CN107709360A - 狂犬病毒g蛋白表位及与其特异性结合的中和狂犬病毒的结合分子 - Google Patents
狂犬病毒g蛋白表位及与其特异性结合的中和狂犬病毒的结合分子 Download PDFInfo
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Abstract
本发明涉及狂犬病毒G蛋白表位,和与其特异性结合的中和狂犬病毒的结合分子。在本发明中,鉴定出了狂犬病毒G蛋白的不同表位位点,并发现与该表位位点结合的结合分子及结合分子的鸡尾酒保留了针对各种狂犬病毒的中和活性。
Description
技术领域
本发明涉及一种狂犬病毒G蛋白(糖蛋白)表位,和与其特异性结合的中和狂犬病毒的结合分子。
背景技术
狂犬病是一种病毒性动物传染病,主要影响野生动物和伴侣动物以及包括人的哺乳动物,并因此引起急性脑部疾病。狂犬病是一种致命的疾病,通过一次感染就引起死亡的风险,与AIDS一起被认为是死亡率最高的疾病。这样的狂犬病遍布世界各地,每年有超过1000万人在感染后接受治疗,同时每年有4万至7万人死亡。
狂犬病通过唾液和血液传播,通常是由被感染狂犬病的狗或猫咬伤而导致的。它也可以由包括臭鼬、蝙蝠等的大多数哺乳动物携带。
狂犬病毒在通过身体的末梢神经组织到达颅神经后显现出实际发病症状。人脑原本含有阻断外来物质入侵的血脑屏障,所以病毒无法侵入。但是,狂犬病毒经由RVG蛋白(狂犬病毒糖蛋白)穿过血脑屏障,来感染大脑的中枢神经***。
在狂犬病初期,除与感冒相似的症状外,在咬伤区域还感到瘙痒或发热。随着狂犬病的发展,可能会出现神经***异常,如焦虑、恐水(吞咽诸如水的液体引起肌肉痉挛和剧烈疼痛,从而招致对水的恐惧)、怕风(风使感觉器官更加敏感)、兴奋、麻痹、精神障碍等。狂犬病还会引起对阳光的过度敏感。在观察到这些症状2至7天后,整个身体的神经和肌肉麻痹,诱发昏迷,结果造成导致死亡的呼吸衰竭。
暴露于狂犬病后的治疗包括咬伤后的治疗(暴露后预防)。咬伤后的治疗包括给药用于被动免疫的抗体,即时的局部伤口保护(抗狂犬病免疫球蛋白:下文称为“抗狂犬病抗体”),以及给药用于主动免疫的疫苗。目前开发出来的抗狂犬病抗体包括人源狂犬病免疫球蛋白(下文称为“HRIG”)和马源狂犬病免疫球蛋白(下文称为“ERIG”)。HRIG价格昂贵,无法有效供应;且它是多克隆抗体,从而每单位重量的效力低。此外,HRIG源自人血,潜在感染诸如HIV的人源性疾病的风险高。另一方面,虽然ERIG便宜,但所显示的治疗效率比HRIG低,因此以高得多的用量来给药患者。然而,ERIG是源自不同于人的马的抗体,因此可能导致过敏性反应。所以,为了克服无法有效供应及与多克隆抗体有关的问题,已提出使用能够中和狂犬病毒的单克隆抗体。在二十世纪八十年代,开发了一种中和狂犬病毒的小鼠单克隆抗体(Schumacher CL et al.,J.Clin.Invest.Vol.84,p.971-975,1989),但是将该单克隆抗体直接给药予人类患者受到限制,这归因于诸如在人体中的半衰期短、缺乏抗体介导的免疫应答、诱导HAMA(人抗小鼠的抗体)等缺陷。
此外,WHO已提出若干建议以取代现有的HRIG或ERIG(WHO对用于狂犬病暴露后治疗的狂犬病单克隆抗体鸡尾酒的研讨会(WHO Consultation on a Rabies MonoclonalAntibody Cocktail for Rabies Post-Exposure Treatment),WHO,日内瓦,2002年5月23至24日)。在这些建议中,已提出:为了使单克隆抗体用作狂犬病的治疗剂,应当将两种或三种抗体混合并与狂犬病毒表面糖蛋白的不同位点结合。
因此,为了有效治疗狂犬病,存在开发针对任意狂犬病毒的人单克隆抗体和抗体鸡尾酒的迫切需求,其中人单克隆抗体和抗体鸡尾酒不来源于血液,从而就潜在感染而言安全性高,能够通过孵育来大量生产,而且仅由有效力的抗体组成,从而确保了质量一致并表现出每单位用量的效率高。
