CN114605539B - 人源化的抗IL-4Rα单域抗体及其应用 - Google Patents
人源化的抗IL-4Rα单域抗体及其应用 Download PDFInfo
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Abstract
本发明公开了人源化的抗IL‑4Rα单域抗体及其应用,涉及抗体技术领域。本发明公开的抗IL‑4Rα单域抗体具有互补决定区和人源化改造的骨架区。本发明提供的抗IL‑4Rα单域抗体经过了人源化改造,保持了其亲和力和肿瘤细胞增殖阻断效果,并有效减低了免疫副反应。
Description
技术领域
本发明涉及抗体技术领域,具体而言,涉及人源化的抗IL-4Rα单域抗体及其应用。
背景技术
人体机体的2型炎症反应是由2型辅助T细胞(T helper 2,TH2)引起的,这些反应具有统一的特点,所以被称为过敏性疾病,例如:哮喘和一系列其他炎症性疾病。传统的降炎方法一般是采用广谱性免疫抑制剂来抑制疾病痛苦,或者采用特异性靶向TH2细胞下游产物,例如IgE的靶向药物进行疾病治疗。与传统治疗方法相比,靶向由TH2细胞分泌的2型细胞因子—IL-4,IL-5,IL-13—在多种免疫性疾病的治疗中已经展现出很有潜力的疗法,患者获得了更好的治疗效果。在哮喘患者中针对IL-4,IL-5或IL-13的疗法取得了几项令人失望的临床结果之后,研究者采用个性化方法对表现出“过敏”表型的哮喘亚型取得了治疗益处。最近,有益的疗效也扩展到了更广泛的哮喘患者身上。这表明,如果信号通路中关键的上游驱动因子得到适当的阻断,则2型炎症与严重哮喘人群是密切相关的。此外,同时抑制IL-4和IL-13已显示出在通常与哮喘并存的疾病中的治疗效果—特应性皮炎和鼻息肉等慢性鼻窦炎—支持以下假设:靶向关键“驱动因子途径”可以使多种过敏性疾病收获治疗效果。
过敏性疾病正日益成为一种全球流行病。流行病学研究表明,食物过敏,鼻结膜炎,特应性皮炎和哮喘的患病率在不断上升。过敏是由遗传和环境因素之间复杂的相互作用导致的对无害抗原(过敏原)的全身性2型炎症反应。该反应最终导致免疫球蛋白E(IgE)产生和各种相关的炎性免疫反应增加。从轻度危害到危及生命,患者可能会出现多种疾病严重程度,涉及单个或多个器官***和组织。过敏性疾病可能因其独特的器官和组织表现而看起来完全不同,并且通常由具有不同医学专长的临床医生进行治疗。但是,多种***反应性疾病以并发或渐进的方式出现(即“特应性行军”)的趋势表明,这些疾病可能具有共同的潜在驱动因素。沿着这些思路,人们早已认识到,2型辅助T细胞介导的2型炎症反应在哮喘和特应性皮炎(两种在肺和皮肤分别具有不同组织特异性表现的高度流行的慢性疾病)中均很重要。
尽管使用2型途径调节剂的初始临床研究有些令人失望,但过敏性哮喘患者的临床数据(由生物标记物鉴定)为三种特定的2型细胞因子的重要作用提供了支持:白介素5(IL-5)以及具有共同受体的姐妹细胞因子IL-4和IL-13(图1)。用IL-5特异性人源化单克隆抗体(mAb)美泊利珠单抗(葛兰素史克(GlaxoSmithKline)开发)在治疗患有哮喘和伴有鼻息肉的慢性鼻窦炎(CSwNP)患者的部分患者中显示出疗效。此外,使用完全人源IL-4受体亚基α(IL-4Rα)阻断抗体(dupilumab;由Regeneron/Sanofi开发)同时阻断IL-4和IL-13信号传导已证明可治疗三种过敏性疾病:特应性皮炎,CSwNP和哮喘。这些最新的临床数据提出了一个有趣的可能性,即以关键的中心“驱动因子”为目标可能对以多种器官特异性临床表现为特征的过敏性疾病具有实质性的治疗作用。现在是时候定义和分类过敏性疾病,从而根据常见的免疫途径调整治疗方法了。
