连接子中含有的半胱氨酸结合。此处,连接子可包含免疫球蛋白的铰链区。
编码融合蛋白的多核苷酸
在本发明的另一方面提供了一种编码包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白的多核苷酸。所述FcεRIα-ECD和抗IL-4R抗体的片段如上所述。
多核苷酸可具有SEQ ID NO:19的序列。
如果多核苷酸编码相同的多肽,一个或多个核苷酸可通过取代、缺失、插入或其组合发生突变。当多核苷酸序列是通过化学合成的方法来制备时,该合成方法在本领域所熟知,例如,文献中描述的方法(Engels and Uhlmann,Angew Chem IntEd Engl.,37:73-127,1988),可包括三酯、亚磷酸酯、磷酰胺和H-磷酸方法、PCR和其他自聚体方法、固体支撑上的寡核苷酸合成方法等。
根据实施方式,该多肽可包括与SEQ ID NO:19的核苷酸序列具有至少约70%、至少约75%、至少约80%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%或至少约100%同一性的核酸序列。
多核苷酸可进一步包含信号序列或前导序列。所本文所使用,术语“信号序列”指编码指导目标蛋白的分泌的信号肽的核酸。信号肽在宿主细胞中被翻译然后剪切。具体来说,本发明的信号序列是编码启动蛋白质跨内质网(ER)膜的迁移的氨基酸序列的核苷酸。
信号序列的特征在本领域所熟知。这种信号序列通常含有16至30个氨基酸残基,并且可含有比这些氨基酸残基更多或更少的氨基酸残基。典型的信号肽由三个区域组成,分别是基础N端区、中心疏水区和更极性的C端区。中央疏水区含有4至12个疏水残基,在未成熟多肽的转运过程中通过膜脂质双分子层固定信号序列。
启动后,信号序列在ER腔内被通常称为信号肽酶的细胞酶剪切。此处,信号序列可为组织型纤溶酶原激活剂(tPa)的分泌信号序列、单纯疱疹病毒糖蛋白D(HSV gD)的分泌信号序列、IgG信号序列或生长激素。优选地,可以使用在哺乳动物等高等真核细胞中使用的分泌信号序列。
本发明中有用的信号序列包括抗体轻链信号序列,例如,抗体14.18(Gillies etal.,J.Immunol.Meth 1989.125:191-202),抗体重链信号序列,例如,MOPC141抗体重链信号序列(Sakano et al.,Nature,1980.286:676-683),和其他本领域已知的信号序列(参见,例如,Watson et al.,Nucleic Acid Research,1984.12:5145-5164)。在实施方案中,由SEQ ID NO:1的氨基酸组成的信号序列可被用作信号序列。
装载有多核苷酸的载体
在本发明的另一方面提供了一种包含多核苷酸的表达载体,该多核苷酸编码包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白。此处,多核苷酸可具有SEQ ID NO:19的序列。
如本文所使用,术语“载体”意在导入到宿主细胞,并能与宿主细胞的基因组重组并插入其中。或者,载体被理解为包含核苷酸序列的核酸,其为可自主复制的游离基因。载体包括线性核酸、质粒、噬菌粒、粘粒、RNA载体、病毒载体、微型染色体及其类似物等。病毒载体的例子包括但不限于逆转录病毒、腺病毒和腺相关病毒。
具体来说,载体可为质粒DNA、噬菌体DNA等、商业开发的质粒(pUC18、pBAD、pIDTSAMRT-AMP等)、大肠杆菌来源的质粒(pYG601BR322、pBR325、pUC118、pUC119等)、枯草芽孢杆菌来源的质粒(pUB110、pTP5等)、酵母来源的质粒(YEp13、YEp24、YCp50等)、噬菌体DNA(Charon4A、Charon21A、EMBL3、EMBL4、λgt10、λgt11、λZAP等)、动物病毒载体(逆转录病毒、腺病毒、牛痘病毒等)、昆虫病毒载体(杆状病毒等)等。由于载体根据宿主细胞展现出不同的蛋白表达水平和修饰,为此目的优选选择和使用最适合的宿主细胞。
此外,质粒可含有可选择标记,例如抗生素抗性基因,维持质粒的宿主细胞可在选择性条件下培养。
如本文所使用,术语目的蛋白的“基因表达”或“表达”被理解为意为DNA序列的转录、mRNA转录本的翻译和融合蛋白产物或其片段的分泌。有用的表达载体可为RcCMV(Invitrogen,卡尔斯巴德)或其变体。表达载体可含有人巨细胞病毒(CMV)启动子以促进靶基因在哺乳动物细胞中的持续转录,以及牛生长激素多聚腺苷酸化信号序列以增加转录后RNA的稳定性水平。
表达融合蛋白的转化细胞
在本发明的另一方面提供了一种转化细胞,其中导入了包含编码包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白的多核苷酸的表达载体。
如本文所使用,术语“转化细胞”指可导入重组表达载体的原核细胞和真核细胞。转化细胞可通过将载体导入宿主细胞并对其进行转化来制备。此外,本发明的融合蛋白可通过表达载体中含有的多核苷酸而产生。
转化可通过各种方法进行。只要它能产生本发明的融合蛋白,则不对其作特别限制。具体来说,作为转化方法,CaCl2沉淀法、在CaCl2沉淀法中通过加入二甲基亚砜(DMSO)等还原剂来提高效率的Hanahan法、电转、磷酸钙沉淀法、原生质体融合法、碳化硅纤维搅拌法、农杆菌介导的转化法、利用PEG的转化法、利用硫酸葡聚糖的转化法、利用脂质体的转化法和干燥/抑制介导的转化法等可被使用。此外,通过使用感染作为手段,使用病毒颗粒能将目标对象运送到细胞中。此外,载体还可通过基因轰击等导入宿主细胞。
此外,只要用于生产转化细胞的宿主细胞也能生产本发明的融合蛋白,则不对其作特别限制。具体来说,宿主细胞可包括但不限于原核细胞、真核细胞和哺乳动物、植物、昆虫、真菌或细菌来源的细胞。作为原核细胞的例子,可以使用大肠杆菌。此外,作为真核细胞的例子,可以使用酵母。此外,作为哺乳动物细胞,可以使用CHO细胞、F2N细胞、COS细胞、BHK细胞、Bowes黑色素瘤细胞、HeLa细胞、911细胞、AT1080细胞、A549细胞、SP2/0细胞、人淋巴母细胞、NSO细胞、HT-1080细胞、PERC.6细胞、HEK293细胞、HEK293T细胞等,但不限于此,可以使用本领域普通技术人员所知的可作为哺乳动物宿主细胞的任何细胞。
如上所述,为了优化融合蛋白作为治疗剂或任何其他目的的性质,可通过本领域技术人员所知的方法操作宿主细胞所拥有的糖基化相关基因来调整融合蛋白的糖基化模式(例如,唾液酸化、岩藻糖基化、糖基化等)。
生产融合蛋白的方法
在本发明的另一方面提供了一种生产包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体的方法。
生产融合蛋白的方法可包含:i)培养转化细胞;和ii)回收本发明的包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体。
如本文所使用,术语“培养“指在适当的人工控制的环境条件下生长微生物的方法。
培养转化细胞的方法可使用本领域已熟知的方法进行。具体来说,培养不受特别限制,只要它能表达并产生本发明的融合蛋白。具体来说,培养可在间歇过程中进行,也可在补料间歇或重复补料间歇过程中连续进行。
此外,从培养物中回收融合蛋白二聚体可通过本领域已知的方法进行。具体来说,回收方法不受特别限制,只要它能回收本发明产生的融合蛋白。优选地,回收方法可为离心、过滤、提取、喷雾、干燥、蒸发、沉淀、结晶、电泳、分级溶解(例如,硫酸铵沉淀)、层析(例如,离子交换、亲和性、疏水性和尺寸排阻等)等。
融合蛋白的应用
在本发明的另一方面提供了一种用于预防或治疗过敏性疾病的药物组合物,其包含含有FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体。
在本说明书中,术语“过敏性疾病”意为由例如肥大细胞脱颗粒的肥大细胞活化介导的过敏反应引起的病理症状。这种过敏性疾病包括食物过敏、特应性皮炎、哮喘、过敏性鼻炎、过敏性结膜炎、过敏性皮炎、过敏性接触性皮炎、过敏反应、荨麻疹、瘙痒症、昆虫过敏、慢性特发性荨麻疹、慢性自发性荨麻疹、药物过敏等。特别是,过敏性疾病可能是IgE介导的。
术语“预防”指通过施用药物组合物来抑制过敏性疾病的发生或延缓过敏性疾病的发作的任何行为。术语“治疗”指通过施用药物组合物来改善或有益地改变过敏性疾病的症状的任何行为。
在本发明用于治疗或预防过敏性疾病的药物组合物中,可根据用途、配方、混合用途等,含有任意量(有效量)的融合蛋白二聚体,只要它能展现出抗过敏活性。常规的有效量可在组合物总重量基础上的0.001%重量至20.0%重量的范围内确定。此处,“有效量”指能诱导抗过敏作用的活性成分的量。这种有效量可在本领域技术人员的公知常识的范围内通过实验确定。
此处,药物组合物可进一步包含药学上可接受的载体。药学上可接受的载体可为任何载体,只要该载体是适合递送给患者的无毒物质。载体可含有蒸馏水、乙醇、脂肪、蜡和惰性固体。药物组合物中也可含有药学上可接受的佐剂(缓冲剂、分散剂)。
具体来说,本发明的药物组合物,除融合蛋白二聚体外,还含有药学上可接受的载体,并可根据给药途径,通过本领域所知的常规方法制备成肠外制剂。此处,术语“药学上可接受的”意为在不抑制融合蛋白二聚体活性的情况下,不具有比待施用(开处方)的受试者所能承受的毒性更大的毒性。
