CN114957472B - 抗IL-4Rα的单域抗体以及应用和药物 - Google Patents
抗IL-4Rα的单域抗体以及应用和药物 Download PDFInfo
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Abstract
本发明公开了抗IL‑4Rα的单域抗体以及应用和药物,涉及抗体技术领域。本发明公开的单域抗体的氨基酸序列如SEQ ID NO.1‑7、SEQ ID NO.9‑12或SEQ ID NO.14‑18中的任一项所示。该单域抗体可特异性结合IL‑4Rα,可用于IL‑4Rα相关疾病如自身免疫疾病的预防诊断和/或治疗。
Description
技术领域
本发明涉及抗体技术领域,具体而言,涉及抗IL-4Rα的单域抗体以及应用和药物。
背景技术
IL-4和IL-4Rα是理想的药物治疗靶点,主要用于治疗二型辅助T(Th2)细胞异常相关的人体疾病。人IL-4Rα亚基(Swiss Prot数据库收录号:P24394)是一个分子量为140kDa的I型膜蛋白,和人IL-4的结合具有高亲和力。IL-4/IL-4Rα复合体可以通过IL-4分子上的结构域使IL-4Rα与CD132或IL-13Rα1亚基形成二聚体,从而形成两种不同的信号分子复合物,分别对应I类和II类受体。除此之外,IL-13结合IL-13Rα1后形成的复合物可以募集IL-4Rα亚基,同样可以形成II类受体复合物。所以IL-4Rα可以调节IL-4,IL-13两个分子相关的生物学活性(Gessner等,Immunobiology,201:285,2000)。体外实验研究表明IL-4和IL-13的激活效应对多种细胞都有作用,这些细胞包括:T淋巴细胞,B淋巴细胞,嗜酸性粒细胞,巨细胞,嗜碱性粒细胞,气道平滑肌细胞,肺纤维细胞和内皮细胞。
IL4Rα在不同类型的细胞上表达水平都不高,一般是每个细胞表达100-5000个分子(Lowenthal等,J Immunol,140:456,1988),例如外周血T细胞,单核细胞,气道上皮细胞,B细胞和肺成纤维细胞。I型受体在造血细胞表面具有表达优势,而II型受体在造血细胞和非造血细胞表面都有表达。
IL-4Rα在人类群体中的多态性已有研究做过讨论(Gessner et al,Immunobiology,201:285,2000),研究显示在某些群体中该分子的多态性是与IgE水平或临床特应性相关的,例如,V75R576 IL-4Rα与变应性哮喘以及IL-4Rα功能增强有关(Risma等,J.Immunol.169(3)1604-1610,2002)。
许多证据表明,IL-4/IL-13途径在哮喘病理学(有关综述参见Chatila,Trends inMolecular Med,10:493,2004)以及大量罗列于本文它处的其它病症中起着重要作用。目前认为,IL-4和IL-13的分泌增加引发并维持这种疾病过程。IL-13被认为是触发气道高反应性(AHR)、粘液分泌过多以及气道重塑的重要配体,而IL-4则被认为是Th2极化和IgE产生的主要诱发因素(Wynn,Annu Rev Immunol,21:425,2003)。
动物模型的证据进一步支持IL-4Rα在哮喘中的作用。在用卵清蛋白(OVA,一种模型变应原)进行变应原刺激的过程中,IL-4R拮抗剂(IL-4突变体;C118缺失)抑制了OVA敏化引起的功能性鼠体内过敏性气道嗜酸性粒细胞增多以及AHR的发生(Tomkinson等,J.Immunol.166(9):5792-5800,2001)。此外,多项体内研究证实了在哮喘动物模型中阻断IL-13或IL-14的正面作用。例如,在OVA-诱导持续性气道炎症的慢性模型中,治疗剂量的抗IL-13单克隆抗体抑制了AHR、中止了上皮下的纤维化和炎症的进展、并将粘液分泌过多状态恢复到了基础水平(Yang等,J.Pharmacol.Exp.Ther.313(1):8-15,2005)。在小鼠OVA模型中,但在免疫期间给药时,用抗IL-4抗体抑制IL-4显示出使嗜酸性粒细胞浸润的显著降低的效果(Coyle等,Am J Resp Cell Mol Biol,13:54,1995)。在类似模型中,OVA刺激后,IL-4缺陷型小鼠在支气管肺泡灌洗液中的嗜酸性粒细胞明显较少,支气管周围炎症也少得多(Brusselle等,Clin Exp Allergy,24:73,1994)。
对于人,临床IIa期研究显示,在哮喘病人当中,IL-4Rα拮抗剂(所谓IL-4突变蛋白)降低变应原诱导的延迟哮喘反应并减弱哮喘患者肺的静息期炎症状态(Wenzel等,Lancet,370:1422,2007)。这些临床数据进一步强化了IL-4Rα拮抗剂在哮喘方面具有临床实用性的主张。
除了其在哮喘中的作用,IL-4Rα与许多其它病理学情形有关,例如COPD,包括患各种程度的慢性支气管炎、小气道疾病和肺气肿的患者群。COPD的根本发病原因仍知之不详。“荷兰假说”认为,COPD和哮喘存在着共同的易感性,因此,类似的机理可能会造成这两种病症发病(Sluiter等,Eur Respir J,4(4):p.479-89,1991)。Zheng等人(J Clin Invest,106(9):1081-93,2000)证实,IL-13在小鼠肺中的过度表达引起肺气肿、提高粘膜产量及炎症,可以反映了人COPD的诸多特征。此外,作为过敏性炎症的小鼠模型中的IL-13依赖性应答,AHR显示可预测吸烟者的肺功能减退(Tashkin等,Am J Respir Crit Care Med,153(6Pt1):1802-11,1996)。另外还确立了IL-13启动子多态性与产生COPD易感性之间的关联(VanDer Pouw Kraan等人,Genes Immun,3(7):436-9,2002)。因此,正是IL-4/IL-13途径,尤其是IL-13,在COPD的发病机理中起着重要作用。
IL-13在炎性肠病的发病机理可能有作用。Heller等人(Heller等,Immunity,17(5):629-38,2002)报道,给予可溶性IL-13Rα2中和IL-13改善了人溃疡性结肠炎的鼠模型中的结肠炎症。相应地,与对照相比,溃疡性结肠炎患者的直肠活检试样中IL-13的表达较高(Inoue等,Am J Gastroenterol,94(9)JMl-6,I999)。
除哮喘外,IL-4/IL-13途径还与其它纤维化病症相关,像全身性硬皮病(Hasegawa等,J Rheumatol,24(2):328-32,1997)、肺纤维化(Hancock等,Am J Respir Cell MolBiol,18(1):60-5,1998)、寄生虫诱导的肝纤维化(Fallon等,J Immunol,164(5)2585-91,2000;Chiaramonte等,J Clin Invest,104(6):777-85,1999;Chiaramonte,Hepatology 34(2):273-82,2001),以及膀胱纤维化(Hauber等,J.Cyst Fibr,2 189,2003)。
IL-4对于B细胞介导的活性是决定性的,比如B细胞增生、免疫球蛋白分泌、以及FcεR的表达。IL-4Rα抑制剂的临床应用包括例如在变态反应治疗中用于遏制IgE合成(例如包括特应性皮炎和食物变态反应)、在移植治疗中用于预防移植排异、以及遏制延迟型过敏性或接触过敏性反应。
IL-4R拮抗剂还可用作变态反应免疫疗法的佐剂以及用作疫苗佐剂。针对IL-4Rα的抗体已有描述。两个例子是中和性鼠抗IL-4Rα单克隆抗体ΜΑΒ230(克隆25463)和16146(克隆25463.11),分别由R&D公司(R&D Systems)和Sigma公司提供。这些抗体属于IgG2a亚型,是通过小鼠杂交瘤方法获得的,是从被纯化后的重组人IL-4Rα(杆状病毒来源)免疫的小鼠开发出的。另外两个中和性鼠抗IL-4Rα抗体M57和X2/45-12分别由BDBiosciences和eBioscience提供。这些是IgGl抗体,也是由用重组可溶性IL-4Rα免疫的小鼠通过小鼠杂交瘤技术获得的。
但是本领域仍需要能够与IL-4Rα高亲和力结合,并且能够阻断IL-4与IL-4Rα结合的抗IL-4Rα抗体,特别是抗IL-4Rα重链单域抗体。
鉴于此,特提出本发明。
发明内容
本发明的目的在于提供一种抗IL-4Rα的单域抗体以及应用和药物。该单域抗体可特异性结合IL-4Rα,其亲和力较高,且易于制备,生产成本低,此外,该单域抗体以免疫异质性低,作为药物使用时,不会产生较强的免疫反应,其应用前景广阔。
本发明是这样实现的:
第一方面,本发明提供一种抗IL-4Rα的单域抗体,其包括如下互补决定区:CDR1、CDR2和CDR3;
其中,CDR1的氨基酸序列如SEQ ID NO.37-53中的任意一种所示,CDR2的氨基酸序列如SEQ ID NO.54-68中的任意一种所示,CDR3的氨基酸序列如SEQ ID NO.69-85中的任意一种所示。
本发明提供的抗IL-4Rα的单域抗体,其CDR1、CDR2和CDR3可以分别在SEQ IDNO.37-53、SEQ ID NO.54-68以及SEQ ID NO.69-85序列范围内变化或选择,CDR1、CDR2和CDR3无论以何种序列组合,所得到的单域抗体都可以与IL-4Rα特异性结合,具有不错的亲和力,可用于制备治疗IL-4Rα介导的相关疾病,也可用于制备检测IL-4Rα的试剂,该单域抗体用途广泛且多样。