2型炎症占主导地位是过敏性疾病的关键驱动因素。抗原的类型与环境因素和潜在的遗传因素相结合,会影响一系列细胞因子的释放,从而导致固有免疫细胞和淋巴样细胞引发或传播2型炎症过程。在环境刺激的屏障界面,上皮来源的细胞因子,例如IL-25,IL-33和胸腺基质淋巴细胞生成素(TSLP)可以启动2型免疫反应或放大现有的2型炎症。这些上游介质刺激先天细胞产生2型细胞因子,也有助于将幼稚T细胞极化为CD4+TH2细胞。TH淋巴细胞亚群是根据与特定细胞因子相关的免疫应答和每个亚群特有的炎症介质进行分类的。例如,TH1细胞产生干扰素-γ(IFNγ),TH2细胞产生IL-4,IL-5和IL-13,TH9细胞产生IL-9,TH17细胞产生IL-17A,IL-17F,IL-21和IL22,TH22细胞产生IL-22,调节性T细胞(TREG)可产生IL-10。在其他作用中,TH2细胞诱导B细胞增殖并随后经历抗体类型转换的步骤,从而导致高水平的循环IgE。因此,IgE是TH2细胞激活的关键下游生物标志物。IgE与嗜碱性粒细胞和肥大细胞上发现的高亲和力IgE受体(FcεRI)结合,这些细胞上IgE的交联会导致细胞活化以及多种炎症介质的脱颗粒。这些炎性介质包括组胺,***素和其他促炎细胞因子(例如IL-4,IL-5和IL-13),从而放大了2型反应。在下呼吸道中,这种2型炎性环境导致嗜酸性粒细胞增多,粘液产生和平滑肌收缩。这些过程虽然是消除寄生虫感染的重要保护性免疫功能,但对无害抗原或过敏原具有病理作用,导致过敏。
除了经典定义的变应性疾病(包括哮喘,特应性皮炎,食物过敏,变应性鼻炎和结膜炎)外,各种病因不明的疾病也具有2型临床特征(最明显的是嗜酸性粒细胞增多症和/或高血清IgE水平)。此类疾病包括慢性特发性荨麻疹,CSwNP和嗜酸性食管炎。
尽管某些过敏性疾病(例如过敏性鼻炎)可以很好地与抗组胺药和特异性免疫疗法配合使用,非特异性免疫抑制是更严重过敏性疾病(如特应性皮炎和哮喘)的主要治疗手段,但在这两种疾病中,异常的炎症反应都会加剧并传播疾病症状。通过全身性使用广泛作用的免疫抑制剂(例如口服或静脉注射皮质类固醇,环孢菌素A,甲氨蝶呤,硫唑嘌呤或霉酚酸酯)减轻炎症,可有效缓解严重疾病的症状。这些试剂的免疫抑制活性是由靶向下游介质如转录因子产生的。例如,皮质类固醇结合糖皮质激素受体并抑制驱动炎症的关键转录因子如核因子-κB(NF-κB)的表达。环孢菌素A是一种钙调神经磷酸酶抑制剂,可防止产生IL-2(通过活化的T细胞的转录因子核因子(NFAT)),这是T细胞活化和增殖所必需的。但是,由于环孢菌素A和皮质类固醇的广泛作用机制,全身免疫抑制疗法会导致多效性作用,从而导致毒性,例如积液滞留,葡萄糖耐受不良,高血压,肌肉无力,胃肠道耐受不良,潜在的骨丢失,下丘脑抑制-垂体-肾上腺轴和增加的感染易感性。局部给药(即吸入药物,局部应用滴剂,鼻喷剂或乳膏)可减少这些免疫抑制剂的副作用;然而,局部免疫抑制不足以治疗这些疾病的更严重形式。因此,仍然非常需要特异性更强的疗法。
采用暴力手段抑制炎症并不能提供是哪些免疫途径导致并传播疾病的见解。例如,作用广泛的药物环孢菌素A可有效治疗牛皮癣和特应性皮炎。相比之下,在牛皮癣和特应性皮炎中特异性靶向肿瘤坏死因子(TNF)导致不同的临床功效,表明这两种皮肤病具有不同的驱动途径。TNF阻滞剂被批准用于治疗牛皮癣,但尚未证明其在特应性皮炎(一种2型炎症驱动疾病)中具有持续的疗效。
奥马珠单抗,Omalizumab(Xolair;Novartis/Genentech)通过靶向2型炎症的最终介质以及肥大细胞和嗜碱性粒细胞脱粒的有效触发物IgE,在过敏性疾病中诱导更特异性的免疫抑制。这种IgE特异性人源化单克隆抗体是第一种获得哮喘病监管批准的单克隆抗体疗法,但对特应性皮炎无效。奥马珠单抗降低了游离血清IgE的水平,并且通过这种新型抗炎机制,它显示出可减轻加重的功效,但在强制呼气(FEV1)的第一秒,即对肺功能的测量中,对强制呼气量的改善很小。奥马珠单抗还改善了合并病CSwNP的症状。它还被批准用于治疗因抗组胺药难治的慢性特发性荨麻疹。在关键性试验中,奥马珠单抗在瘙痒和疾病活动终点方面显示出显着改善。相反,在特应性皮炎中,血清游离IgE水平的降低不足以实现良好的临床反应。用奥马珠单抗治疗16周的中度特应性皮炎患者的疾病终点(湿疹面积和严重程度指数(EASI),以及研究者总体评估)并未改善。此外,与安慰剂组相比,接受治疗的患者的瘙痒评分略有恶化。这些结果表明,即使在2型炎症驱动的疾病中,TH2途径的最终产物IgE也不是疾病的统一调节器。
可能需要靶向2型炎症途径的关键上游驱动因子而不是下游介质,才能实现在多种过敏性疾病中的最佳治疗效果。为此,三种关键的2型细胞因子IL-4,IL-5和IL-13是有希望成为过敏性炎症疾病共同结节的候选者。