当本发明的药物组合物作为口服制剂制备时,它可根据本领域已知的方法与合适的载体一起制备成粉末、颗粒、片剂、丸剂、滴丸、胶囊、液体、凝胶、糖浆、悬液、晶片等形式。此处,合适的药学上可接受的载体的例子可包括糖类,例如乳糖、葡萄糖、蔗糖、右旋葡萄糖、山梨醇、甘露醇和木糖醇;淀粉,例如玉米淀粉、马铃薯淀粉、小麦淀粉;纤维素,例如纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素;聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、硬脂酸镁、矿物油、麦芽、明胶、滑石粉、多元醇、植物油等。在制剂的情况下,如有必要,它可被配制为包括稀释剂和/或赋形剂,例如填料、扩展剂、粘合剂、润湿剂、崩解剂和表面活性剂。
当本发明的药物组合物被制备为肠外制剂时,它可根据本领域已知的方法与合适的载体一起制备成注射剂、透皮药物、鼻吸入剂和栓剂的形式。在被配制为注射剂的情况下,无菌水、乙醇、甘油或丙二醇等多元醇,或其混合物可作为合适的载体。对于载体,可优选地使用等渗溶液,例如Ringer’s溶液、含有三乙醇胺的磷酸盐缓冲液(PBS)或注射用无菌水和5%右旋葡萄糖等。
药物组合物的配制在本领域已知,具体可参考Remington's PharmaceuticalSciences(1995年第19版)等。该文献被认为是本说明书的一部分。
另一方面,本发明的药物组合物以药学上有效量给药。如本文所使用,术语“给药(施用)”意为通过适当的方法向受试者导入预定的物质,并且该组合物可通过任何常规途径给药,只要它能达到目标组织。给药途径可包括口服给药、腹腔给药、静脉给药、肌肉注射、皮下给药、皮内给药、局部给药、鼻腔给药和直肠给药,但不限于此。
术语“药学上有效量”指以合理的获益/风险比例适用于医疗且不引起副作用的足以治疗疾病的量。有效剂量的水平可由本领域技术人员根据包括患者的性别、年龄、体重和健康状况、疾病的类型和严重程度、药物的活性、对药物的敏感性、给药方法、给药时间、给药途径和排泄率、治疗时间、联合用或同时使用的药物以及医疗领域已知的其他因素等因素容易地确定。
根据患者的病情、体重、性别、年龄、疾病严重程度或给药途径,本发明的药物组合物的优选每日剂量可在每天0.01μg/kg至10g/kg的范围,优选每天0.01mg/kg至1g/kg。给药可每日进行一次或数次。这种剂量不应被解释为限制本发明的范围。
术语“受试者”指本发明的组合物可应用(开处方)的受试者,可为哺乳动物,例如人类、大鼠、小鼠或家畜。优选地,它可为人类,但不限于此。除融合蛋白二聚体外,本发明的抗过敏组合物可进一步包括已知具有抗过敏活性且已被证明具有安全的抗过敏活性的增强和巩固的任何化合物或天然提取物。此处,融合蛋白二聚体和具有抗过敏活性的化合物或天然提取物可同时或按顺序给药。
在本发明的另一方面提供了一种用于改善或减轻过敏症状的食品组合物,包括含有FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体。
此处,融合蛋白二聚体可与合适的递送手段相结合,从而高效地递送进入肠道。此外,本发明的食品组合物可被制备为任何形式,也可被制备为,例如,茶、果汁、碳酸饮料和离子饮料等饮料的形式,牛奶和酸奶等加工乳制品的形式,片剂、胶囊、丸剂、颗粒、液体、粉剂、薄片、糊剂、糖浆、凝胶、果冻、条剂等健康功能性食品制剂的形式。此外,本发明的食品组合物只要在制造和分销时符合实施条例,就可属于法律或功能分类中的任何产品类别。例如,根据健康功能食品法(Health Functional Food Act),食品组合物可为健康功能食品,或根据食品卫生法的食品标准准则(Food Standards Code of the Food SanitationAct)(食品药品安全部公告,食品标准与规范(Ministry of Food and Drug SafetyAnnouncement,Food Standards and Specifications))中的每一种食品类型,它可为糕点、豆类、茶、饮料、特殊用途食品等。对于包括在本发明食品组合物中的其他食品添加剂,根据食品卫生法,可参考食品安全准则(Food Safety Code)或食品添加剂准则(FoodAdditives Code)。
在本发明的另一方面提供了包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体在制备用于治疗或预防过敏性疾病的药物中的应用。此处,FcεRIα-ECD、抗IL-4R抗体、过敏性疾病、治疗和预防如上所述。
在本发明的另一方面提供了包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体在治疗或预防过敏性疾病中的应用。此处,FcεRIα-ECD、抗IL-4R抗体、过敏性疾病、治疗和预防如上所述。
在本发明的另一方面提供了一种治疗或预防过敏性疾病的方法,包含给受试者施用包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体。此处,FcεRIα-ECD、抗IL-4R抗体、施用、过敏性疾病、治疗和预防如上所述。
受试者可为哺乳动物,优选为人类。此外,受试者可为患有过敏性疾病的患者,也可为高概率患有过敏性疾病的受试者。
包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体的给药途径、剂量和给药频率可根据患者的病情和有无副作用而异,因此它可以各种方式和数量施用给受试者。最佳的给药方式、剂量和给药频率可被本领域技术人员在适当范围内选择。此外,包含FcεRIα-ECD和抗IL-4R抗体的片段的融合蛋白二聚体可与已知的对于待治疗疾病有治疗作用的其他药物或生理活性的物质联合给药,也可被配制为与其他药物的组合制剂的形式。
本发明具体实施方式
在下文中,本发明将参考以下实施例进行更详细的描述。这些实施例被参考来说明本发明,且本发明的范围不会被解释为受限于这些实施例,这对于本领域技术人员来说是显而易见的。
制备实施例1.FcεRIαECD-Fc-抗IL-4R scFv融合蛋白:GI-350的制备
为了生产包含FcεRIα链胞外结构域、Fc结构域和与IL-4受体(IL-4R)特异性结合的抗体的融合蛋白,从N端依次合成包含编码包含FcεRIα链胞外结构域(SEQ ID NO:2)、连接子(SEQ ID NO:3)、IgG4 Fc结构域(SEQ ID NO:4)、连接子(SEQ ID NO:5)和与IL-4受体特异性结合的抗体的scFv(SEQ ID NO:6)的核苷酸序列(SEQ ID NO:19)的多核苷酸,并装载到pcDNA3.4载体(Genscript)。
将载体导入CHO细胞(ExpiCHO-S细胞)。随后,在37℃、8% CO2、无血清的ExpiCHOTM表达培养基(Thermo Fisher Scientific)中培养14天。随后,收集培养液,利用亲和层析(亲和纯化柱)纯化融合蛋白。
纯化的融合蛋白通过SDS-PAGE和Western blot证实分子量和纯度。SDS-PAGE和Western blot的分析结果证实该蛋白在非还原条件和还原条件下均被检测到。由此证实纯化的融合蛋白形成二聚体(图2和图3)。融合蛋白二聚体被命名为“GI-305(也被称为FcεRIαECD-Fc-抗IL-4R scFv)”。
制备实施例2.作为对照的FcεRIαECD-Fc融合蛋白的制备
制备实施例2.1.GI-301的制备
为了产生包含FcεRIα链胞外结构域和Fc结构域的融合蛋白作为对照,从N端依次合成包含编码包含FcεRIα链胞外结构域(SEQ ID NO:2)、连接子(SEQ ID NO:28)和已修饰的IgG4 Fc结构域(SEQ ID NO:29)的融合蛋白的核苷酸序列(SEQ ID NO:30)的多核苷酸,并装载到pcDNA3.4载体(Genscript)。
将载体导入CHO细胞(ExpiCHO-S细胞)。随后,在37℃、8% CO2、无血清的ExpiCHOTM表达培养基(Thermo Fisher Scientific)中培养14天。随后,收集培养液,利用亲和层析(亲和纯化柱)纯化融合蛋白。
制备实施例2.2.GI-305CN的制备
为了生产包含FcεRIα链胞外结构域和Fc结构域的融合蛋白,从N端依次合成包含编码包含FcεRIα链胞外结构域(SEQ ID NO:2)、连接子(SEQ ID NO:3)和IgG4 Fc结构域(SEQ ID NO:4)的融合蛋白的核苷酸序列(SEQ ID NO:31)的多核苷酸,并装载到pcDNA3.4载体(Genscript)。
将载体导入CHO细胞(ExpiCHO-S细胞)。随后,在37℃、8% CO2、无血清的ExpiCHOTM表达培养基(Thermo Fisher Scientific)中培养14天。随后,收集培养液,利用亲和层析(亲和纯化柱)纯化融合蛋白。
制备实施例3.作为对照的Fc-抗IL4RαscFv:GI-305C1的制备
为了生产包含Fc结构域和与IL-4受体(IL-4R)特异性结合的抗体的融合蛋白,从N端一次合成包含编码包含IgG4 Fc结构域(SEQ ID NO:4)、连接子(SEQ ID NO:5)和与IL-4受体特异性结合的抗体的scFv(SEQ ID NO:6)的融合蛋白的核苷酸序列(SEQ ID NO:32)的多核苷酸,并装载到pcDNA3.4载体(Genscript)。
将载体导入CHO细胞(ExpiCHO-S细胞)。随后,在37℃、8% CO2、无血清的ExpiCHOTM表达培养基(Thermo Fisher Scientific)中培养14天。随后,收集培养液,利用亲和层析(亲和纯化柱)纯化融合蛋白。
实验实施例1.GI-305融合蛋白二聚体与人IgE结合能力的鉴定