发明内容
技术问题
为了解决上述问题,本发明人证明了与狂犬病毒结合从而具有中和活性的人抗体(韩国专利申请号10-2014-0178030)的表位位于狂犬病毒G蛋白(SEQ ID NO:2)的氨基酸第33、34、35、38、200、202和215位,或者位于狂犬病毒G蛋白(SEQ ID NO:2)的氨基酸第331和333位,并还确定了含与不同表位结合的两种抗体的抗体鸡尾酒的中和活性。
因此,本发明旨在提供一种中和狂犬病毒的结合分子,所述结合分子与位于野生型狂犬病毒G蛋白的第33至333位氨基酸残基的表位结合,所述野生型狂犬病毒G蛋白如SEQID NO:2所示。
此外,本发明旨在提供一种免疫偶联物,所述免疫偶联物经配置使得至少一种标签额外地偶联至所述结合分子。
此外,本发明旨在提供编码所述结合分子的核酸分子。
此外,本发明旨在提供一种表达载体,其中,所述核酸分子***至所述表达载体中。
此外,本发明旨在提供一种细胞系,所述细胞系经配置使得用所述表达载体来转化宿主细胞,以产生与狂犬病毒结合并具有中和活性的结合分子。
此外,本发明旨在提供一种用于诊断、预防或治疗狂犬病的药物组合物,所述药物组合物包括所述结合分子。
此外,本发明旨在提供一种用于诊断、预防或治疗狂犬病的试剂盒,所述试剂盒包括所述结合分子。
此外,本发明旨在提供一种使用所述结合分子来诊断、预防或治疗狂犬病的方法。
此外,本发明旨在提供一种通过孵育所述细胞系来生产所述结合分子的方法。
此外,本发明旨在提供一种使用所述结合分子来检测狂犬病毒的方法。
此外,本发明旨在提供一种用于预防或治疗狂犬病的药物组合物,所述药物组合物包括:a)第一结合分子,所述第一结合分子与位于野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位结合,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示;和b)第二结合分子,所述第二结合分子与野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位结合,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
此外,本发明旨在提供一种用于诊断、预防或治疗狂犬病的方法,所述方法包括:a)将上述组合物以治疗有效量给药予受试者;b)将所述第一结合分子和所述第二结合分子以治疗有效量同时给药予受试者;或者c)将所述第一结合分子和所述第二结合分子以治疗有效量依次给药予受试者。
此外,本发明旨在提供一种多肽,所述多肽包括位于野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
此外,本发明旨在提供一种多肽,所述多肽包括位于野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
此外,本发明旨在提供一种筛选中和狂犬病毒的结合分子的方法,所述结合分子与上述多肽特异性结合。
此外,本发明旨在提供一种含上述多肽的狂犬病毒疫苗组合物。
技术方案
因此,本发明的实施方式提供了一种中和狂犬病毒的结合分子,所述结合分子与位于野生型狂犬病毒G蛋白的第33至333位氨基酸残基的表位结合,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
在本发明的实施方式中,所述表位可以是位于野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示;且更具体地,可以是包括选自由该野生型狂犬病毒G蛋白的第33、34、35、38、200、202和215位氨基酸残基所组成的组中的至少一个氨基酸残基的表位。