IL-4是驱动TH2型反应的关键分化因素。IL-4会引发T细胞向TH2亚型的分化,并诱导2型相关细胞因子和趋化因子的产生,例如IL-5,IL-9,IL-13,TARC和嗜酸性粒细胞趋化因子。在B细胞中,IL-4诱导同种型转换为IgE。在体外,IL-4促进TH幼稚T细胞向2型辅助T细胞分化。在体内,IL-4的缺乏会导致对寄生虫感染的2型细胞因子产生受阻。反过来,IL-4负调节与IFNγ产生、巨噬细胞活化相关的TH1型应答,从而维持针对2型应答的免疫极化。
IL-4和IL-13是2型免疫的有效的调介体,与它们的受体表达模式有关的功能重叠且不同。尽管IL-4和IL-13仅具有25%的氨基酸同源性,但这些细胞因子共享一个共同的受体部分IL-4Rα,该受体与独特的辅助链结合以诱导信号传导。IL-4Rα在造血细胞和非造血细胞上均表达;然而,在不同细胞类型中辅助链的差异表达已经揭示了它们的功能差异(图1)。1型受体由IL-4Rα与共同的γ链组成,后者仅在造血细胞中发现。2型受体复合物由IL-4Rα与IL-13Rα1组成,后者在许多非造血细胞中发现,例如角质形成细胞,毛囊,表皮皮脂腺和汗腺,鼻和支气管上皮细胞,平滑肌细胞和成纤维细胞。IL-4通过1型和2型受体复合物发出信号,而IL-13仅通过2型受体复合物发出信号。这是因为IL-13与其自身的主要结合链(IL-13Rα1)结合,而IL-4主要与IL-4Rα结合。
另外,两种细胞因子具有不同的效力和信号传导动力学。IL-4与IL-4Rα高结合不依赖于γ链或IL-13Rα1结合的亲和力(KD),而IL-4Rα的存在增加了IL-13与IL-13Rα1结合的亲和力(KD从10mM变为30pM)。此外,IL-4的2型受体参与激活的细胞内信号传导的时间过程比IL-13更快。在寄生虫感染和***反应的小鼠模型中,通过细胞因子敲除和过表达表型分析了IL-4和IL-13的生理差异,如下所述仔细检查这些表型可以支持以下假设:IL-4是TH2细胞分化,B细胞生长,同种型类别转换(尤其是IgE)的启动和嗜酸性粒细胞募集的中心媒介。尽管IL-13在这些促炎过程中具有一定的冗余性,但IL-13在介导杯状细胞增生和平滑肌收缩力中还有其他作用,可能与2型受体复合物的独特表达模式和局部细胞因子产生有关。
IL-4和IL-13都通过对B细胞的活性介导IgE产生。敲除小鼠中的IL-4或IL-13会导致对过敏原激发的IgE产生严重缺陷。尽管IL-4可以启动并促进同种型转换和B细胞生长,但有证据表明IL-13也可以与活化的人类B细胞结合,这表明IL-13有助于IgE产生的持续并解释了在基因敲除小鼠中观察到的表型。
IL-4,IL-5和IL-13可促进2型炎症的组织和血液嗜酸性粒细胞增多。IL-5是一种有效的嗜酸性粒细胞因子。它负责骨髓的生长和分化,存活和动员,以及从骨髓到血液的迁移。IL-5与细胞因子特异性亚基受体IL-5Rα结合,后者与一个共享的信号亚基β链形成复合物;粒细胞-巨噬细胞集落刺激因子(GM-SCF)和IL-3也需要β链信号传导。IL-5Rα在嗜酸性粒细胞和嗜酸性粒细胞祖细胞中高度表达,并且在嗜碱性粒细胞中也存在。在没有IL-5的情况下(在基因敲除中或在用IL-5特异性抗体治疗后),血液和组织对过敏原激发的嗜酸性粒细胞应答被消除了。
2型上游细胞因子的产生可以通过上皮衍生的细胞因子IL-25,IL-33和TSLP促进表达,并可能在组织损伤或过敏原暴露后在屏障界面释放。这些上皮来源的细胞因子对多种先天细胞类型(例如,第2类先天淋巴样细胞和肥大细胞)的活性可诱导IL-4,IL-5和IL-13的产生,并且还可以促进TH2型响应。特别是,IL-33充当“alarmin”(细胞或组织损伤的信号),可使幼稚T细胞极化为TH2细胞,并放大现有的2型反应。IL-33与IL-25一起还诱导先天淋巴样细胞产生高水平的2型细胞因子,尤其是IL-5和IL-13。TSLP促进嗜碱性粒细胞,单核细胞和自然杀伤性T细胞中细胞因子的产生,并且还激活树突状细胞以引发和激活TH2细胞。
综上所述,IL-4,IL-5和IL-13具有多效性,可以协调2型免疫反应,并在驱动2型和TH2途径活化标志的表现中扮演不同的角色:IgE产生和嗜酸性粒细胞增多。临床前数据提供了确凿的证据,证明哮喘和特应性皮炎均由2型炎症的这些介质驱动。过表达所有三种2型细胞因子IL-4,IL-5和IL-13的转基因小鼠自发发展为哮喘样肺病和特应性皮炎样皮肤病,其特征是夸张的2型反应:即高血清IgE水平,皮肤和肺中广泛的细胞浸润(包括嗜酸性粒细胞和淋巴细胞),皮肤增厚和气道上皮肥大。进一步的研究表明,IL-4和IL-13独立地足以引起类似的病理。这些临床前数据暗示IL-4和IL-13是关键的近端疾病驱动因素。