将上述实施例1的方法获得的包含FcεRIαECD与抗IL-4R抗体的片段的融合蛋白GI-305进行IgE结合能力测量。此次,使用Octet RED 384(Forte Bio)鉴定与IgE的结合能力。浸入1X动力学缓冲液10分钟的AHC(抗人IgG捕获)生物传感器被使用。将GI-305制备为10μg/mL的浓度并涂布于生物传感器上,将IgE连续稀释至1.6至100nM来鉴定在各浓度的结合能力。作为结果,测量的GI-305融合蛋白二聚体与IgE的结合能力如图4和表2所示。
表2
实验实施例2.GI-305融合蛋白二聚体对IL-4和IL-13活性的抑制作用的鉴定
为了鉴定GI-305融合蛋白二聚体作为抗IL-4R抗体的活性,使用细胞因子依赖的细胞生长细胞系TF-1细胞进行实验。TF-1细胞是对包括IL-4和IL-13的多种细胞因子有响应的细胞系,鉴定了GI-305融合蛋白二聚体是否抑制TF-1细胞中IL-4或IL-13介导的细胞增殖。
TF-1细胞(ATCC,#CRL-2003)被培养在含有人GM-CSF(4ng/mL,R&D Systems)的培养基(RPMI-1640+10% FBS+1%青霉素/链霉素)中。在分析前,将TF-1细胞以1,500rpm离心5分钟沉淀,去除培养基,然后将细胞重悬于不含GM-CSF的检测培养基中。将重悬的细胞以5Х104个/孔的密度分装到96孔板的每孔中。将各种浓度的GI-305融合蛋白二聚体分别与IL-4(100ng/mL)和IL-13(100ng/mL)混合,加入孔中。检测板在5%CO2、37℃孵育24小时。随后,每孔加入10μL的WST-1(Roche)孵育4小时。
随后,用酶标仪记录450nm波长处的吸光度,用GraphPad Prism软件分析数据。结果表明,GI-305抑制IL-4或IL-13诱导的TF-1细胞生长(图5)。
实验实施例3.GI-305融合蛋白二聚体对血清IgE水平降低效果的鉴定
IL-4和IL-13促进B细胞增殖,协同刺激CD40/CD40L,并诱导IgG4和IgE的类别转换。评价了GI-305融合蛋白二聚体对IL-4诱导的B细胞释放IgE的影响。外周血单核细胞(PBMC)购自Cellular Technology Limited,并进行实验。PBMC被培养在检测培养基(RPMI-1640+10% FBS+1%青霉素/链霉素)中。
在分析前,将储存在LN2罐中的PBMC以1,500rpm离心5分钟沉淀,吸去培养基,然后将细胞重悬于检测培养基中。将细胞以2Х105个/孔的密度分装到96孔板的每孔中。将市售的抗IgE抗体奥马珠单抗(omalizumab)(产品名:Xolair)和抗IL-4Rα抗体度普利尤单抗(产品名:Dupixent)作为对照,GI-301(FcεRIαECD-已修饰的Fc)、GI-305CN(FcεRIαECD-IgG4Fc)、GI-305C1(IgG4 Fc-IL-4RαscFv)在上述制备实施例中制备,受试物GI-305分别与IL-4(30ng/mL)和抗人CD40抗体(1μg/mL)混合后加入板孔中。对照和受试物配制为0.008nM或0.04nM的浓度来使用。检测板在5% CO2、37℃孵育12天。随后,以1,500rpm离心沉淀,用R-PLEX检测试剂盒(MSD)测量存在于上清中IgE的水平。
具体来说,将25μL生物素化的捕获抗体分装到MSD GOLD 96孔链霉亲和素微孔板中。室温孵育1小时后,每孔加入150μL的PBST(含有0.05% Tween 20的PBS)洗涤5次。随后,每孔加入25μL样品,室温孵育1小时。然后,每孔用150μL的PBST洗涤5次。洗涤后,150μL的硫酸化标签检测抗体被分装到每个孔。室温孵育1小时后,每孔用150μL的PBST洗涤5次。随后,150μL的MSD GOLD读数缓冲液被分装到每个孔,并用MESO QuickPlex SQ 120测量。使用GraphPad Prism软件进行数据分析。
结果发现,与抗IgE抗体奥马珠单抗、抗IL-4Rα抗体度普利尤单抗、GI-301(FcεRIαECD-已修饰的Fc)、GI-305CN(FcεRIαECD-IgG4 Fc)和GI-305C1(IgG4 Fc-IL-4Rαsc Fv)相比,通过抑制B细胞活性,GI-305融合蛋白二聚体在抑制IgE产生中展现出显著优异的效果(图6和图7)。
SEQUENCE LISTING
<110> GI医诺微新
<120> 包含IgE Fc受体α亚基胞外结构域和抗IL-4R抗体的融合蛋白及其应用
<130> P22119983WP
<150> KR 10-2020-0088941
<151> 2020-07-17
<160> 32
<170> PatentIn version 3.5
<210> 1
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> mIgG信号
<400> 1
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser
<210> 2
<211> 180
<212> PRT
<213> Artificial Sequence
<220>
<223> FceRIa ECD
<400> 2
Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile
1 5 10 15
Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe
20 25 30
Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu
35 40 45
Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly
50 55 60
Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr
65 70 75 80
Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val
85 90 95
Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn
100 105 110
Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys
115 120 125
Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu
130 135 140
Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr
145 150 155 160
Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys
165 170 175
Tyr Trp Leu Gln
180
<210> 3
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> NL028铰链连接子
<400> 3
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
20 25 30
<210> 4
<211> 216
<212> PRT
<213> Artificial Sequence
<220>
<223> hIgG4Fc
<400> 4
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
115 120 125
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Leu Gly
210 215
<210> 5
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> (G4S)2GG连接子
<400> 5
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
1 5 10
<210> 6
<211> 257
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗IL-4R scFv
<400> 6
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
130 135 140
Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro
145 150 155 160
Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr
165 170 175
Ser Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln
180 185 190
Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val
195 200 205
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys
210 215 220
Ile Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln
225 230 235 240
Ala Leu Gln Thr Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
245 250 255
Lys
<210> 7
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗IL-4R_重链
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 8
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗IL-4R_轻链
<400> 8
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Tyr Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 9
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> HC-LC连接子
<400> 9
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> 10
<211> 695
<212> PRT
<213> Artificial Sequence
<220>
<223> GI-305(FceRIa ECD-Fc-抗IL-4R scFv)
<400> 10
Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile
1 5 10 15
Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe
20 25 30
Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu
35 40 45
Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly
50 55 60
Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr
65 70 75 80
Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val
85 90 95
Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn
100 105 110
Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys
115 120 125
Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu
130 135 140
Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr
145 150 155 160
Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys
165 170 175
Tyr Trp Leu Gln Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
180 185 190
Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
195 200 205
Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro
210 215 220
Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr
225 230 235 240
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
245 250 255
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
260 265 270
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
275 280 285
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
290 295 300
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
305 310 315 320
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
325 330 335
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
340 345 350
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
355 360 365
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
370 375 380
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
385 390 395 400
Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr
405 410 415
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Gly
420 425 430
Gly Gly Gly Ser Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly
435 440 445
Leu Glu Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly
450 455 460
Phe Thr Phe Arg Asp Tyr Ala Met Thr Trp Val Arg Gln Ala Pro Gly
465 470 475 480
Lys Cys Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr
485 490 495
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
500 505 510
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
515 520 525
Thr Ala Val Tyr Tyr Cys Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg
530 535 540
Pro Arg Tyr Tyr Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr
545 550 555 560
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Leu
580 585 590
Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser
595 600 605
Ser Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr
610 615 620
Leu Gln Lys Ser Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser
625 630 635 640
Asn Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
645 650 655
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
660 665 670
Phe Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Tyr Thr Phe Gly Cys
675 680 685
Gly Thr Lys Leu Glu Ile Lys
690 695
<210> 11
<211> 540
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码FceRIa ECD的多核苷酸
<400> 11
gtgcctcaga aacccaaagt gtctctgaac cctccttgga accggatctt caagggcgag 60
aacgtgaccc tgacctgcaa cggcaacaac ttcttcgagg tgtcctccac caagtggttc 120
cacaacggct ccctgtccga ggaaacaaac tccagcctga acatcgtgaa cgccaagttc 180
gaggactccg gcgagtacaa gtgccagcac cagcaagtga acgagtccga gcctgtgtac 240
ctggaagtgt tctccgactg gctgctgctc caggcttctg ccgaggttgt gatggaaggc 300
cagcctctgt tcctgagatg tcacggctgg cggaactggg acgtgtacaa agtgatctac 360
tacaaggacg gcgaggccct gaagtattgg tacgagaacc acaacatctc catcaccaac 420
gccaccgtgg aagattccgg cacctactac tgcaccggca aagtgtggca gctggactac 480