另外,本发明提供的单域抗体结构简单,易于制备,生产成本低,且由于其具有较低的免疫异质性,将其作为药物用于治疗IL-4Rα介导的相关疾病时,不易产生免疫反应,具有良好的应用前景。
需要说明的是,在本发明公开了上述互补决定区的结构基础上,本领域技术人员容易想到在其基础上进行一个或多个氨基酸的替换或删除,以获得对IL-4Rα的结合活性或亲和力大致相同的或者是提高的单域抗体突变体,这是本领域技术人员容易实现的,基于此,这类单域抗体突变体也是属于本发明的保护范围。
可选地,在本发明的一些实施方案中,所述单域抗体的互补决定区如以下(1)-(18)中的任意一项所示:
(1):CDR1如SEQ ID NO.53所示,CDR2如SEQ ID NO.61所示,CDR3如SEQ ID NO.73所示;
(2):CDR1如SEQ ID NO.37所示,CDR2如SEQ ID NO.61所示,CDR3如SEQ ID NO.72所示;
(3):CDR1如SEQ ID NO.39所示,CDR2如SEQ ID NO.58所示,CDR3如SEQ ID NO.78所示;
(4):CDR1如SEQ ID NO.53所示,CDR2如SEQ ID NO.63所示,CDR3如SEQ ID NO.72所示;
(5):CDR1如SEQ ID NO.42所示,CDR2如SEQ ID NO.64所示,CDR3如SEQ ID NO.74所示;
(6):CDR1如SEQ ID NO.46所示,CDR2如SEQ ID NO.66所示,CDR3如SEQ ID NO.所69示;
(7):CDR1如SEQ ID NO.50所示,CDR2如SEQ ID NO.68所示,CDR3如SEQ ID NO.85所示;
(8):CDR1如SEQ ID NO.48所示,CDR2如SEQ ID NO.55所示,CDR3如SEQ ID NO.80所示;
(9):CDR1如SEQ ID NO.47所示,CDR2如SEQ ID NO.60所示,CDR3如SEQ ID NO.83所示;
(10):CDR1如SEQ ID NO.49所示,CDR2如SEQ ID NO.67所示,CDR3如SEQ ID NO.81所示;
(11):CDR1如SEQ ID NO.38所示,CDR2如SEQ ID NO.58所示,CDR3如SEQ ID NO.77所示;
(12):CDR1如SEQ ID NO.45所示,CDR2如SEQ ID NO.54所示,CDR3如SEQ ID NO.70所示;
(13):CDR1如SEQ ID NO.41所示,CDR2如SEQ ID NO.59所示,CDR3如SEQ ID NO.84所示;
(14):CDR1如SEQ ID NO.43所示,CDR2如SEQ ID NO.57所示,CDR3如SEQ ID NO.82所示;
(15):CDR1如SEQ ID NO.40所示,CDR2如SEQ ID NO.56所示,CDR3如SEQ ID NO.76所示;
(16):CDR1如SEQ ID NO.44所示,CDR2如SEQ ID NO.58所示,CDR3如SEQ ID NO.75所示;
(17):CDR1如SEQ ID NO.52所示,CDR2如SEQ ID NO.62所示,CDR3如SEQ ID NO.71所示;
(18):CDR1如SEQ ID NO.51所示,CDR2如SEQ ID NO.65所示,CDR3如SEQ ID NO.79所示。
具有上述第(1)-(18)项所示的CDR结构的单域抗体,能够与IL-4Rα特异性结合,具有较高的亲和力,尤其是第(1)、第(3)以及第(6)项所示的CDR结构。
可选地,在本发明的一些实施方案中,所述单域抗体包括如下骨架区:FR1、FR2、FR3和FR4;
其中,FR1的氨基酸序列如SEQ ID NO.86-97中的任意一种所示;FR2的氨基酸序列如SEQ ID NO.98-109中的任意一种所示;FR3的氨基酸序列如SEQ ID NO.110-127中的任意一种所示;FR4的氨基酸序列如SEQ ID NO.128所示。
需要说明的是,单域抗体实现与IL-4Rα特异性结合的功能主要依赖于CDR区,基于此,在本发明公开了单域抗体骨架区和CDR区序列的基础上,本领域技术人员容易想到在CDR区序列保持不变或稍微改动的前提下,采用与本发明所公开的骨架区序列相似的序列例如同源性达到80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%以上的序列作为单域抗体的骨架区序列,以使得到的单域抗体的功能与本发明前述的单域抗体具有相同的或相似的功能,这也是属于本发明的保护范围。
可选地,在本发明的一些实施方案中,所述单域抗体的骨架区FR1、FR2和FR3如下(a)-(r)中的任意一项所示:
(a)FR1如SEQ ID NO.88所示,FR2如SEQ ID NO.100所示,FR3如SEQ ID NO.115所示;
(b)FR1如SEQ ID NO.88所示,FR2如SEQ ID NO.100所示,FR3如SEQ ID NO.114所示;
(c)FR1如SEQ ID NO.95所示,FR2如SEQ ID NO.102所示,FR3如SEQ ID NO.123所示;
(d)FR1如SEQ ID NO.86所示,FR2如SEQ ID NO.100所示,FR3如SEQ ID NO.117所示;
(e)FR1如SEQ ID NO.94所示,FR2如SEQ ID NO.105所示,FR3如SEQ ID NO.113所示;
(f)FR1如SEQ ID NO.87所示,FR2如SEQ ID NO.99所示,FR3如SEQ ID NO.110所示;
(g)FR1如SEQ ID NO.91所示,FR2如SEQ ID NO.109所示,FR3如SEQ ID NO.111所示;
(h)FR1如SEQ ID NO.87所示,FR2如SEQ ID NO.100所示,FR3如SEQ ID NO.119所示;
(i)FR1如SEQ ID NO.89所示,FR2如SEQ ID NO.101所示,FR3如SEQ ID NO.124所示;
(j)FR1如SEQ ID NO.93所示,FR2如SEQ ID NO.98所示,FR3如SEQ ID NO.112所示;
(k)FR1如SEQ ID NO.94所示,FR2如SEQ ID NO.106所示,FR3如SEQ ID NO.125所示;
(l)FR1如SEQ ID NO.92所示,FR2如SEQ ID NO.107所示,FR3如SEQ ID NO.127所示;
(m)FR1如SEQ ID NO.87所示,FR2如SEQ ID NO.103所示,FR3如SEQ ID NO.120所示;
(n)FR1如SEQ ID NO.87所示,FR2如SEQ ID NO.108所示,FR3如SEQ ID NO.126所示;
(o)FR1如SEQ ID NO.97所示,FR2如SEQ ID NO.105所示,FR3如SEQ ID NO.121所示;
(p)FR1如SEQ ID NO.90所示,FR2如SEQ ID NO.105所示,FR3如SEQ ID NO.122所示;
(q)FR1如SEQ ID NO.88所示,FR2如SEQ ID NO.100所示,FR3如SEQ ID NO.116所示;
(r)FR1如SEQ ID NO.96所示,FR2如SEQ ID NO.104所示,FR3如SEQ ID NO.118所示。
可选地,在本发明的一些实施方案中,所述单域抗体的氨基酸序列如SEQ IDNO.1-18中的任一项所示。
第二方面,本发明提供一种融合蛋白,其包括能够特异性结合IL-4Rα的功能结构域,所述功能结构域由如上一项所述的抗IL-4Rα的单域抗体构成。
本发明提供的单域抗体可以与其他的任意蛋白或物质融合,以实现不同的目的,例如与荧光蛋白、酶或放射性元等结合以实现易于检测的目的,再如与治疗IL-4Rα介导相关疾病的药物分子融合以实现更佳的治疗目的。与该单域抗体融合的蛋白类型,本领域技术人员可以根据实际需要或目的合理选择,无论融合何种类型的物质融合,其都是属于本发明的保护范围。
第三方面,本发明提供一种抗IL-4Rα的抗体,所述抗体为传统抗体或其功能性片段,所述抗体的重链可变区由如上任一项所述的抗IL-4Rα的单域抗体构成。
传统抗体在结构上由两条相同的重链和两条相同的轻链组成,轻链具有轻链可变区(VL)和轻链恒定区(CL);重链具有重链可变区(VH)和重链恒定区(CH1,CH2,CH3和/或CH4)。在本发明公开了具有能够特异性结合IL-4Rα的单域抗体抗体的结构前提下,本领域技术人员容易想到利用本发明的单域抗体对传统抗体以改造,例如将本发明单域抗体的CDR区结构应用到传统抗体上,以获得可以特异性结合IL-4Rα的传统抗体,这类传统体也是属于本发明的保护范围;进一步地,基于传统抗体的结构,其部分结构例如Fab、Fab’、(Fab’)2、Fv、scFv或sdFv结构等也是具有IL-4Rα结合特异性的,这也是属于本发明的保护范围。
可选地,在本发明的一些实施方案中,所述功能性片段为所述传统抗体的Fab、Fab’、(Fab’)2、Fv、scFv或sdFv结构。
如上任一项所述的抗IL-4Rα的单域抗体、如上所述的融合蛋白或如上所述的抗体在制备以IL-4Rα为靶点以治疗疾病的药物中的应用。
可选地,在本发明的一些实施方案中,所述疾病选自哮喘、过敏性皮炎、湿疹、关节炎、疱疹、慢性原发性荨麻疹、硬皮病、肥大性瘢痕、慢性阻塞性肺疾病(chronicobstructive pulmonary disease,COPD)、特应性皮炎、特发性肺纤维化、川崎病、镰状细胞病、格雷夫斯氏病、舍格伦综合征、自体免疫淋巴组织增生性综合征、自体免疫性溶血性贫血、巴雷特食管、自体免疫葡萄膜炎、结核病和肾病。