此外,人源化抗体主要指非人源单克隆抗体以基因克隆及DNA重组技术改造,重新表达的抗体,其大部分氨基酸序列为人源序列取代,基本保留亲本单克隆抗体的亲和力和特异性,又降低了其异源性,有利应用于人体。而目前缺乏靶向IL-4Rα的驼源单域抗体的人源化抗体。
发明内容
本发明的目的在于提供一种人源化的抗IL-4Rα单域抗体及其应用。本发明提供的抗IL-4Rα单域抗体经过了人源化改造,保持了其亲和力和肿瘤细胞增殖阻断效果,并有效减低了免疫副反应。
本发明是这样实现的:
一方面,本发明提供一种人源化的抗IL-4Rα单域抗体,其具有互补决定区和骨架区;所述互补决定区包括CDR1、CDR2和CDR3;所述骨架区包括FR1、FR2、FR3和FR4;
其中,CDR1的氨基酸序列如SEQ ID NO.3所示,CDR2的氨基酸序列如SEQ ID NO.12所示,CDR3的氨基酸序列如SEQ ID NO.18所示;
FR1的氨基酸序列如SEQ ID NO.2所示,FR2的氨基酸序列选自SEQ ID NO.4-11中的任意一者,FR3的氨基酸序列选自SEQ ID NO.13-17中的任意一者,FR4的氨基酸序列如SEQ ID NO.20或21所示。
本发明的发明人在SEQ ID NO.22的驼源抗IL-4Rα单域抗体基础上,在合适的位置,经过科学合理的人源化改造,得到的保持其亲和力和肿瘤细胞增殖阻断效果,并有效减低了免疫副反应的人源化的抗IL-4Rα单域抗体。
上述各互补决定区和各骨架通过如下顺序连接形成本发明单域抗体一级序列结构:FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
在可选的实施方式中,FR2的氨基酸序列如SEQ ID NO.11所示,FR3的氨基酸序列如SEQ ID NO.15所示,FR4的氨基酸序列如SEQ ID NO.21所示。
相较于其他的人源化单域抗体,该实施方式的单域抗体表现了出更为优异的技术效果,其具有更高的亲和力和更低的免疫副反应。
另一方面,本发明提供一种融合蛋白其包括如上所述的抗IL-4Rα单域抗体。
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。
另一方面,本发明提供一种双特异性抗体,其包括如上所述的抗IL-4Rα单域抗体。
基于本发明给出的单域抗体的序列或其结构,本领域技术人员容易想到将其与其他的特异性抗体融合进而获得具有可以特异性结合两个或多个抗原的双特异性抗体或多特异性抗体。这对本领域技术人员来说是容易实现的。因此,无论何种抗体融合所述得到的双特异性抗体均属于本发明的保护范围。
另一方面,本发明提供如上所述的抗IL-4Rα单域抗体、如上所述的融合蛋白、或者如上所述的双特异性抗体在制备以IL-4Rα为靶点以治疗疾病的药物中的应用。
本发明提供的单域抗体、融合蛋白以及双特异性抗体可用于任何以IL-4Rα为治疗靶点的疾病,包括但不限于哮喘、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、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。
另一方面,本发明提供一种治疗疾病的药物,其包括如上所述的抗IL-4Rα单域抗体、如上所述的融合蛋白、或者如上所述的双特异性抗体,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。本领域技术人员可以根据需要合理选择。
另一方面,本发明提供一种分离的核酸分子,其编码如上所述的抗IL-4Rα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。
另一方面,本发明提供含有如上所述的核酸分子的载体或重组细胞。
另一方面,本发明提供制备如上所述的抗IL-4Rα单域抗体的方法,其包括:培养重组细胞,从培养产物中分离纯化得所述单域抗体;所述重组细胞含有重组表达载体,所述重组表达载体含有上述的核酸分子。
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IL4/IL-13以及IL-5信号通路示意图;