gagagcgagc ctctgaacat caccgtgatc aaggccccta gagagaagta ctggctgcaa 540
<210> 12
<211> 90
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码NL028铰链连接子的多核苷酸
<400> 12
ggatctggcg gcggaggttc tggcggaggt ggaagcggtg gcggaggatc tgctgagtct 60
aagtatggcc ctccttgtcc tccatgtcct 90
<210> 13
<211> 648
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码hIgG4Fc的多核苷酸
<400> 13
gctccagaag ctgctggcgg gccctccgtg tttctgttcc ctccaaagcc taaggaccag 60
ctgatgatct ctcggacacc cgaagtgacc tgcgtggtgg tggatgtgtc tcaagaggac 120
cctgaggtgc agttcaattg gtacgtggac ggcgtggaag tgcacaacgc caagaccaag 180
cctagagagg aacagttcaa ctccacctac agagtggtgt ccgtgctgac cgtgctgcac 240
caggattggc tgaacggcaa agagtacaag tgcaaggtgt ccaacaaggg cctgccttcc 300
agcatcgaaa agaccatctc caaggccaag ggccagccta gggaacccca ggtttacacc 360
ctgcctccaa gccaagagga aatgaccaag aaccaggtgt ccctgacctg cctggtcaag 420
ggcttctacc cttccgacat tgccgtggaa tgggagagca atggccagcc tgagaacaac 480
tacaagacca cacctcctgt gctggactcc gacggctcct tctttctgta ctcccgcctg 540
accgtggaca agtccagatg gcaagagggc aacgtgttct cctgctctgt gctgcacgag 600
gccctgcaca atcactacac ccagaagtcc ctcagcctgt cccttggc 648
<210> 14
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码(G4S)2GG连接子的多核苷酸
<400> 14
ggaggcggtg gatcaggtgg cggaggatct ggcgga 36
<210> 15
<211> 771
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码抗-IL-4R scFv的多核苷酸
<400> 15
gaagtgcagc tggttgaatc tggcggcgga ttggaacagc ctggcggatc tctgagactg 60
tcttgtgccg gctctggctt caccttcaga gactacgcta tgacctgggt ccgacaggct 120
cctggcaaat gtctggaatg ggtgtcctcc atctctggct ctggcggcaa tacctactac 180
gccgactctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 240
ctccagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacaga 300
ctgtccatca ccatccggcc tcggtactac ggactggatg tttggggcca gggcaccaca 360
gtgacagtgt cctccggagg cggaggaagt ggcggcggag gatcaggcgg tggtggatct 420
ggcggaggcg gttctgacat tgtgatgacc cagtctccac tgagcctgcc tgtgacacct 480
ggcgagcctg cttccatctc ttgccggtca tctcagtccc tgctgtactc catcggctac 540
aactacctgg actggtatct ccagaagtcc ggacagtctc cccagctgct gatctacctg 600
ggctccaata gagcctccgg cgtgcccgat agattctccg gatctggctc tggcaccgac 660
ttcaccctga agatctccag agtggaagcc gaggacgtgg gcttctacta ctgtatgcag 720
gccctccaga caccttacac ctttggctgt ggcaccaagc tggaaatcaa g 771
<210> 16
<211> 375
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码抗-IL-4R_重链的多核苷酸
<400> 16
gaagtgcagc tggttgaatc tggcggcgga ttggaacagc ctggcggatc tctgagactg 60
tcttgtgccg gctctggctt caccttcaga gactacgcta tgacctgggt ccgacaggct 120
cctggcaaat gtctggaatg ggtgtcctcc atctctggct ctggcggcaa tacctactac 180
gccgactctg tgaagggcag attcaccatc agccgggaca actccaagaa caccctgtac 240
ctccagatga actccctgag agccgaggac accgccgtgt actactgcgc caaggacaga 300
ctgtccatca ccatccggcc tcggtactac ggactggatg tttggggcca gggcaccaca 360
gtgacagtgt cctcc 375
<210> 17
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码抗-IL-4R_轻链的多核苷酸
<400> 17
gacattgtga tgacccagtc tccactgagc ctgcctgtga cacctggcga gcctgcttcc 60
atctcttgcc ggtcatctca gtccctgctg tactccatcg gctacaacta cctggactgg 120
tatctccaga agtccggaca gtctccccag ctgctgatct acctgggctc caatagagcc 180
tccggcgtgc ccgatagatt ctccggatct ggctctggca ccgacttcac cctgaagatc 240
tccagagtgg aagccgagga cgtgggcttc tactactgta tgcaggccct ccagacacct 300
tacacctttg gctgtggcac caagctggaa atcaag 336
<210> 18
<211> 57
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码mIgG信号的多核苷酸
<400> 18
atggaatggt cctgggtgtt cctgttcttc ctgtccgtga ccaccggcgt gcactct 57
<210> 19
<211> 2085
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码GI-305的多核苷酸
<400> 19
gtgcctcaga aacccaaagt gtctctgaac cctccttgga accggatctt caagggcgag 60
aacgtgaccc tgacctgcaa cggcaacaac ttcttcgagg tgtcctccac caagtggttc 120
cacaacggct ccctgtccga ggaaacaaac tccagcctga acatcgtgaa cgccaagttc 180
gaggactccg gcgagtacaa gtgccagcac cagcaagtga acgagtccga gcctgtgtac 240
ctggaagtgt tctccgactg gctgctgctc caggcttctg ccgaggttgt gatggaaggc 300
cagcctctgt tcctgagatg tcacggctgg cggaactggg acgtgtacaa agtgatctac 360
tacaaggacg gcgaggccct gaagtattgg tacgagaacc acaacatctc catcaccaac 420
gccaccgtgg aagattccgg cacctactac tgcaccggca aagtgtggca gctggactac 480
gagagcgagc ctctgaacat caccgtgatc aaggccccta gagagaagta ctggctgcaa 540