本发明的抗体可以用于治疗以IL-4Rα为靶点中和IL-4Rα进而实现治疗疾病的效果,该类疾病包括但不限于上述的疾病,用于其他疾病的治疗也属于本发明的保护范围。
第四方面,本发明提供一种治疗疾病的药物,其包括如上任一项所述的抗IL-4Rα的单域抗体、如上所述的融合蛋白或如上所述的抗体,以及药学上可接受的辅料。
上述药学上可接受的辅料是指药学领域的药用辅料,例如:稀释剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、崩解剂、吸附载体、润滑剂等。另外还可以加入其他辅料如香味剂、甜味剂等。即所述的辅料为稀释剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、崩解剂、吸附载体、润滑剂、香味剂、甜味剂中的一种或两种以上。
本发明所提供的药物的剂型并没有严格的限制,可根据药剂领域的现有方法制备成各种剂型,通过口服、鼻吸、直肠、肠胃外或经皮给药等方式施用于需要治疗的患者。
第五方面,本发明提供一种分离的核酸分子,其编码如上任一项所述的单域抗体。
需要说明的是,基于本发明公开的内容,本领域技术人员通过本领域常规技术容易获得编码上述单域抗体以及融合蛋白的多核苷酸分子,并基于密码子的简并性,该多核酸分子是多变的,其具体的碱基序列存在多种可能性,基于此,无论其多核酸分子如何变化,只要其能够编码本发明的单域抗体或融合蛋白即属于本发明的保护范围。
可选地,在本发明的一些实施方案中,所述核酸分子的碱基序列如SEQ ID NO.19-36中的任一项所示。
第六方面,本发明提供含有如上所述的核酸分子的载体。
第七方面,本发明提供含有如上所述的载体的重组细胞。
第八方面,本发明提供制备如上任一项所述的单域抗体的方法,其包括:培养如上所述的重组细胞,从培养产物中分离纯化得所述单域抗体。
需要说明的是,制备本发明的单域抗体、融合蛋和抗体可以通过化学合成的方法,也可以是通过基因工程技术实现,或者是其他的方法,无论以何种方法制备本发明前述的单域抗体、融合蛋白或抗体,其都是属于本发明的保护范围。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,应当理解,以下附图仅示出了本发明的某些实施例,因此不应被看作是对范围的限定,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他相关的附图。
图1为人源重组蛋白IL-4Rα纯化结果分析图。
图2公司自产IL-4Rα重组蛋白与工具抗体的结合活性的测定,其中近岸购买的IL-4Rα重组蛋白为对照代号Novo,自产IL-4Rα重组蛋白代号为RJK,工具抗体代号为Tab,人源IgG为阴性同型对照抗体。
图3为针对IL-4Rα重组蛋白的单域抗体文库筛选后的富集情况,其中P/N=生物淘选中阳性孔洗脱下的噬菌体感染TG1细菌后生长的单克隆细菌数/阳性孔洗脱下的噬菌体感染TG1细菌后生长的单克隆细菌数,该参数在富集发生后会逐渐增大;I/E=生物淘选中每轮加入阳性孔的噬菌体总量/生物淘选中每轮从阳性孔洗脱出的噬菌体总量,该参数在富集发生后会逐渐趋近于1,实施中第三轮富集P/N=1000,I/E=2。
图4为镍柱一步亲和层析后的单域抗体的SDS-PAGE分析结果。
图5为纯化后的单域抗体与IL-4Rα的亲和力量效曲线。
图6为纯化后的Fc融合单域纳米抗体在IL-4诱导的TF-1细胞增殖实验中的中和实验量效曲线。
图7为纯化后的Fc融合单域纳米抗体在IL-13诱导的TF-1细胞增殖实验中的中和实验量效曲线。
图8为单域抗体1H1和4E9的亲和力动力学测定曲线和曲线的拟合结果。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
构建人源重组IL-4Rα蛋白的表达载体
方法如下:
(1)在NCBI中检索获得IL-4Rα的编码序列,收录号为NM_000418.3,该序列编码产生的氨基酸序列登录号为NP_000409.1。
(2)分别通过TMHMM和SMART网站对NP_000409.1对应的氨基酸序列进行蛋白跨膜区和胞外端的分析。
(3)分析结果显示IL-4Rα蛋白的胞外端为1-232位氨基酸,其中1-25位为该蛋白的信号肽。
(4)利用基因合成的方式将编码IL-4Rα蛋白的26-232位氨基酸的核苷酸序列克隆到载体pcDNA3.4中。
(5)将构建好的载体进行Sanger测序,比对原始序列,确认无误后,将该重组质粒进行批量抽提,去除内毒素,转染悬浮293F进行目的蛋白的表达、纯化,纯化后IL-4Rα重组蛋白的SDS-PAGE和western blot分析结果如图1所示。
实施例2人源重组蛋白的结合活性的测定
结合活性的实验方法参考专利申请号为202010166444.8发明名称为可特异性结合EpCAM的单域抗体及其应用的中国发明专利中所公开的方法进行,以购自近岸的重组IL-4Rα蛋白作为阳性对照重组蛋白,人源IgG作为工具抗体的阴性同型对照。绘制曲线,结果如图2所示,虽然在高浓度下与对照相比自产蛋白的显色较弱,但是其与工具抗体结合能力(EC50)相当,人源IgG同型对照与近岸购买和公司自产的IL-4Rα重组蛋白都不结合。
实施例3
构建针对IL-4Rα蛋白的单域抗体文库
方法如下:
(1)将2mg实施例1中纯化获得的IL-4Rα重组蛋白与等体积的弗氏完全佐剂混合,免疫一只内蒙古阿拉善双峰驼,每周免疫一次,共连续免疫7次,除首次免疫外,其余六次均是用1mg IL-4Rα重组蛋白与弗氏不完全佐剂等体积混合进行动物免疫,该免疫过程是为了集中刺激骆驼使其产生针对IL-4Rα的抗体。
(2)动物免疫结束后,抽取骆驼外周血淋巴细胞100mL并提取细胞的RNA。
(3)利用提取的总RNA合成cDNA,并通过套式PCR反应以cDNA为模板扩增VHH(重链抗体可变区)。
(4)利用限制性内切酶分别酶切pMECS载体和VHH片段,然后将酶切后的片段和载体连接。
(5)将连接后的片段转化至感受态细胞TG1中,构建IL-4Rα蛋白的噬菌体展示文库并测定库容,文库的库容大小约为1×109。
实施例4
筛选针对IL-4Rα蛋白的单域抗体
方法如下:
(1)取200μL实施例2的重组TG1细胞接种至2×TY培养基中培养,期间加入40μL辅助噬菌体VCSM13侵染TG1细胞,并培养过夜以扩增噬菌体,次日利用PEG/NaCl沉淀噬菌体,离心收集扩增噬菌体。
(2)将稀释在100mM pH 8.3的NaHCO3中的IL-4Rα重组蛋白500μg偶联在酶标板上,4℃放置过夜,同时设立阴性对照孔。
(3)第二天加入200μL的3%的脱脂乳,室温封闭2h。
(4)封闭结束后,加入100μL扩增后噬菌体文库(大约2×1011个噬菌体颗粒),室温作用1h。
(5)作用1小时后,用PBS(含0.05%Tween-20)洗5遍,以洗掉未结合的噬菌体。
(6)用终浓度为2.5mg/mL的胰蛋白酶将与IL-4Rα重组蛋白特异性结合的噬菌体解离下,并感染处于对数生长期的大肠杆菌TG1细胞,37℃培养1h,产生并收集噬菌体用于下一轮的筛选,相同筛选过程重复1轮,逐步得到富集,当富集倍数达到10倍以上时,富集效果如图3所示。
实施例5
用噬菌体的酶联免疫方法(ELISA)筛选针对IL-4Rα的特异性阳性克隆。
方法如下:
(1)根据实施例2单域抗体筛选方法对IL-4Rα重组蛋白进行3轮筛选,筛选结束后,针对IL-4Rα重组蛋白的噬菌体富集因子达到10以上,从筛选获得的阳性克隆中挑选400个单菌落分别接种于含100μg/mL氨苄青霉素的TB培养基的96深孔板中,并设置空白对照,37℃培养至对数期后,加入终浓度为1mM的IPTG,28℃培养过夜;
(2)利用渗透涨破法获得粗提抗体;将IL-4Rα重组蛋白分别释至100mM pH 8.3的NaHCO3中,并将100μg IL-4Rα重组蛋白在酶标板中4℃包被过夜;
(3)将上述步骤中获得的抗体粗提液取100μL转移至加入抗原的ELISA板上,室温孵育1h;
(4)用PBST洗去未结合的抗体,加入100μl经1:2000稀释后的Mouse anti-HAtagantibody(鼠抗HA抗体,Thermo Fisher),在室温孵育1h;
(5)用PBST洗去未结合的抗体,加入100ul经1:20000稀释后的Anti-Rabbit HRPconjugate(山羊抗兔辣根过氧化物酶标记抗体,购自于Thermo Fisher),在室温孵育1h;
(6)用PBST洗去未结合的抗体,加入辣根过氧化物酶显色液,37℃下反应15min后,加入中止液,于酶标仪上450nm波长处,读取吸收值;
(7)当样品孔OD值大于对照孔5倍以上时,判定为阳性克隆孔;
(8)将阳性克隆孔的菌转摇在含有100μg/μL氨苄青霉素的LB培养基中以便提取质粒并进行测序;
(9)根据序列比对软件Vector NTI分析各个克隆株的基因序列,将CDR1,CDR2,CDR3序列相同的株视为同一克隆株,而序列不同的株视为不同克隆株,获得特异性针对IL-4Rα蛋白的单域抗体。其抗体的氨基酸序列为FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4结构,构成整个VHH。获得的单域抗体重组质粒可以在原核系统中进行表达,获得针对IL-4Rα蛋白的单域抗体。
各单域抗体的编号及其氨基酸序列分析结果即对应的序列标识符(SEQ ID NO.)参见下表1。
表1实施例各单域抗体的CDR和FR对应的序列标识符(SEQ ID NO.)