图2为抗IL-4Rα单克隆抗体4E9人源化后部分克隆序列比对结果。
图3为不同的人源化4E9抗体克隆中和IL-4诱导的TF-1增殖实验结果。
图4为优选的人源化4E9抗体克隆中和IL-13诱导的TF-1增殖实验结果。
图5为IL-4Rα/IL-5双特异性抗体4E9-V10-2B3v2阻断IL-4Rα与IL-4结合的实验结果(ELISA)。
图6为IL-4Rα/IL-5双特异性抗体4E9-V10-2B3v2阻断IL-5R与IL-5结合的实验结果(ELISA)。
图7为IL-4Rα/IL-5双特异性抗体4E9-V10-2B3v2中和IL-4诱导的TF-1增殖实验结果。
图8为IL-4Rα/IL-5双特异性抗体4E9-V10-2B3v2中和IL-13诱导的TF-1增殖实验结果。
图9为IL-4Rα/IL-5双特异性抗体4E9-V10-2B3v2中和IL-5诱导的TF-1增殖实验结果。
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
人源化改造
在SEQ ID NO.22的抗IL-4Rα单域抗体(命名为4E9-V0)基础上进行人源化改造。
改造得到的人源化单域抗体(分别命名为4E9 V1-V14)的序列如表1所示,部分人源化抗体序列的比对结果如图2所示。
表1各人源化单域抗体各区域对应的序列标识符(SEQ ID NO.)
FR1 | CDR1 | FR2 | CDR2 | FR3 | CDR3 | FR4 | |
4E9-V0 | 1 | 3 | 4 | 12 | 13 | 18 | 20 |
4E9-V1 | 2 | 3 | 5 | 12 | 14 | 18 | 21 |
4E9-V2 | 2 | 3 | 6 | 12 | 14 | 18 | 21 |
4E9-V3 | 2 | 3 | 6 | 12 | 15 | 18 | 21 |
4E9-V4 | 1 | 3 | 4 | 12 | 13 | 19 | 20 |
4E9-V5 | 2 | 3 | 5 | 12 | 14 | 19 | 21 |
4E9-V6 | 2 | 3 | 7 | 12 | 15 | 18 | 21 |
4E9-V7 | 2 | 3 | 8 | 12 | 16 | 18 | 21 |
4E9-V8 | 2 | 3 | 9 | 12 | 16 | 18 | 21 |
4E9-V9 | 2 | 3 | 10 | 12 | 15 | 18 | 21 |
4E9-V10 | 2 | 3 | 11 | 12 | 15 | 18 | 21 |
4E9-V11 | 2 | 3 | 8 | 12 | 15 | 18 | 21 |
4E9-V12 | 2 | 3 | 7 | 12 | 16 | 18 | 21 |
4E9-V13 | 2 | 3 | 7 | 12 | 17 | 18 | 21 |
4E9-V14 | 2 | 3 | 7 | 12 | 14 | 18 | 21 |
实施例2
人源化单域抗体中和IL-4或IL-13诱导TF1细胞增殖的检测
(1)将复苏后传代3-4待次的TF-1细胞按10000个每孔铺入96孔板;
(2)将不同的Tab、表1中的人源化单域抗体配制为10μg/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的Tab抗体(参考申请号为CN202010576200.7,发明名称为抗IL-4Rα的单域抗体以及应用和药物的中国发明专利的方法获取)、人源化单域抗体与EC80浓度的IL-4或IL13(参考申请号为CN202010576200.7,发明名称为抗IL-4Rα的单域抗体以及应用和药物的中国发明专利的方法获取)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人源化单域抗体中和IL-4或IL13诱导TF-1细胞增殖的EC50浓度,结果如表2、表3和图3、图4所示。
表2 IL-4Rα人源化单域抗体中和IL-4诱导的TF-1增殖实验结果
表3 IL-4Rα人源化单域抗体中和IL-13诱导的TF-1增殖实验结果
结果显示,在所有的人源化抗体序列中,4E9-V10抗体的细胞增殖效果的中和能力最强,其EC50在0.27nM,效果最差的为4E9-V1,具有一定中和效果的是4E9-V6、4E9-V8、4E9-V12和4E9-V13。