在本发明的实施方式中,与上述表位结合的中和狂犬病毒的结合分子可具有小于1×10-8M的结合亲和力(KD)。在另一实施方式中,所述结合分子可具有小于5×10-9M的结合亲和力。在又一实施方式中,所述结合分子可具有小于1×10-9M的结合亲和力。在再一实施方式中,所述结合分子可具有小于5×10-10M的结合亲和力。在再又一实施方式中,所述结合分子可具有小于1×10-10M的结合亲和力。在进一步的实施方式中,所述结合分子可具有小于5×10-11M的结合亲和力。在又进一步的实施方式中,所述结合分子可具有小于1×10-11M的结合亲和力。在再进一步的实施方式中,所述结合分子可具有小于5×10-12M的结合亲和力。在又再进一步的实施方式中,所述结合分子可具有小于1×10-12M的结合亲和力。
在本发明的实施方式中,与上述表位结合的中和狂犬病毒的结合分子可以是包括以下项的结合分子:a)含SEQ ID NO:3的CDR1、SEQ ID NO:4的CDR2和SEQ ID NO:5的CDR3的可变区;和/或含b)SEQ ID NO:6的CDR1、SEQ ID NO:7的CDR2和SEQ ID NO:8的CDR3的可变区。
在另一实施方式中,所述结合分子可以是包括以下项的结合分子:SEQ ID NO:15的可变区和/或SEQ ID NO:16的可变区。在又一实施方式中,所述结合分子可以是包括以下项的结合分子:SEQ ID NO:19的重链和/或SEQ ID NO:20的轻链。
在本发明的另一实施方式中,所述表位可以是位于野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示;且更具体地,可以是包括选自由该野生型狂犬病毒G蛋白的第331和333位氨基酸残基所组成的组中的至少一个氨基酸残基的表位。
在本发明的实施方式中,与上述表位结合的中和狂犬病毒的结合分子可具有小于1×10-9M的结合亲和力(KD)。在另一实施方式中,所述结合分子可具有小于3×10-10M的结合亲和力。在又一实施方式中,所述结合分子可具有小于1×10-10M的结合亲和力。在再一实施方式中,所述结合分子可具有小于3×10-11M的结合亲和力。在再又一实施方式中,所述结合分子可具有小于1×10-11M的结合亲和力。在进一步的实施方式中,所述结合分子可具有小于3×10-12M的结合亲和力。在又进一步的实施方式中,所述结合分子可具有小于1×10-12M的结合亲和力。在再进一步的实施方式中,所述结合分子可具有小于3×10-13M的结合亲和力。在又再进一步的实施方式中,所述结合分子可具有小于1×10-13M的结合亲和力。
结合亲和力(KD)可使用如BIACORE***的表面等离子共振来测量。
在本发明的实施方式中,与上述表位结合的中和狂犬病毒的结合分子可以是包括以下项的结合分子:a)含SEQ ID NO:9的CDR1、SEQ ID NO:10的CDR2和SEQ ID NO:11的CDR3的可变区;和/或含b)SEQ ID NO:12的CDR1、SEQ ID NO:13的CDR2和SEQ ID NO:14的CDR3的可变区。
在另一实施方式中,所述结合分子可以是包括以下项的结合分子:SEQ ID NO:17的可变区和/或SEQ ID NO:18的可变区。在又一实施方式中,所述结合分子可以是包括以下项的结合分子:SEQ ID NO:21的重链和/或SEQ ID NO:22的轻链。
同时,在本发明中,使用由Kabat等设计的***(Kabat et al.,Sequences ofProteins of Immunological Interest(5th),National Institutes of Health,Bethesda,MD.(1991)),通过典型的方法来确定可变区的CDR。虽然,在本发明中使用Kabat方法来确定CDR,但是含通过如IMGT方法、Chothia方法、AbM方法等其它方法确定的CDR的结合分子,也落入本发明的范围内。