ggatctggcg gcggaggttc tggcggaggt ggaagcggtg gcggaggatc tgctgagtct 600
aagtatggcc ctccttgtcc tccatgtcct gctccagaag ctgctggcgg gccctccgtg 660
tttctgttcc ctccaaagcc taaggaccag ctgatgatct ctcggacacc cgaagtgacc 720
tgcgtggtgg tggatgtgtc tcaagaggac cctgaggtgc agttcaattg gtacgtggac 780
ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagttcaa ctccacctac 840
agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agagtacaag 900
tgcaaggtgt ccaacaaggg cctgccttcc agcatcgaaa agaccatctc caaggccaag 960
ggccagccta gggaacccca ggtttacacc ctgcctccaa gccaagagga aatgaccaag 1020
aaccaggtgt ccctgacctg cctggtcaag ggcttctacc cttccgacat tgccgtggaa 1080
tgggagagca atggccagcc tgagaacaac tacaagacca cacctcctgt gctggactcc 1140
gacggctcct tctttctgta ctcccgcctg accgtggaca agtccagatg gcaagagggc 1200
aacgtgttct cctgctctgt gctgcacgag gccctgcaca atcactacac ccagaagtcc 1260
ctcagcctgt cccttggcgg aggcggtgga tcaggtggcg gaggatctgg cggagaagtg 1320
cagctggttg aatctggcgg cggattggaa cagcctggcg gatctctgag actgtcttgt 1380
gccggctctg gcttcacctt cagagactac gctatgacct gggtccgaca ggctcctggc 1440
aaatgtctgg aatgggtgtc ctccatctct ggctctggcg gcaataccta ctacgccgac 1500
tctgtgaagg gcagattcac catcagccgg gacaactcca agaacaccct gtacctccag 1560
atgaactccc tgagagccga ggacaccgcc gtgtactact gcgccaagga cagactgtcc 1620
atcaccatcc ggcctcggta ctacggactg gatgtttggg gccagggcac cacagtgaca 1680
gtgtcctccg gaggcggagg aagtggcggc ggaggatcag gcggtggtgg atctggcgga 1740
ggcggttctg acattgtgat gacccagtct ccactgagcc tgcctgtgac acctggcgag 1800
cctgcttcca tctcttgccg gtcatctcag tccctgctgt actccatcgg ctacaactac 1860
ctggactggt atctccagaa gtccggacag tctccccagc tgctgatcta cctgggctcc 1920
aatagagcct ccggcgtgcc cgatagattc tccggatctg gctctggcac cgacttcacc 1980
ctgaagatct ccagagtgga agccgaggac gtgggcttct actactgtat gcaggccctc 2040
cagacacctt acacctttgg ctgtggcacc aagctggaaa tcaag 2085
<210> 20
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR1
<400> 20
Gly Phe Thr Phe Arg Asp Tyr Ala
1 5
<210> 21
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR2
<400> 21
Ile Ser Gly Ser Gly Gly Asn Thr
1 5
<210> 22
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> HCDR3
<400> 22
Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
1 5 10 15
Asp Val
<210> 23
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR1
<400> 23
Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr
1 5 10
<210> 24
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR2
<400> 24
Leu Gly Ser
1
<210> 25
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> LCDR3
<400> 25
Met Gln Ala Leu Gln Thr Pro Tyr Thr
1 5
<210> 26
<211> 125
<212> PRT
<213> Artificial Sequence
<220>
<223> 度普利尤单抗重链
<400> 26
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 度普利尤单抗轻链
<400> 27
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 28
<211> 30
<212> PRT
<213> Artificial Sequence
<220>
<223> GI-301铰链连接子
<400> 28
Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys
1 5 10 15
Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro
20 25 30
<210> 29
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> GI-301修饰的Fc
<400> 29
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
1 5 10 15
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
20 25 30
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
35 40 45
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
50 55 60
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
65 70 75 80
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
85 90 95
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
100 105 110
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
115 120 125
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
130 135 140
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
145 150 155 160
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
165 170 175
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
180 185 190
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
195 200 205
Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 30
<211> 1275
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码GI-301的多核苷酸
<400> 30
gtgccccaga agcccaaggt gagcctgaac cctccctgga acagaatctt caagggcgag 60