实施例3
差示扫描法检测人源化单域抗体热稳定性
实验方法:
(1)采用8联管或者是96孔PCR板中加入45μL的0.1mg/mL的上述人源化单域抗体溶液,再加入5μL的100×Sypro orange染料,此时染料终浓度为5×;每个样品做3个重复,用1×PBS作为空白。
(2)实验类型Melt curve,报告基团:ROX,淬灭基团:None;升温程序:25℃5min,扫描范围25-95℃,升温速度1%(约1℃/min)。
(3)取熔解曲线一阶导数极大值对应的温度即为该蛋白对应的变性温度(Tm值)。
实验结果如表4所示。
表4
结果显示,在所有人源化单域抗体中,4E9-V13的热稳定性最高,4E9-V3的热稳定性最差,未检出,4E9-V10的热稳定性在所有抗体中排名第三。
实施例4
人源化单域抗体的亲和力测定
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%;将IL-4Rα结合分子(上述的部分人源化单域抗体)用SD缓冲液配制成10μg/mL的浓度;
抗原工作液配制:抗原先以SD缓冲液配制成200nM,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SD缓冲液的空白对照;
再生液的配制:取适量浓度为0.1M的甘氨酸储备液,用去离子水稀释10倍,混匀,获得再生液;
实验步骤: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;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,然后设定机器程序按照:基线→抗体→基线→结合抗原→解离抗原→再生传感器的步骤进行实验操作,实验结果如表5所示。
表5
结果显示,4E9-V6和4E9-V10的KD值最低,二者的抗原亲和力最高。
综合上述结果,基于细胞的抗体功能检测结果以及理化分析结果,4E9-V10是所有人源化序列中综合效果最好的人源化单域抗体,这是发明人无法预料的,在随后的实施例采用4E9-V10进行测试。
实施例5
抗IL-4Rα/IL-5蛋白的双特异性单域抗体的Fc融合抗体真核表达载体的构建
(1)通过序列合成的方式将密码子优化后的抗IL-4Rα的人源化单域抗体(4E9V10)的基因序列(SEQ ID NO.23的第1-345位)或抗IL-5的人源化单域抗体(命名为2B3V2)的基因序列(SEQ ID NO.23的第1069-1434位)分别合成至载体RJK-V4-3(参考申请号为CN202010576200.7,发明名称为抗IL-4Rα的单域抗体以及应用和药物的中国发明专利的方法获取)中;
(2)将构建好的重组真核表达载体转化至DH5α大肠杆菌中,培养进行质粒大提,去除内毒素;
(3)将大提后的质粒再进行序列测序鉴定;
(4)鉴定无误后,再将抗IL-4Rα抗体序列亚克隆至含抗IL-5的抗体序列的真核表达载体中:具体操作是使用限制性内切酶XbaⅠ和BamHⅠ将抗IL-4Rα抗体序列从其所在的真核表达载体上酶切下来并与具有相同限制性内切酶粘性末端的含抗IL-5的抗体序列的真核表达载体连接、转化、测序鉴定;测序正确的克隆进行质粒大提,去除内毒素;将大提后的质粒再进行序列测序鉴定;将确定无误后的重组载体准备后续真核细胞转染表达。获得抗IL-4Rα/IL-5蛋白的双特异性单域抗体的真核表达载体。抗IL-4Rα/IL-5蛋白的双特异性单域抗体(氨基酸序列如SEQ ID NO.24所示,对应的基因序列为SEQ ID NO.23)命名为4E9V10-2B3V2,其包括三个部分:4E9V10-Fc段-2B3V2;4E9V10在氨基端(SEQ ID NO.24中第1-115位),Fc段为SEQ ID NO.24中的第116-356位,2B3V2在羧基端(SEQ ID NO.24中第357-478位)。
实施例6
抗IL-4Rα/IL-5蛋白的双特异性单域抗体在悬浮ExpiCHO-S细胞中表达,实验方法参考申请号为CN202010576200.7,发明名称为抗IL-4Rα的单域抗体以及应用和药物的中国发明专利进行。
实施例7
抗IL-4Rα/IL-5蛋白的双特异性单域抗体在悬浮293F细胞中的表达,实验方法参考申请号为CN202010576200.7,发明名称为抗IL-4Rα的单域抗体以及应用和药物的中国发明专利进行。