在本发明的实施方式中,所述结合分子可以是抗体或抗体片段。所述结合分子可以是但不限于Fab、Fv、双价抗体(diabody)、嵌合抗体、人源化抗体或人抗体。本发明的实施方式提供了一种与狂犬病毒结合的完全人抗体(fully human antibody)。如本文所使用的,术语“抗体”用来具有尽可能广泛的含义,具体包括完整的单克隆抗体,多克隆抗体,由两种或多种完整抗体形成的多特异性抗体(如双特异性抗体),以及显示所需生物活性的抗体片段。抗体是由免疫***产生的能够识别特定抗原并与其结合的蛋白质。抗体通常配置为含有四条氨基酸链(两条重链和两条轻链)的Y型蛋白质。每个抗体均具有两种结构域,包括可变区和恒定区。位于Y臂末端的可变区与靶抗原结合并与其相互作用。可变区包括识别特定抗原上的特定结合位点并与其结合的互补决定区(CDR)。位于Y尾部的恒定区被免疫***识别并与其相互作用。靶抗原具有被抗体上的CDR所识别的多个结合位点,该结合位点被称作表位。与不同表位特异性结合的各抗体具有不同的结构。因此,单一抗原可具有与其对应的至少一种抗体。
此外,本发明包括抗体的功能性变体。只要该抗体变体能够与本发明的抗体竞争以与狂犬病毒或其G蛋白特异性结合,则被认为是本发明的抗体的功能性变体。这样的功能性变体包括但不限于初级构象序列基本相似的衍生物,其实例包括体外或体内的化学和/或生物化学的修饰,未在本发明的亲本单克隆抗体中发现它们。这样的修饰的实例可包括乙酰化、酰化、核苷酸或核苷酸衍生物的共价键合、脂质或脂质衍生物的共价键合、交联、二硫键键合、糖基化、羟基化、甲基化、氧化、聚乙二醇化、蛋白水解和磷酸化。与亲本抗体的氨基酸序列相比,功能性变体可以选择性地为如下抗体,该抗体包括由经过至少一个氨基酸替换、***、缺失或它们的组合所产生的氨基酸序列。此外,功能性变体可包括在氨基末端和羧基末端中的一端或两端截短的氨基酸序列的形式。本发明的功能性变体可具有与本发明的亲本抗体相同或不同(即更高或更低)的结合亲和力,但仍可以与狂犬病毒或其G蛋白结合。例如,可变区的氨基酸序列(包括但不限于骨架结构或高变区,尤其是CDR3)可被修饰。通常轻链或重链结构域包括:具有三个CDR的三个高变区;和更保守的结构域,即骨架区(FR)。高变区包括来自CDR的氨基酸残基和来自高变环的氨基酸残基。落入本发明范围内的功能性变体可具有与本发明的亲本抗体,约50%~99%,约60%~99%,约80%~99%,约90%~99%,约95%~99%,或约97%~99%的氨基酸序列同源性。为了最佳地排列待比较的氨基酸序列,并且为了定义相似或一致的氨基酸残基,在计算机算法中,可以使用本领域技术人员已知的Gap或Best-fit。亲本抗体或其一部分经过已知的分子生物学过程或有机合成过程可获得功能性变体,其中已知的分子生物学过程包括使用寡聚核苷酸的PCR或诱变/部分诱变,但本发明不限于此。
同时,狂犬病毒可源自选自以下项所组成的组中的任一个体:狗、牛、猫鼬、蝙蝠、臭鼬、浣熊、郊狼、狐狸和狼,但不限于此。
此外,本发明提供了一种免疫偶联物,该免疫偶联物经配置使得至少一种标签进一步与所述结合分子偶联。例如,可以将药物额外地附着于根据本发明的抗体。根据本发明的抗体可以以含药物的抗体-药物偶联物的形式来使用。当使用抗体-药物偶联物(ADC)(即免疫偶联物)局部递送药物时,药物部分靶向递送至被感染的细胞成为可能。当给药未被偶联的药物试剂时,可能对正常细胞造成不可接受的水平的毒性。通过增加药物偶联和药物释放性,并且增加多克隆抗体和单克隆抗体(mAb)的选择性,可获得ADC的最大效力和最小毒性。
使用将药物部分附着于抗体的典型手段(例如通过共价键合),可能产生异种分子混合物,其中药物部分附着于抗体的许多位点。例如,细胞毒性药物通过抗体的许多赖氨酸残基偶联至抗体,从而产生异种抗体-药物偶联物的混合物。取决于反应条件,这样的异种混合物通常所具有的分布,使得与药物部分连接的抗体数量在0至至少约8的范围内。此外,以特定整数比含有药物部分和抗体的偶联物各亚组是潜在的异种混合物,其中药物部分附着至抗体的不同位点。抗体是大的、复杂的且结构上多样的生物分子,常常具有许多反应性官能团。接头(linker)试剂和药物-接头中间体的反应性取决于诸如pH、浓度、盐浓度和助溶剂的因素。