实施例5
IL-4Rα蛋白的特异性单域抗体在宿主菌大肠杆菌中的纯化及表达。
方法如下:
(1)将上述测序分析所获得不同克隆株的质粒(pMECS-VHH)电转化到大肠杆菌HB2151中,并将其涂布在LB+amp+glucose即含有氨苄青霉素和葡萄糖的培养平板上,37℃培养过夜;
(2)挑选单个菌落接种在5mL含有岸边青霉素的LB培养液中,37℃摇床培养过夜;
(3)接种1mL的过夜培养菌种至330mL TB培养液中,37℃摇床培养,培养到OD600nm值达到0.6-0.9时,加入1M IPTG,28℃摇床培养过夜;
(4)离心,收集大肠杆菌,利用渗透胀破法,获得抗体粗提液;
(5)通过镍柱亲和层析法纯化出抗体,纯化后的单域抗体SDS-PAGE分析结果如图4所示,图中VHH1-18分别对于表1中的抗体编号。
实施例6
制备Fc融合上述单域抗体的Fc融合抗体,制备方法参考专利申请号为202010166444.8,发明名称为可特异性结合EpCAM的单域抗体及其应用的中国发明专利申请中所公开的方法进行。
实施例7
IL-4Rα蛋白的特异性单域抗体的结合量效曲线测定。
实验方法参考专利申请号为202010166444.8,发明名称为可特异性结合EpCAM的单域抗体及其应用的中国发明专利中所公开的方法进行,绘制曲线,计算EC50,结果如图5和下表2所示。
表2单域抗体结合IL-4Rα重组蛋白的EC50
抗体编号 | 1A9 | 1B1 | 1B2 | 1B4 | 1C4 | 1D9 | 1H1 | 2A7 | 2C10 |
EC50(nM) | 2.724 | 0.850 | 5.816 | 0.404 | 2.686 | 0.103 | 1.132 | 3.060 | 4.150 |
抗体编号 | 2C9 | 2H2 | 3C11 | 3E10 | 3F9 | 3G10 | 4B3 | 4E9 | 4H11 |
EC50(nM) | 26.29 | 2.168 | 1.379 | 1.838 | 1.602 | 5.207 | 1.364 | 2.135 | 16.290 |
可以看出,在18株纯化后的单域抗体的结合检测中,除4H11和2C9两株抗体的结合能力在10nM以上,其余抗体结合能力均在10nM以下,且抗体1B4和1D9的结合能力在1nM以下,证明本实施例筛选获得的单域抗体整体结合能力较好。
实施例8
靶向人源IL-4Rα的工具抗体(Tool antibody,Tab)的表达和纯化,Tab1(dupilumab)序列来自IMGT,Tab2(L1012H1031)、Tab3(L1020H1031)序列来自专利(专利号:CN107474134)。
方法如下:
(1)将Tab序列委托通用生物系统(安徽)有限公司进行哺乳动物细胞表达系统密码子优化,并克隆至pcDNA3.1载体。
(2)经过抗性筛选,选择质粒阳性菌扩增,使用质粒中提试剂盒(Macherey Nagel,Cat#740412.50)抽提质粒。
(3)按照每100mL细胞加入100μg质粒(50μg重链+50μg轻链),使用PEI在293F细胞(培养基:FreeStyle 293Expression medium,Thermo,Cat#12338026+F-68,Thermo,Cat#24040032)中瞬转表达。
(4)转染6~24h后加入5%体积的10%Peptone(Sigma,Cat#P0521-100G),8%CO2、130rpm培养约7~8天。
(5)细胞活率降至50%时收取表达上清,使用ProteinA(GE,Cat#17-5438-02)重力柱纯化。
(6)PBS透析后,使用Nanodrop测定浓度,SEC鉴定纯度,间接ELISA验证结合能力。
(7)通过上述方法获得的Tab,浓度不小于2mg/ml,纯度大于94%,与IL-4Rα(Novoprotein,Cat#CS33)和自产IL-4Rα重组蛋白结合EC50均在0.25±0.05nM。
实施例9
人源IL-4诱导的TF1细胞增殖以及工具抗体中和增殖实验。
1人源IL-4诱导的TF1细胞增殖实验方法:
(1)将复苏后传代3-4次的TF-1细胞按10000个每孔铺入96孔板;
(2)将人源IL-4蛋白配置最高浓度为500ng/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的IL-4溶液按细胞培养液的等体积加入细胞培养孔;
(4)孵育72h后,用发光法细胞活力检测试剂盒检测细胞活力;
(5)根据检测结果计算IL-4诱导TF-1细胞增殖的EC80浓度。
2工具抗体(Tab)中和人源IL-4诱导的TF1细胞增殖实验方法:
(1)将复苏后传代3-4次的TF-1细胞按10000个每孔铺入96孔板;
(2)将不同的Tab配制为10μg/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的Tab与增殖实验中获得的EC80浓度的IL-4按1:1混合,制成混合液;
(4)将上步骤中的混合液按细胞培养液的等体积加入细胞培养孔;
(5)孵育72h后,用发光法细胞活力检测试剂盒检测细胞活力;
(6)根据检测结果计算Tab中和IL-4诱导TF-1细胞增殖的EC50浓度,结果如表3所示。
表3工具抗体(Tab)中和IL-4诱导的TF-1增殖检测结果
抗体名称 | Tab1 | Tab2 | Tab3 |
EC50(nM) | 0.18 | 0.067 | 0.098 |
实施例10
人源IL-13诱导的TF1细胞增殖以及工具抗体中和增殖实验。
1人源IL-13诱导的TF1细胞增殖实验方法:
(1)将复苏后传代3-4次的TF-1细胞按10000个每孔铺入96孔板;
(2)将人源IL-4蛋白配置最高浓度为500ng/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的IL-4溶液按细胞培养液的等体积加入细胞培养孔;
(4)孵育72h后,用发光法细胞活力检测试剂盒检测细胞活力;
(5)根据检测结果计算IL-13诱导TF-1细胞增殖的EC80浓度。
2工具抗体(Tab)中和人源IL-13诱导的TF1细胞增殖实验方法:
(1)将复苏后传代3-4次的TF-1细胞按10000个每孔铺入96孔板;
(2)将不同的Tab配制为10μg/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的Tab与增殖实验中获得的EC80浓度的IL-13按1:1混合,制成混合液;
(4)将上步骤中的混合液按细胞培养液的等体积加入细胞培养孔;
(5)孵育72h后,用发光法细胞活力检测试剂盒检测细胞活力;
(6)根据检测结果计算Tab中和IL-13诱导TF-1细胞增殖的EC50浓度。结果如表4所示。
表4工具抗体(Tab)中和IL-13诱导的TF-1增殖检测结果
抗体名称 | Tab1 | Tab2 | Tab3 |
EC50(nM) | 0.073 | 0.097 | 0.047 |
实施例11
特异性针对IL-4Rα的单域抗体中和IL-4诱导TF1细胞增殖的检测。
方法如下:
(1)将复苏后传代3-4次的TF-1细胞按10000个每孔铺入96孔板;
(2)将实施例8不同的Tab、Fc融合的单域抗体(来自实施例6)配制为10μg/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的Tab和单域抗体分别与增殖实验中获得的EC80浓度的IL-4按1:1混合,制成混合液;
(4)将上步骤中的混合液按细胞培养液的等体积加入细胞培养孔;
(5)孵育72h后,用发光法细胞活力检测试剂盒检测细胞活力;
(6)根据检测结果计算不同单域抗体中和IL-4诱导TF-1细胞增殖的EC50浓度,结果如图6和下表5所示。
表5单域抗体中和IL-4诱导的TF-1增殖实验量效曲线检测结果
抗体名称 | 1A9 | 1B1 | 1B2 | 1B4 | 1C4 | 1D9 | 1H1 | 2A7 | 2C10 |
EC50(nM) | 0.099 | 0.302 | 0.363 | 0.190 | 0.055 | 0.086 | 0.072 | 0.119 | 28.1 |
抗体名称 | 2C9 | 2H2 | 3C11 | 3E10 | 3F9 | 3G10 | 4B3 | 4E9 | 4H11 |
EC50(nM) | 2.375 | 0.149 | 0.083 | 0.175 | 0.133 | 0.507 | 0.231 | 0.071 | 16680000 |
可以看出,18株抗体中,与表5中其他单域抗体相比较,4H11的中和效果最差,2C10的中和效果一般,2C9的中和效果虽然不错,但是其EC50仍在1nM以上,其余单域抗体抗体其EC50均在1nM一下,中和效果较好,其中,单域抗体抗体1C4、4E9、1H1的中和效果排名前三,其中1C4的EC50达到55pM。
实施例12
特异性针对IL-4Rα的单域抗体中和IL-13诱导TF1细胞增殖的检测。
方法如下:
(1)将复苏后传代3-4次的TF-1细胞按10000个每孔铺入96孔板;
(2)将实施例8不同的Tab、Fc融合的单域抗体(来自实施例6)配制为10μg/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的Tab和单域抗体分别与增殖实验中获得的EC80浓度的IL-13按1:1混合,制成混合液;
(4)将上步骤中的混合液按细胞培养液的等体积加入细胞培养孔;
(5)孵育72h后,用发光法细胞活力检测试剂盒检测细胞活力;
(6)根据检测结果计算不同单域抗体中和IL-13诱导TF-1细胞增殖的EC50浓度,结果如图7和下表6所示。
表6单域抗体中和IL-13诱导的TF-1增殖实验量效曲线检测结果
抗体名称 | 1A9 | 1B1 | 1B2 | 1B4 | 1C4 | 1D9 | 1H1 | 2A7 | 2C10 |
EC50(nM) | 0.097 | 0.602 | 1.704 | 0.26 | 0.093 | 0.089 | 0.07 | 0.17 | 2.2e+1011 |
抗体名称 | 2C9 | 2H2 | 3C11 | 3E10 | 3F9 | 3G10 | 4B3 | 4E9 | 4H11 |
EC50(nM) | 1.17 | 0.166 | 0.072 | 0.27 | 0.149 | 0.487 | 0.135 | 0.077 | 1.1e+1011 |
可以看出,18株抗体中,与表5中其他单域抗体相比较,4H11和2C10的中和效果较差,2C9、1B2的中和效果虽然不错,但是其EC50仍在1nM以上,其他单域抗体的EC50均在1nM以下,其中,单域抗体1H1、3C11、4E9的中和效果排名前三,1H1的EC50为70pM。
实施例13
结合实施例11和实施例12的实验结果,单域抗体1H1和4E9综合中和效果最好,选择该两株抗体使用Octet RED96仪器进行抗原抗体亲和力测定。具体实施方案如下:
(1)SD缓冲液配制:取适量牛血清白蛋白和吐温20以1×PBS(pH7.4)溶解,使得牛血清白蛋白和吐温20质量(或体积)分数分别为0.1%和0.02%。
(2)抗原工作液配制:抗原(IL-4Rα重组蛋白)以SD缓冲液配制成10μg/mL。
(3)抗体工作液配制:抗体先以SD缓冲液配制成100nM,再按2倍梯度稀释,共设置5个浓度梯度,除此之外再设置一个零浓度。
(4)系统:开启Octet 96及其配套电脑中Data Acquisiton软件,用擦镜纸取适量75%的乙醇清洁采集探头的底面和侧面,仪器预热15min以上。
(5)Sensor预湿:Sensor在实验开始前置于SD缓冲液中浸泡10分钟以上,待用。
(6)结合和解离时间如表7所示:
表7上机步骤
实验步骤 | 时间(s) | 样品 |
Baseline1 | 60 | SD |
Loading | 300 | 抗原 |
Baseline2 | 60 | SD |
Association | 300 | 抗体 |
Dissociation | 300 | SD |
(7)分析结束,关闭仪器和电脑。
(8)数据分析:Data Analysis软件中计算KD,Ka,Kd,Full R2等相关常数,结果如图8和表8所示
表8克隆1H1和4E9亲和力动力学数据汇总表
克隆名 | KD(M) | Ka(1/Ms) | Kd(1/s) |
1H1 | 1.41E-11 | 5.32E+05 | 7.50E-06 |
4E9 | 2.39E-10 | 5.56E+05 | 1.33E-04 |
根据现有文献(专利CN107474134)显示,Tab2和Tab3的亲和力分别为1.04×10-10M和1.83×10-10M,本发明实施例得到的单域抗体1H1的亲和力要明显优于对照抗体,为1.41×10-11,而4E9则与对照抗体基本相当。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 南京融捷康生物科技有限公司
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Gly Tyr Gly Gly Ile Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
50 55 60
Ile Ser Gln Asp Asn Gly Lys His Thr Met Tyr Leu Gln Met Asp Asn
65 70 75 80
Leu Gln Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys Ala Asp Gly Arg
85 90 95
Arg Tyr Arg Gly Thr Cys Ser Ser Phe Ala Thr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 8
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ala Ser Gly Tyr Ile Thr Ser Tyr Cys Met Ala Trp Phe Arg
20 25 30
Gln Ala Pro Gly Lys Glu Arg Glu Ala Val Ala Ser Ile His Thr Arg
35 40 45
Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60
Lys Asp Ile Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Met Leu Lys
65 70 75 80
Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Gly Ser Thr Gly Tyr
85 90 95
Cys Arg Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 9
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Thr Ser Gly Val Phe Tyr Cys Met Ala Trp Phe Arg Gln Ala
20 25 30
Pro Gly Lys Glu Arg Glu Ala Val Ala Thr Ile Arg Ser Gly Gly Arg
35 40 45
Thr Ala Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
50 55 60