实施例8
抗IL-4Rα/IL-5蛋白的双特异性单域抗体的纯化,实验方法参考申请号为CN202010576200.7,发明名称为抗IL-4Rα的单域抗体以及应用和药物的中国发明专利进行。
实施例9
双特异性单域抗体的受体配体结合阻断检测
(1)用蛋白稀释液稀释受体蛋白(IL-4Rα或IL-5R)至1μg/ml,4℃包被过夜。
(2)洗板,用5%脱脂牛奶37℃封闭。
(3)将偶联生物素的配体蛋白(IL-4或IL-5)稀释至2倍的EC80浓度,将抗体稀释至2倍起始浓度,5倍梯度稀释,将配体蛋白和稀释后的抗体(dupilumab、4E9V10-2B3V2、4E9V0或2B3(SEQ ID NO.25))以及hIgG按1:1转至新的配药板混匀。
(4)洗板,将稀释后的配体蛋白/抗体混合物转至ELISA板,两复孔,37℃孵育。
(5)洗板,加入稀释后的Streptavidin[HRP],37℃孵育。
(6)洗板,加入单组分TMB,室温避光显色。
(7)加入终止液,立刻用酶标仪读取OD450,作图计算EC50,以4E9V0、针对IL-5的非人源化单域抗体2B3、dupilumab、reslizumab、hIgG作为对照,结果分别如表6和表7,图5和图6所示。
表6双特异性抗体阻断IL-4与IL-4Rα结合的EC50检测结果
4E9V0 | 4E9V10-2B3V2 | dupilumab | hIgG | |
EC50(nM) | 4.447 | 3.653 | 4.321 | 2.038 |
表7双特异性抗体阻断IL-5与IL-5R结合的EC50检测结果
2B3 | 4E9V10-2B3V2 | reslizumab | hIgG | |
EC50(nM) | 6.911 | 3.612 | 6.208 | 27387599489 |
结果显示,人源化后的双特异性抗体与非人源化抗体相比,在分别阻断IL-4/IL-4Rα或IL-5/IL-5R受体配体结合方面,其阻断效果没有降低,并具有略微优势,而与其对应的上市药物相对,其阻断能力基本相当,也具有略微优势。
实施例10
双特异性单域抗体的IL-4或IL-13诱导TF1细胞增殖的检测
检测方法参考实施例2。
检测结果如表8、表9和图7、8所示。
表8双特异性单域抗体中和IL-4诱导的TF-1细胞增殖实验结果
4E9V0 | 4E9V10-2B3V2 | dupilumab | hIgG | |
EC50(nM) | 0.2812 | 0.2618 | 0.1297 | 0.3750 |
表9双特异性单域抗体中和IL-13诱导的TF-1细胞增殖实验结果
4E9V0 | 4E9V10-2B3V2 | dupilumab | hIgG | |
EC50(nM) | 0.2291 | 0.2154 | 0.1783 | 0.1312 |
结果显示,人源化后的双特异性抗体与非人源化抗体相比在中和IL-4诱导的TF-1细胞增殖方面,其阻断效果没有降低,并具有略微优势,而与其对应的上市药物相对,其阻断能力基本相当。
实施例11
人源重组IL-5蛋白诱导的TF1细胞增殖以及工具抗体(Tab)中和增殖实验。
A.人源重组IL-5蛋白诱导的TF1细胞增殖实验:
(1)将复苏后传代3-4待次的TF-1细胞按10000个每孔铺入96孔板。
(2)将人源IL-5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-5蛋白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-5诱导TF-1细胞增殖的EC80浓度,计算结果为2.96ng/mL。
B.Tab中和人源IL-5诱导的TF1细胞增殖实验:
(1)将复苏后传代3-4待次的TF-1细胞按10000个每孔铺入96孔板。
(2)将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-5按1:1混合,制成混合液。
(4)将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-5诱导TF-1细胞增殖的EC50浓度。
实施例12
人源化双特异性单域抗体中和IL-5诱导TF1细胞增殖的检测。
(1)将复苏后传代3-4待次的TF-1细胞按10000个每孔铺入96孔板;