aacgtgaccc tgacctgcaa cggcaacaac ttcttcgagg tgagcagcac caagtggttc 120
cacaatggca gcctgagcga ggagaccaac agctccctga acatcgtgaa cgccaagttc 180
gaggacagcg gcgagtacaa gtgccagcac cagcaggtga acgagagcga gcccgtgtac 240
ctggaggtgt tcagcgactg gctgctgctg caggccagcg ccgaggtggt gatggagggc 300
cagcccctgt tcctgagatg ccacggctgg agaaactggg acgtgtacaa ggtgatctac 360
tacaaggatg gcgaggccct gaagtactgg tacgagaacc acaacatctc catcaccaac 420
gccaccgtgg aggacagcgg cacctactac tgcacaggca aggtgtggca gctggactac 480
gagagcgagc ccctgaacat caccgtgatc aaggctccca gagagaagta ctggctgcag 540
aggaacaccg gcagaggagg cgaggaaaag aaaggaagca aggagaagga ggagcaggag 600
gaaagagaaa ccaagacccc cgagtgcccc agccacaccc agcccctggg cgtgttcctg 660
ttccccccca agcccaagga caccctgatg atcagcagaa cccccgaggt gacctgcgtg 720
gtcgtggatg tgagccagga agatcccgaa gtgcagttca actggtacgt ggatggcgtg 780
gaagtgcaca acgccaagac caagcccaga gaagagcagt tcaactccac ctacagagtg 840
gtgagcgtgc tgaccgtgct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 900
gtgtccaaca aaggcctgcc cagctccatc gagaagacca tcagcaaagc caaaggccag 960
cccagagaac cccaggtgta caccctgcct cccagccagg aagagatgac caagaaccag 1020
gtgtccctga cctgcctggt gaaaggcttc taccccagcg acatcgccgt ggagtgggaa 1080
agcaacggcc agcccgagaa caattacaag acaacccctc ccgtgctgga tagcgatggc 1140
agcttctttc tgtacagcag actgaccgtg gacaagagca gatggcagga aggcaacgtg 1200
ttcagctgca gcgtgatgca cgaagccctg cacaaccact acacccagaa gagcctgtcc 1260
ctgagcctgg gcaag 1275
<210> 31
<211> 1278
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码GI-305CN的多核苷酸
<400> 31
gtgcctcaga aacccaaagt gtctctgaac cctccttgga accggatctt caagggcgag 60
aacgtgaccc tgacctgcaa cggcaacaac ttcttcgagg tgtcctccac caagtggttc 120
cacaacggct ccctgtccga ggaaacaaac tccagcctga acatcgtgaa cgccaagttc 180
gaggactccg gcgagtacaa gtgccagcac cagcaagtga acgagtccga gcctgtgtac 240
ctggaagtgt tctccgactg gctgctgctc caggcttctg ccgaggttgt gatggaaggc 300
cagcctctgt tcctgagatg tcacggctgg cggaactggg acgtgtacaa agtgatctac 360
tacaaggacg gcgaggccct gaagtattgg tacgagaacc acaacatctc catcaccaac 420
gccaccgtgg aagattccgg cacctactac tgcaccggca aagtgtggca gctggactac 480
gagagcgagc ctctgaacat caccgtgatc aaggccccta gagagaagta ctggctgcaa 540
ggatctggcg gcggaggttc tggcggaggt ggaagcggtg gcggaggatc tgctgagtct 600
aagtatggcc ctccttgtcc tccatgtcct gctccagaag ctgctggcgg gccctccgtg 660
tttctgttcc ctccaaagcc taaggaccag ctgatgatct ctcggacacc cgaagtgacc 720
tgcgtggtgg tggatgtgtc tcaagaggac cctgaggtgc agttcaattg gtacgtggac 780
ggcgtggaag tgcacaacgc caagaccaag cctagagagg aacagttcaa ctccacctac 840
agagtggtgt ccgtgctgac cgtgctgcac caggattggc tgaacggcaa agagtacaag 900
tgcaaggtgt ccaacaaggg cctgccttcc agcatcgaaa agaccatctc caaggccaag 960
ggccagccta gggaacccca ggtttacacc ctgcctccaa gccaagagga aatgaccaag 1020
aaccaggtgt ccctgacctg cctggtcaag ggcttctacc cttccgacat tgccgtggaa 1080
tgggagagca atggccagcc tgagaacaac tacaagacca cacctcctgt gctggactcc 1140
gacggctcct tctttctgta ctcccgcctg accgtggaca agtccagatg gcaagagggc 1200
aacgtgttct cctgctctgt gctgcacgag gccctgcaca atcactacac ccagaagtcc 1260
ctcagcctgt cccttggc 1278
<210> 32
<211> 1494
<212> DNA
<213> Artificial Sequence
<220>
<223> 编码GI-305C1的多核苷酸
<400> 32
gctgagtcta agtatggccc tccttgtcct ccatgtcctg ctccagaagc tgctggcggg 60
ccctccgtgt ttctgttccc tccaaagcct aaggaccagc tgatgatctc tcggacaccc 120
gaagtgacct gcgtggtggt ggatgtgtct caagaggacc ctgaggtgca gttcaattgg 180
tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagttcaac 240
tccacctaca gagtggtgtc cgtgctgacc gtgctgcacc aggattggct gaacggcaaa 300
gagtacaagt gcaaggtgtc caacaagggc ctgccttcca gcatcgaaaa gaccatctcc 360
aaggccaagg gccagcctag ggaaccccag gtttacaccc tgcctccaag ccaagaggaa 420
atgaccaaga accaggtgtc cctgacctgc ctggtcaagg gcttctaccc ttccgacatt 480
gccgtggaat gggagagcaa tggccagcct gagaacaact acaagaccac acctcctgtg 540
ctggactccg acggctcctt ctttctgtac tcccgcctga ccgtggacaa gtccagatgg 600
caagagggca acgtgttctc ctgctctgtg ctgcacgagg ccctgcacaa tcactacacc 660
cagaagtccc tcagcctgtc ccttggcgga ggcggtggat caggtggcgg aggatctggc 720
ggagaagtgc agctggttga atctggcggc ggattggaac agcctggcgg atctctgaga 780
ctgtcttgtg ccggctctgg cttcaccttc agagactacg ctatgacctg ggtccgacag 840
gctcctggca aatgtctgga atgggtgtcc tccatctctg gctctggcgg caatacctac 900