Asp Asn Ala Lys Asp Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro
65 70 75 80
Glu Asp Ser Ala Met Tyr Tyr Cys Ala Val Gly Val Asp Gly Asp Cys
85 90 95
Arg Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 10
<211> 126
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Thr Val Ser Gly Tyr Asn Tyr Asn Ser Ala Tyr Ile Gly Trp Phe
20 25 30
Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Val Ile Tyr Ser
35 40 45
Gly Gly Gly Ser Thr Val Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
50 55 60
Ile Ser Leu Asp Ile Ala Gln Asn Thr Val Tyr Leu Gln Met Asn Ser
65 70 75 80
Leu Lys Pro Asp Asp Thr Ala Met Tyr Tyr Cys Ala Ala Ser Val Ala
85 90 95
Arg Arg Gly Ser Thr Leu Pro Gln Pro Leu Arg Leu Gln Pro Ala Tyr
100 105 110
Tyr Asn Lys Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 11
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ala Ser Ala Val Asp Met Tyr Cys Met Ala Trp Phe Arg Gln
20 25 30
Thr Pro Gly Asn Glu Arg Glu Gly Val Ala Ser Ile Arg Ala Gly Thr
35 40 45
Asp Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60
Arg Asp Arg Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys
65 70 75 80
Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Gly Pro Ser Gly Ala
85 90 95
Cys Thr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 12
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Thr Ala Ser Gly Phe Thr Phe Asp Asn Ser Asp Met Gly Trp Tyr
20 25 30
Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val Ser Lys Ile Gly Ser
35 40 45
Thr Arg Thr Pro Tyr Tyr Ser Asp Ser Val Ala Gly Arg Phe Thr Ile
50 55 60
Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Leu Asn Ser Leu
65 70 75 80
Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp Gly Pro Phe
85 90 95
Tyr Val Arg Thr Ser Cys Arg Asp Asp Tyr Arg Gly Pro Ser Tyr Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 13
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ala Ser Gly Asp Phe Tyr Cys Met Ala Trp Phe Arg Gln Ala
20 25 30
Pro Gly Lys Glu Arg Glu Gly Val Ala Thr Ile Arg Ser Gly Gly Arg
35 40 45
Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Lys
50 55 60
Asp Asn Ala Lys Asp Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro
65 70 75 80
Glu Asp Thr Ala Met Tyr Tyr Cys Ala Val Gly Val Asp Gly Asn Cys
85 90 95
Arg Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 14
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ala Ser Gly Phe Lys Phe Gly Thr Ser Val Met Ser Trp Val
20 25 30
Arg Gln Ala Pro Gly Lys Gly Leu Glu Arg Val Ser Leu Ile Asn Arg
35 40 45
Asp Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr
50 55 60
Ile Ser Arg Asp Asn Ala Lys Asn Met Leu Tyr Leu Gln Met Asn Ser
65 70 75 80
Leu Lys Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala Lys Asp Trp Thr
85 90 95
Pro Gly Thr Trp Pro Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 15
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly Ser Leu Arg Val Ser
1 5 10 15
Cys Ala Ala Ser Glu Tyr Thr Tyr Asn Met Tyr Cys Met Ala Trp Phe
20 25 30
Arg Gln Ala Pro Gly Asn Glu Arg Glu Ala Val Ala Ser Ile Lys Thr
35 40 45
Asp Thr Asp Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
50 55 60
Ile Ser Gln Asp Lys Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
65 70 75 80
Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Gly Leu Ser
85 90 95
Gly Ser Cys Thr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
100 105 110
Ser
<210> 16
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Val Ser Gly Phe Thr Asp Ser Leu Tyr Cys Met Ala Trp Phe
20 25 30
Arg Gln Ala Pro Gly Asn Glu Arg Glu Ala Val Ala Ser Ile Arg Ala
35 40 45
Gly Thr Asp Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
50 55 60
Ile Ser Gln Asp Lys Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
65 70 75 80
Leu Arg Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Gly His Ser
85 90 95
Gly Leu Cys Thr Asp Tyr Ser Gly Gln Gly Thr Gln Val Thr Val Ser
100 105 110
Ser
<210> 17
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ser Thr Tyr Thr Tyr Ile Pro Tyr Cys Met Ala Trp Phe Arg
20 25 30
Gln Ala Pro Gly Lys Glu Arg Glu Ala Val Ala Ser Ile Arg Ser Gly
35 40 45
Arg Ile Thr Tyr Tyr Ala Asp Ser Val Lys Ala Arg Phe Thr Ile Ser
50 55 60
Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys
65 70 75 80
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Asp Ser Gly Asn
85 90 95
Cys Asn Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 18
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Glu Ser Ser Thr Ser Thr Ser Ser Ile Tyr Cys Met Ala Trp Phe
20 25 30
Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val Ala Ser Ile Ser Pro
35 40 45
Ala Arg Gly Arg Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ala
50 55 60
Ile Ser Gln Asp Asn Ala Lys Ser Val Leu Tyr Leu Gln Met Asn Ser
65 70 75 80
Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Gly Arg Ser
85 90 95
Gly Thr Cys Asp Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
100 105 110
Ser
<210> 19
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccagcacc 60
tacacctaca ccccctactg catggcctgg ttcaggcagg cccccggcaa ggagagggag 120
gccgtggcca gcatcaggag cggcaggatc gcctactacg ccgacagcgt gaaggccagg 180
ttcaccatca gcctggacaa cgccaagaac accgtgtacc tggagatgaa cagcctgagg 240
cccgaggaca ccggcgtgta ctactgcgcc gccggcgacg tgggcagctg caacaactac 300
tggggccagg gcacccaggt gaccgtgagc agc 333
<210> 20
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccagcagg 60
tacacctaca ccccctactg catggcctgg ttcaggcagg cccccggcaa ggagagggag 120
gccgtggcca gcatcaggag cggcaggatc gcctactacg ccgacagcgt gaaggccagg 180
ttcaccatca gccacgacaa cgccaagaac accgtgtacc tgcagatgaa cagcctgagg 240
cccgaggaca ccggcgtgta ctactgcgcc gccggcgacg tgggcagctg cgacaactac 300
tggggccagg gcacccaggt gaccgtgagc agc 333
<210> 21
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
gagagcggcg gcggcagcgt gcagaccggc ggcagcctga ggctgagctg cgccaccagc 60
gagtacacca gcaacctgta ctgcatggcc tggttcaggc aggcccccgg caaggagagg 120
gagggcatcg ccagcatcag ggccggcacc gacaggacct actacgccga cagcgtgaag 180
ggcaggttca ccatcagcag ggacaaggcc aagaacaccc tgtacctgca gatgaacagc 240
ctgaagcccg aggacaccgc catgtactac tgcgccgccg gccccagcgg cctgtgcacc 300
gactactggg gccagggcac ccaggtgacc gtgagcagc 339
<210> 22
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
gagagcggcg gcggcgccgt ggaggccggc ggcagcctga ggctgagctg cttcagcacc 60
tacacctaca ccccctactg catggcctgg ttcaggcagg cccccggcaa ggagagggag 120
gccgtggcca gcatcaggag cggcaggacc gcctactacg ccgacagcgt gaaggccagg 180
ttcaccatca gccaggacaa cgccaagaac accgtgtacc tgcagatgaa cagcctgagg 240
cccgaggaca ccggcgtgta ctactgcgcc gccggcgacg tgggcagctg cgacaactac 300
tggggccagg gcacccaggt gaccgtgagc agc 333
<210> 23
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 23
gagagcggcg gcggcagcgt gcagaccggc ggcagcctga ggctgagctg cgccgccagc 60