此外,本发明提供了编码所述结合分子的核酸分子。例如,本发明包括编码中和狂犬病毒的结合分子的分离的核酸分子,所述中和狂犬病毒的结合分子与野生型狂犬病毒G蛋白的表位结合。
上述核酸分子包括任意的核酸分子,其中本发明的抗体的氨基酸序列被翻译成本领域技术人员已知的多核苷酸序列。因此,各种多核苷酸序列可以使用ORF(开放阅读框)来制备,并且也可以并入到本发明的核酸分子中。
此外,本发明提供了一种表达载体,在该表达载体中***了所述核酸分子。
在本发明的实施方式中,上述表达载体可包括但不限于选自由以下项组成的组的任一表达载体:购买自Celltrion的表达载体,如MarEx载体(韩国专利号10-1076602),和商业上广泛使用的pCDNA载体、F、R1、RP1、Col、pBR322、ToL和Ti载体;粘粒;噬菌体,如λ、λ形(lambdoid)、M13、Mu、pi P22、Qμ、T偶数(T-even)、T2、T3、T7等噬菌体;和植物病毒。而且本领域技术已知的任何表达载体都可用于本发明中,并且可根据感兴趣的宿主细胞的性质来选择表达载体。可以通过磷酸钙转染、病毒感染、DEAE-葡聚糖介导的转染、脂质体转染或电穿孔将载体导入宿主细胞中,但是本发明不限于此,本领域技术人员可以采用适用于表达载体和宿主细胞的导入方法。表达载体优选含有至少一种选择标记物,但不限于此,选择可以取决于是否能够使用不含选择标记物的载体获得产物。选择标记物的选取取决于感兴趣的宿主细胞,并使用本领域技术人员已知的任何方法来进行,因此本发明不限于此。
为了容易地对本发明的结合分子进行纯化,可以将标签序列***到表达载体中,从而被融合。标签可包括但不限于,六聚组氨酸标签、血凝素标签、myc标签或flag标签,任何标签只要是本领域技术人员已知有利于纯化的,都可用于本发明。
此外,本发明提供了一种细胞系,该细胞系经配置使得宿主细胞经所述表达载体转化,以产生与狂犬病毒结合并从而具有中和活性的结合分子。
此外,本发明提供了一种生产与狂犬病毒结合并具有中和活性的结合分子的方法,所述方法包括:a)孵育所述细胞系;和b)回收所表达的结合分子。
在本发明的实施方式中,所述细胞系可包括但不限于,哺乳动物、植物、昆虫、真菌或细胞来源的细胞。选自由哺乳动物细胞,如CHO细胞、F2N细胞、CSO细胞、BHK细胞、Bowes黑素瘤细胞、HeLa细胞、911细胞、AT1080细胞、A549细胞、HEK 293细胞和HEK293T细胞组成的组中的任一种细胞可用作宿主细胞,但本发明不限于此,并可以使用任何细胞,只要本领域技术人员已知它们可用作哺乳动物的宿主细胞。
此外,本发明提供了一种用于诊断、预防或治疗狂犬病的药物组合物,所述药物组合物包括所述结合分子。
除具有中和狂犬病毒的活性的中和分子外,根据本发明的用于预防或治疗的药物组合物还可包括药学上可接受的赋形剂。药学上可接受的赋形剂是本领域技术人员已知的。
此外,根据本发明的用于预防或治疗的药物组合物可包括至少一种其它的狂犬病治疗剂,并还可包括多种单克隆抗体,从而显示出协同的中和活性。
此外,根据本发明的用于预防或治疗的药物组合物可进一步包括至少一种其它的治疗剂或诊断剂。所述治疗剂可包括但不限于抗病毒的药物。这样的药物可以是抗体、小分子、有机或无机化合物、酶、多核苷酸序列、抗病毒肽等。
根据本发明的用于预防或治疗的药物组合物在生产和贮藏条件下是无菌的且稳定的,并可以粉末的形式来提供,以便在递送期间或递送前被重构至合适的药学上可接受的赋形剂内。优选通过真空干燥和冻干来获得用于制备无菌注射溶液的无菌粉末,以从其经预先灭菌-过滤的溶液中生产活性成分粉末和额外的所需成分。本发明的药物组合物可以处于溶液相中,并且可以包括在递送前或递送期间加入和/或混合的适当的药学上可接受的赋形剂,以提供单位剂量的给药形式。优选地,本发明中所使用的药学上可接受的赋形剂对于药物浓度是足够的且能够保持合适的流动性,并可以根据需要延迟它的吸收。