tacgccgact ctgtgaaggg cagattcacc atcagccggg acaactccaa gaacaccctg 960
tacctccaga tgaactccct gagagccgag gacaccgccg tgtactactg cgccaaggac 1020
agactgtcca tcaccatccg gcctcggtac tacggactgg atgtttgggg ccagggcacc 1080
acagtgacag tgtcctccgg aggcggagga agtggcggcg gaggatcagg cggtggtgga 1140
tctggcggag gcggttctga cattgtgatg acccagtctc cactgagcct gcctgtgaca 1200
cctggcgagc ctgcttccat ctcttgccgg tcatctcagt ccctgctgta ctccatcggc 1260
tacaactacc tggactggta tctccagaag tccggacagt ctccccagct gctgatctac 1320
ctgggctcca atagagcctc cggcgtgccc gatagattct ccggatctgg ctctggcacc 1380
gacttcaccc tgaagatctc cagagtggaa gccgaggacg tgggcttcta ctactgtatg 1440
caggccctcc agacacctta cacctttggc tgtggcacca agctggaaat caag 1494
Claims (19)
1.一种包含IgE Fc受体α亚基胞外结构域(FcεRIα-ECD)和抗IL-4R抗体的片段的融合蛋白。
2.如权利要求1所述的融合蛋白,其中所述融合蛋白包含免疫球蛋白的Fc区。
3.如权利要求1所述的融合蛋白,其中所述IgE Fc受体α亚基胞外结构域由SEQ ID NO:2的氨基酸序列或其片段组成。
4.如权利要求1所述的融合蛋白,其中所述抗IL-4R抗体的片段包含
重链可变区包含SEQ ID NO:20的HCDR1、SEQ ID NO:21的HCDR2和SEQ IDNO:22的HCDR3;和
轻链可变区包含SEQ ID NO:23的LCDR1、SEQ ID NO:24的LCDR2和SEQ ID NO:25。
5.如权利要求1所述的融合蛋白,其中所述抗IL-4R抗体的片段包含SEQ ID NO:7的重链可变区和SEQ ID NO:8的轻链可变区。
6.如权利要求5所述的融合蛋白,其中所述SEQ ID NO:7的重链可变区和SEQ IDNO:8的轻链可变区由肽连接子连接。
7.如权利要求1所述的融合蛋白,其中所述融合蛋白由以下结构式(I)或(II)组成:
N’-X-连接子(1)-Fc区片段或其变体-连接子(2)-Y-C’(I)
N’-Y-连接子(1)-Fc区片段或其变体-连接子(2)-X-C’(II)
在所述结构式(I)和(II)中,
N’为所述融合蛋白的N端,
C’为所述融合蛋白的C端,
X为FcεRIα-ECD或其片段,
Y为抗IL-4R抗体的片段,和
所述连接子(1)和连接子(2)为肽连接子。
8.如权利要求7所述的融合蛋白,其中所述融合蛋白的Fc区来源于人IgG4。
9.一种融合蛋白二聚体由两个如权利要求1至8中任一项所述的融合蛋白结合。
10.一种编码如权利要求1至8中任一项所述的融合蛋白的多核苷酸。
11.一种包含如权利要求10所述的多核苷酸的表达载体。
12.一种导入了如权利要求11所述的载体的转化细胞。
13.一种生产融合蛋白二聚体的方法,包含:
i)培养如权利要求12所述的转化细胞;和
ii)回收融合蛋白二聚体。
14.一种用于预防或治疗过敏性疾病的药物组合物,包含如权利要求9所述的融合蛋白二聚体。
15.如权利要求14所述的药物组合物,其中所述过敏性疾病选自由食物过敏、特应性皮炎、哮喘、过敏性鼻炎、过敏性结膜炎、过敏性皮炎、慢性特发性荨麻疹和过敏性接触性皮炎组成的组中的一种。
16.一种用于改善或减轻过敏性症状的食品组合物,包含如权利要求9所述的融合蛋白二聚体。
17.如权利要求9所述的融合蛋白二聚体在制备治疗或预防过敏性疾病的药物中的应用。
18.如权利要求9所述的融合蛋白二聚体在治疗或预防过敏性疾病中的应用。
19.一种治疗或预防过敏性疾病的方法,包含给受试者施用如权利要求9所述的融合蛋白二聚体。
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KR20200088941 | 2020-07-17 | ||
KR10-2020-0088941 | 2020-07-17 | ||
PCT/KR2021/009047 WO2022015049A1 (ko) | 2020-07-17 | 2021-07-14 | IgE Fc 수용체 알파서브유닛의 세포외 도메인 및 항-IL-4R 항체를 포함하는 융합단백질 및 이의 용도 |
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US (1) | US20230279124A1 (zh) |
EP (1) | EP4183803A4 (zh) |
JP (1) | JP2023534024A (zh) |
KR (1) | KR102468170B1 (zh) |
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PT2769992T (pt) | 2006-10-02 | 2021-03-11 | Regeneron Pharma | Anticorpos humanos com elevada afinidade para o receptor de il-4 humana |
KR20120135868A (ko) * | 2011-06-07 | 2012-12-17 | (주)네오팜 | FcεRI 특이적 인간 항체 및 이를 포함하는 알레르기 질환 치료 또는 진단용 조성물 |
TWI633891B (zh) * | 2013-06-04 | 2018-09-01 | 再生元醫藥公司 | 藉由投與il-4r抑制劑以治療過敏及增強過敏原-特異之免疫療法的方法 |
US8980273B1 (en) * | 2014-07-15 | 2015-03-17 | Kymab Limited | Method of treating atopic dermatitis or asthma using antibody to IL4RA |
EP3192806A1 (en) * | 2016-01-13 | 2017-07-19 | Affiris AG | Alpha chain of the high-affinity ige receptor (fceria) |
CA3086222A1 (en) * | 2018-01-08 | 2019-07-11 | Gi Innovation, Inc. | Extracellular domain of alpha subunit of ige fc receptor, pharmaceutical composition comprising same and method for producing same |
KR102038679B1 (ko) * | 2018-01-12 | 2019-10-30 | (주)지아이이노베이션 | 프로바이오틱스 및 IgE에 결합능이 있는 폴리펩티드를 포함하는 조성물 및 이의 용도 |
KR102330596B1 (ko) * | 2018-11-09 | 2021-11-26 | 아주대학교산학협력단 | 인간 il-4 수용체 알파에 대한 고친화도 인간 항체 및 이의 용도 |
-
2021
- 2021-07-14 KR KR1020210092362A patent/KR102468170B1/ko active IP Right Grant
- 2021-07-14 US US18/005,752 patent/US20230279124A1/en active Pending
- 2021-07-14 CN CN202180056780.XA patent/CN116348605A/zh active Pending
- 2021-07-14 JP JP2023502645A patent/JP2023534024A/ja active Pending
- 2021-07-14 WO PCT/KR2021/009047 patent/WO2022015049A1/ko unknown
- 2021-07-14 EP EP21841750.9A patent/EP4183803A4/en active Pending
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WO2022015049A1 (ko) | 2022-01-20 |
JP2023534024A (ja) | 2023-08-07 |
KR20220010449A (ko) | 2022-01-25 |
EP4183803A1 (en) | 2023-05-24 |
EP4183803A4 (en) | 2024-04-17 |
KR102468170B1 (ko) | 2022-11-17 |
US20230279124A1 (en) | 2023-09-07 |
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