ggcgacaccg tgaacatgta ctgcatggcc tggttcaggc aggcccccgg caacgagagg 120
gaggccgtgg ccagcatcag gagcggcacc gacaggacct actacgccga cgccgtgaag 180
ggcaggttca ccatcagcag ggacaaggcc aagaacaccc tgtacctgca gatgaacagc 240
ctgaagcccg aggacaccgc catgtactac tgcgccgccg gccacagcgg cctgtgcacc 300
gactacaggg gccagggcac ccaggtgacc gtgagcagc 339
<210> 24
<211> 375
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 24
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccgccagc 60
ggcagcaccg gcaggcacta cagcctgggc tggttcaggc aggcccccgg caaggagagg 120
gagggcgtgg ccatcatcta cagctgcggc agggacaccg actacgccga cagcgtgaag 180
ggcaggttca ccatcagcca ggacatcgcc gagagcaccc tgtacctgca gatgaacagc 240
ctgaagcccg aggacaccgg catgtactac tgcgccgccg ccctgggcct gagcaggctg 300
aggtgcgaca cccagagcat cagccccgac gagtacaacg tgtggggcca gggcacccag 360
gtgaccgtga gcagc 375
<210> 25
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 25
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgaggtgagc 60
ggctacacca gctgcaggag gtacgacatg agctggtaca ggcaggcccc cggcaaggag 120
agggagttcg tgagcgtgat cgacggctac ggcggcatca actacgccga cagcgtgaag 180
ggcaggttca ccatcagcca ggacaacggc aagcacacca tgtacctgca gatggacaac 240
ctgcagcccg aggacaccgc catgtactac tgcaaggccg acggcaggag gtacaggggc 300
acctgcagca gcttcgccac ctggggccag ggcacccagg tgaccgtgag cagc 354
<210> 26
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 26
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccgccagc 60
ggctacatca ccagctactg catggcctgg ttcaggcagg cccccggcaa ggagagggag 120
gccgtggcca gcatccacac caggggcacc acctactacg ccgacagcgt gaagggcagg 180
ttcaccatca gcaaggacat cgccaagaac accctgtacc tgcagatgaa catgctgaag 240
cccgaggaca ccgccatgta ctactgcgcc gccggcagca ccggctactg cagggactac 300
tggggccagg gcacccaggt gaccgtgagc agc 333
<210> 27
<211> 330
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 27
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccaccagc 60
ggcgtgttct actgcatggc ctggttcagg caggcccccg gcaaggagag ggaggccgtg 120
gccaccatca ggagcggcgg caggaccgcc tactacgccg acagcgtgaa gggcaggttc 180
accatcagca gggacaacgc caaggacacc ctgtacctgc agatgaacag cctgaagccc 240
gaggacagcg ccatgtacta ctgcgccgtg ggcgtggacg gcgactgcag gaactactgg 300
ggccagggca cccaggtgac cgtgagcagc 330
<210> 28
<211> 378
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 28
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg caccgtgagc 60
ggctacaact acaacagcgc ctacatcggc tggttcaggc aggcccccgg caaggagagg 120
gagggcgtgg ccgtgatcta cagcggcggc ggcagcaccg tgtacgccga cagcgtgaag 180
ggcaggttca ccatcagcct ggacatcgcc cagaacaccg tgtacctgca gatgaacagc 240
ctgaagcccg acgacaccgc catgtactac tgcgccgcca gcgtggccag gaggggcagc 300
accctgcccc agcccctgag gctgcagccc gcctactaca acaagtgggg ccagggcacc 360
caggtgaccg tgagcagc 378
<210> 29
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
gagagcggcg gcggcagcgt gcagaccggc ggcagcctga ggctgagctg cgccgccagc 60
gccgtggaca tgtactgcat ggcctggttc aggcagaccc ccggcaacga gagggagggc 120
gtggccagca tcagggccgg caccgacagg acctactacg ccgacagcgt gaagggcagg 180
ttcaccatca gcagggacag ggccaagaac accctgtacc tgcagatgaa cagcctgaag 240
cccgaggaca ccgccatgta ctactgcgcc gccggcccca gcggcgcctg caccgactac 300
tggggccagg gcacccaggt gaccgtgagc agc 333
<210> 30
<211> 366
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg caccgccagc 60
ggcttcacct tcgacaacag cgacatgggc tggtacaggc aggcccccgg caacgagtgc 120
gagctggtga gcaagatcgg cagcaccagg accccctact acagcgacag cgtggccggc 180
aggttcacca tcagccagga caacgccaag aacaccgtgt acctgcagct gaacagcctg 240
aagcccgagg acaccgccgt gtactactgc gccgccgacg gccccttcta cgtgaggacc 300
agctgcaggg acgactacag gggccccagc tactggggcc agggcaccca ggtgaccgtg 360
agcagc 366
<210> 31
<211> 330
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccgccagc 60
ggcgacttct actgcatggc ctggttcagg caggcccccg gcaaggagag ggagggcgtg 120
gccaccatca ggagcggcgg caggagcacc tactacgccg acagcgtgaa gggcaggttc 180
accatcagca aggacaacgc caaggacacc ctgtacctgc agatgaacag cctgaagccc 240
gaggacaccg ccatgtacta ctgcgccgtg ggcgtggacg gcaactgcag gaactactgg 300
ggccagggca cccaggtgac cgtgagcagc 330
<210> 32
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccgccagc 60
ggcttcaagt tcggcaccag cgtgatgagc tgggtgaggc aggcccccgg caagggcctg 120
gagagggtga gcctgatcaa cagggacggc acctacacct actaccccga cagcgtgaag 180
ggcaggttca ccatcagcag ggacaacgcc aagaacatgc tgtacctgca gatgaacagc 240
ctgaagaccg acgacaccgc catgtactac tgcgccaagg actggacccc cggcacctgg 300
cccaggggcc agggcaccca ggtgaccgtg agcagc 336
<210> 33
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
gagagcggcg gcggcagcgt gcagaccggc ggcagcctga gggtgagctg cgccgccagc 60
gagtacacct acaacatgta ctgcatggcc tggttcaggc aggcccccgg caacgagagg 120
gaggccgtgg ccagcatcaa gaccgacacc gacaggacct actacgccga cagcgtgaag 180
ggcaggttca ccatcagcca ggacaaggcc aagaacaccc tgtacctgca gatgaacagc 240
ctgaagcccg aggacaccgc catgtactac tgcgccgccg gcctgagcgg cagctgcacc 300
aactactggg gccagggcac ccaggtgacc gtgagcagc 339
<210> 34
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccgtgagc 60
ggcttcaccg acagcctgta ctgcatggcc tggttcaggc aggcccccgg caacgagagg 120
gaggccgtgg ccagcatcag ggccggcacc gacaggacct actacgccga cagcgtgaag 180
ggcaggttca ccatcagcca ggacaaggcc aagaacaccc tgtacctgca gatgaacagc 240
ctgaggcccg aggacaccgc catgtactac tgcgccgccg gccacagcgg cctgtgcacc 300
gactacagcg gccagggcac ccaggtgacc gtgagcagc 339
<210> 35
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
gagagcggcg gcggcagcgt gcaggccggc ggcagcctga ggctgagctg cgccagcacc 60
tacacctaca tcccctactg catggcctgg ttcaggcagg cccccggcaa ggagagggag 120
gccgtggcca gcatcaggag cggcaggatc acctactacg ccgacagcgt gaaggccagg 180
ttcaccatca gccaggacaa cgccaagaac accgtgtacc tgcagatgaa cagcctgaag 240
cccgaggaca ccgccgtgta ctactgcgcc gccggcgaca gcggcaactg caacaactac 300
tggggccagg gcacccaggt gaccgtgagc agc 333
<210> 36
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 36
gagagcggcg gcggcagcgt gcagaccggc ggcagcctga ggctgagctg cgagagcagc 60
accagcacca gcagcatcta ctgcatggcc tggttcaggc aggcccccgg caagggcagg 120
gagggcgtgg ccagcatcag ccccgccagg ggcaggacct actacgccga cagcgtgaag 180
ggcaggttcg ccatcagcca ggacaacgcc aagagcgtgc tgtacctgca gatgaacagc 240
ctgaagcccg aggacaccgc catgtactac tgcgccgccg gcaggagcgg cacctgcgac 300
gactactggg gccagggcac ccaggtgacc gtgagcagc 339
<210> 37
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Arg Tyr Thr Tyr Thr Pro Tyr Cys
1 5
<210> 38
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Ser Ala Val Asp Met Tyr Cys
1 5
<210> 39
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Ser Glu Tyr Thr Ser Asn Leu Tyr Cys
1 5
<210> 40
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Ser Glu Tyr Thr Tyr Asn Met Tyr Cys
1 5
<210> 41
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Ser Gly Asp Phe Tyr Cys
1 5
<210> 42