(2)将Tab以及前述的人源双特异性单域抗体配制为10μg/mL的溶液,并进行5倍梯度稀释;
(3)将梯度稀释好的Tab、人源化抗体与实施例13-A获得的EC80浓度的IL-5蛋白按1:1混合,制成混合液;
(4)将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-5诱导TF-1细胞增殖的EC50浓度,实验结果如表10和图9所示。
表10双特异性抗体中和IL-5诱导的TF-1细胞增殖实验结果
reslizumab | hIgG | 4E9V10-2B3V2 | 2B3 | |
EC50(nM) | 0.1221 | 0.1080 | 0.1753 | 0.3362 |
结果显示,人源化后的双特异性抗体与非人源化抗体相比在中和IL-5诱导的TF-1细胞增殖方面,其阻断效果没有降低,并具有略微优势,而与其对应的上市药物相对,其阻断能力基本相当。
实施例12
人源化双特异性抗体的亲和动力学检测,检测方法如实施例4所示,检测结果如表11所示。
表11
结果显示,靶向IL4Rα和IL-5的双特异性抗体与两个抗原分别进行亲和力测定,对应亲和力均在1nM以下。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应当了解,在本发明不受上述实施例的限制,上述实施例和说明书中的描述只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
序列表
<110> 南京融捷康生物科技有限公司
<120> 人源化的抗IL-4Rα单域抗体及其应用
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Claims (7)
1.一种人源化的抗IL-4Rα单域抗体,其特征在于,其具有互补决定区和骨架区;所述互补决定区包括CDR1、CDR2和CDR3;所述骨架区包括FR1、FR2、FR3和FR4;
其中,CDR1的氨基酸序列如SEQ ID NO.3所示,CDR2的氨基酸序列如SEQ ID NO.12所示,CDR3的氨基酸序列如SEQ ID NO.18所示;
FR1的氨基酸序列如SEQ ID NO.2所示,FR2的氨基酸序列如SEQ ID NO.11所示,FR3的氨基酸序列如SEQ ID NO.15所示,FR4的氨基酸序列如SEQ ID NO.21所示。
2.一种双特异性单域抗体,其特征在于,包含权利要求1中所述的人源化的抗IL-4Rα单域抗体和抗IL-5的人源化单域抗体;所述双特异性抗体的氨基酸序列如SEQ ID NO.24所示。
3.权利要求1所述的抗IL-4Rα单域抗体或权利要求2所述的双特异性单域抗体在制备以IL-4Rα为靶点以治疗疾病的药物中的应用,其特征在于,所述疾病为哮喘、慢性原发性荨麻疹、慢性阻塞性肺疾病、特应性皮炎、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和自体免疫葡萄膜炎。
4.一种治疗疾病的药物,其特征在于,其包括权利要求1所述的抗IL-4Rα单域抗体或权利要求2所述的双特异性单域抗体,以及药学上可接受的辅料。
5.一种分离的核酸分子,其特征在于,其编码如权利要求1所述的抗IL-4Rα单域抗体。
6.含有权利要求5所述的核酸分子的载体或重组细胞。
7.制备如权利要求1所述的抗IL-4Rα单域抗体的方法,其特征在于,其包括:培养重组细胞,从培养产物中分离纯化得所述单域抗体;所述重组细胞含有重组表达载体,所述重组表达载体含有权利要求5所述的核酸分子。
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PCT/CN2021/077649 WO2022121118A1 (zh) | 2020-12-09 | 2021-02-24 | 人源化的抗IL-4Rα单域抗体及其应用 |
US18/001,934 US20230279123A1 (en) | 2020-12-09 | 2021-02-24 | HUMANIZED ANTI-IL-4Ra SINGLE DOMAIN ANTIBODY AND APPLICATION THEREOF |
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