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Ser Gly Asp Thr Val Asn Met Tyr Cys
1 5
<210> 43
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Ser Gly Phe Lys Phe Gly Thr Ser Val
1 5
<210> 44
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Ser Gly Phe Thr Asp Ser Leu Tyr Cys
1 5
<210> 45
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Ser Gly Phe Thr Phe Asp Asn Ser Asp
1 5
<210> 46
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Ser Gly Ser Thr Gly Arg His Tyr Ser
1 5
<210> 47
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Ser Gly Val Phe Tyr Cys
1 5
<210> 48
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Ser Gly Tyr Ile Thr Ser Tyr Cys
1 5
<210> 49
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Ser Gly Tyr Asn Tyr Asn Ser Ala Tyr
1 5
<210> 50
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Ser Gly Tyr Thr Ser Cys Arg Arg Tyr Asp
1 5 10
<210> 51
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
Ser Thr Ser Thr Ser Ser Ile Tyr Cys
1 5
<210> 52
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Thr Tyr Thr Tyr Ile Pro Tyr Cys
1 5
<210> 53
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
Thr Tyr Thr Tyr Thr Pro Tyr Cys
1 5
<210> 54
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Ile Gly Ser Thr Arg Thr Pro
1 5
<210> 55
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Ile His Thr Arg Gly Thr Thr
1 5
<210> 56
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Ile Lys Thr Asp Thr Asp Arg Thr
1 5
<210> 57
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Ile Asn Arg Asp Gly Thr Tyr Thr
1 5
<210> 58
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Ile Arg Ala Gly Thr Asp Arg Thr
1 5
<210> 59
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
Ile Arg Ser Gly Gly Arg Ser Thr
1 5
<210> 60
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Ile Arg Ser Gly Gly Arg Thr Ala
1 5
<210> 61
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 61
Ile Arg Ser Gly Arg Ile Ala
1 5
<210> 62
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 62
Ile Arg Ser Gly Arg Ile Thr
1 5
<210> 63
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 63
Ile Arg Ser Gly Arg Thr Ala
1 5
<210> 64
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 64
Ile Arg Ser Gly Thr Asp Arg Thr
1 5
<210> 65
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 65
Ile Ser Pro Ala Arg Gly Arg Thr
1 5
<210> 66
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 66
Ile Tyr Ser Cys Gly Arg Asp Thr
1 5
<210> 67
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 67
Ile Tyr Ser Gly Gly Gly Ser Thr
1 5
<210> 68
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 68
Val Ile Asp Gly Tyr Gly Gly Ile
1 5
<210> 69
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 69
Ala Ala Ala Leu Gly Leu Ser Arg Leu Arg Cys Asp Thr Gln Ser Ile
1 5 10 15
Ser Pro Asp Glu Tyr Asn Val Trp
20
<210> 70
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 70
Ala Ala Asp Gly Pro Phe Tyr Val Arg Thr Ser Cys Arg Asp Asp Tyr
1 5 10 15
Arg Gly Pro Ser Tyr Trp
20
<210> 71
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 71
Ala Ala Gly Asp Ser Gly Asn Cys Asn Asn Tyr Trp
1 5 10
<210> 72
<211> 0
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 72
<210> 73
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 73
Ala Ala Gly Asp Val Gly Ser Cys Asn Asn Tyr Trp
1 5 10
<210> 74
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 74
Ala Ala Gly His Ser Gly Leu Cys Thr Asp Tyr Arg
1 5 10
<210> 75
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 75
Ala Ala Gly His Ser Gly Leu Cys Thr Asp Tyr Ser
1 5 10
<210> 76
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 76
Ala Ala Gly Leu Ser Gly Ser Cys Thr Asn Tyr Trp
1 5 10
<210> 77
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 77
Ala Ala Gly Pro Ser Gly Ala Cys Thr Asp Tyr Trp
1 5 10
<210> 78
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 78
Ala Ala Gly Pro Ser Gly Leu Cys Thr Asp Tyr Trp
1 5 10
<210> 79
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 79
Ala Ala Gly Arg Ser Gly Thr Cys Asp Asp Tyr Trp
1 5 10
<210> 80
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 80
Ala Ala Gly Ser Thr Gly Tyr Cys Arg Asp Tyr Trp
1 5 10
<210> 81
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 81
Ala Ala Ser Val Ala Arg Arg Gly Ser Thr Leu Pro Gln Pro Leu Arg
1 5 10 15
Leu Gln Pro Ala Tyr Tyr Asn Lys Trp
20 25
<210> 82
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 82
Ala Lys Asp Trp Thr Pro Gly Thr Trp Pro Arg
1 5 10
<210> 83
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 83
Ala Val Gly Val Asp Gly Asp Cys Arg Asn Tyr Trp
1 5 10
<210> 84
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 84
Ala Val Gly Val Asp Gly Asn Cys Arg Asn Tyr Trp
1 5 10
<210> 85
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 85
Lys Ala Asp Gly Arg Arg Tyr Arg Gly Thr Cys Ser Ser Phe Ala Thr
1 5 10 15
Trp
<210> 86
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 86
Glu Ser Gly Gly Gly Ala Val Glu Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Phe Ser
<210> 87
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 87
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ala
<210> 88
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 88
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ser
<210> 89
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 89
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Thr
<210> 90
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 90
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Val
<210> 91
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 91
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Glu Val
<210> 92
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 92
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Thr Ala
<210> 93
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 93
Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Thr Val
<210> 94
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 94
Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Ala
<210> 95
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 95
Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Ala Thr
<210> 96
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 96
Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly Ser Leu Arg Leu Ser
1 5 10 15
Cys Glu Ser
<210> 97
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 97
Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly Ser Leu Arg Val Ser
1 5 10 15
Cys Ala Ala
<210> 98
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 98
Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala
1 5 10 15
Val
<210> 99
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 99
Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala
1 5 10 15
Ile
<210> 100
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 100
Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val Ala
1 5 10 15
Ser
<210> 101
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 101
Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val Ala
1 5 10 15
Thr
<210> 102
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 102
Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Ile Ala
1 5 10 15
Ser
<210> 103
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 103
Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala
1 5 10 15
Thr
<210> 104
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 104
Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val Ala
1 5 10 15
Ser
<210> 105
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 105
Met Ala Trp Phe Arg Gln Ala Pro Gly Asn Glu Arg Glu Ala Val Ala
1 5 10 15
Ser
<210> 106
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 106
Met Ala Trp Phe Arg Gln Thr Pro Gly Asn Glu Arg Glu Gly Val Ala
1 5 10 15
Ser
<210> 107
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 107
Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val Ser
1 5 10 15
Lys
<210> 108
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 108
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Arg Val Ser
1 5 10 15
Leu
<210> 109
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 109
Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Ser
1 5 10 15
<210> 110
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 110
Asp Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Ile
1 5 10 15
Ala Glu Ser Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Gly Met Tyr Tyr Cys
35
<210> 111
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 111
Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn
1 5 10 15
Gly Lys His Thr Met Tyr Leu Gln Met Asp Asn Leu Gln Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 112
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 112
Val Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Leu Asp Ile
1 5 10 15
Ala Gln Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Asp Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 113
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 113
Tyr Tyr Ala Asp Ala Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys
1 5 10 15
Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 114
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 114
Tyr Tyr Ala Asp Ser Val Lys Ala Arg Phe Thr Ile Ser His Asp Asn
1 5 10 15
Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
20 25 30
Thr Gly Val Tyr Tyr Cys
35
<210> 115
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 115
Tyr Tyr Ala Asp Ser Val Lys Ala Arg Phe Thr Ile Ser Leu Asp Asn
1 5 10 15
Ala Lys Asn Thr Val Tyr Leu Glu Met Asn Ser Leu Arg Pro Glu Asp
20 25 30
Thr Gly Val Tyr Tyr Cys
35
<210> 116
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 116
Tyr Tyr Ala Asp Ser Val Lys Ala Arg Phe Thr Ile Ser Gln Asp Asn
1 5 10 15
Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Val Tyr Tyr Cys
35
<210> 117
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 117
Tyr Tyr Ala Asp Ser Val Lys Ala Arg Phe Thr Ile Ser Gln Asp Asn
1 5 10 15
Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
20 25 30
Thr Gly Val Tyr Tyr Cys
35
<210> 118
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 118
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ala Ile Ser Gln Asp Asn
1 5 10 15
Ala Lys Ser Val Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 119
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 119
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Lys Asp Ile
1 5 10 15
Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Met Leu Lys Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 120
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 120
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Lys Asp Asn
1 5 10 15
Ala Lys Asp Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 121
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 121
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Lys
1 5 10 15
Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 122
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 122
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Lys
1 5 10 15
Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 123
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 123
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys
1 5 10 15
Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 124
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 124
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
1 5 10 15
Ala Lys Asp Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Ser Ala Met Tyr Tyr Cys
35
<210> 125
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 125
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Arg
1 5 10 15
Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 126
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 126
Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
1 5 10 15
Ala Lys Asn Met Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Asp Asp
20 25 30
Thr Ala Met Tyr Tyr Cys
35
<210> 127
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 127
Tyr Tyr Ser Asp Ser Val Ala Gly Arg Phe Thr Ile Ser Gln Asp Asn
1 5 10 15
Ala Lys Asn Thr Val Tyr Leu Gln Leu Asn Ser Leu Lys Pro Glu Asp
20 25 30
Thr Ala Val Tyr Tyr Cys
35
<210> 128
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 128
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
Claims (11)
1.一种抗IL-4Rα的单域抗体,其特征在于,其包括如下互补决定区:CDR1、CDR2和CDR3;
所述单域抗体的互补决定区如以下(1)或(2):
(1):CDR1如SEQ ID NO.53所示,CDR2如SEQ ID NO.61所示,CDR3如SEQ ID NO.73所示;
(2):CDR1如SEQ ID NO.42所示,CDR2如SEQ ID NO.64所示,CDR3如SEQ ID NO.74所示。
2.根据权利要求1所述的抗IL-4Rα的单域抗体,其特征在于,所述单域抗体包括如下骨架区:FR1、FR2、FR3和FR4;
FR4的氨基酸序列如SEQ ID NO.128所示;所述单域抗体的骨架区FR1、FR2和FR3如下(a)或(b)所示:
(a)FR1如SEQ ID NO.88所示,FR2如SEQ ID NO.100所示,FR3如SEQ ID NO.115所示;
(b)FR1如SEQ ID NO.94所示,FR2如SEQ ID NO.105所示,FR3如SEQ ID NO.113所示。
3. 根据权利要求2所述的抗IL-4Rα的单域抗体,其特征在于,所述单域抗体的氨基酸序列如SEQ ID NO.1或5所示。
4.一种融合蛋白,其特征在于,其包括权利要求1-3任一项所述的抗IL-4Rα的单域抗体和Fc。
5.权利要求1-3任一项所述的抗IL-4Rα的单域抗体、权利要求4所述的融合蛋白在制备以IL-4Rα为靶点以治疗疾病的药物中的应用,所述疾病选自哮喘、慢性阻塞性肺疾病、特应性皮炎和慢性原发性荨麻疹中的至少一种。
6.一种治疗疾病的药物,其特征在于,其包括权利要求1-3任一项所述的抗IL-4Rα的单域抗体或权利要求4所述的融合蛋白,以及药学上可接受的辅料。
7.一种分离的核酸分子,其特征在于,其编码如权利要求1-3任一项所述的单域抗体。
8. 根据权利要求7所述的一种分离的核酸分子,其特征在于,所述核酸分子的碱基序列如SEQ ID NO.19或23所示。
9.含有权利要求8所述的核酸分子的载体。
10.含有权利要求9所述的载体的重组细胞。
11.制备如权利要求1-3任一项所述的单域抗体的方法,其特征在于,其包括:培养如权利要求10所述的重组细胞,从培养产物中分离纯化得所述单域抗体。
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JP4394931B2 (ja) * | 2003-11-28 | 2010-01-06 | 第一三共株式会社 | ヒトインターロイキン4およびヒトインターロイキン13のアンタゴニストであるペプチド |
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