根据本发明的用于预防或治疗的药物组合物的最佳给药途径的选择受多种因素影响,这些因素包括药物组合物中的活性分子的物理-化学性质,临床情况的紧迫性,以及活性分子的血浆浓度与所需疗效的关系。例如,本发明的单克隆抗体可以与防止快速释放的载剂(如控释制剂,包括植入物和微胶囊递送***)一同制备。在本发明中,可以使用生物可降解且生物相容性的聚合物,如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。此外,单克隆抗体可包被有用于防止抗体失活的物质或化合物,或与用于防止抗体失活的物质或化合物一同给药。例如,单克隆抗体可与合适的载剂-脂质体或稀释剂一同给药。
根据本发明的用于预防或治疗的药物组合物的给药方法可以包括口服给药和胃肠外给药,例如,给药途径可以是静脉内给药,但不限于此。
口服制剂可以以下形式来提供:片剂、锭剂、药用滴剂、水性或油性混悬剂、散剂或分散颗粒剂、乳剂、硬胶囊、软明胶胶囊、糖浆或酏剂、丸剂、糖衣片剂、液体、凝胶或浆液。这样的制剂可包括但不限于含惰性稀释剂、造粒剂或崩解剂、粘合剂、润滑剂、防腐剂、着色剂、香味剂,甜味剂、植物油或矿物油、润湿剂和增稠剂的药学上可接受的赋形剂。
胃肠外制剂可以水性或非水性等渗无菌无毒的注射剂的形式,或以注射溶液剂或混悬剂的形式来提供。溶液或混悬剂可包括在施加的用量和浓度下对受体无毒的油类,脂肪酸,局部麻醉剂,防腐剂,缓冲液,增粘剂或增溶剂,水溶性抗氧化剂,油溶性抗氧化剂和金属螯合剂,以及药剂,如1,3-丁二醇、林格氏(Ringer's)溶液、汉克(Hank's)溶液和等渗氯化钠溶液。
根据本发明的用于预防或治疗的药物组合物的给药量取决于治疗对象、疾病的严重程度或状态,给药率和医生处方。用作活性成分的结合分子可以0.001至10mg/kg(体重)或0.005至1mg/kg(体重)的用量,每天一次或分成多份给药多次通过肠胃外途径给药予哺乳动物。在一些情况下,低于之前提到的范围的用量可能是更适合的,而且在不导致有害副作用的情况下,可以应用更高的用量并可在一天中分为少量多次。
在用于诊断的药物组合物中使用的本发明的结合分子优选被可检测地标记。可以用于标记生物分子的各种方法是本领域技术人员公知的并且被认为落入本发明的范围内。可用于本发明的标记的实例可以包括酶、放射性同位素、胶体金属、荧光化合物、化学发光化合物和生物发光化合物。常用的标记包括荧光物质(如荧光素、罗丹明、德克萨斯红等)、酶(如辣根过氧化物酶、β-半乳糖苷酶、碱性磷酸酶)、放射性同位素(如32P或125I)、生物素、地高辛、胶体金属、化学发光或生物发光化合物(如二氧杂环丁烷、鲁米诺或吖啶(acridinium))。标记方法例如本领域公知的酶或生物素基团的共价键合、碘化、磷酸化、生物素化等。检测方法包括但不限于放射自显影、荧光显微术、直接和间接酶反应等。常用的检测测定法是放射性同位素或非放射性同位素方法。尤其有用的是Westerm印记、叠置分析、RIA(放射免疫测定(Radioimmuno Assay))和IRMA(免疫同位素放射免疫测定(ImmuneRadioimmunometric Assay))、EIA(酶免疫测定(Enzyme Immuno Assay))、ELISA(酶联免疫吸附测定(Enzyme Linked Immuno Sorbent Assay)),FIA(荧光免疫测定(Fluorescent Immuno Assay))和CLIA(化学发光免疫测定(Chemiluminescent ImmuneAssay))。
此外,本发明提供了一种用于诊断、预防或治疗狂犬病的试剂盒,所述试剂盒包括:a)所述结合分子;和b)容器。
在根据本发明的用于诊断、预防或治疗的试剂盒中,在b)容器中可包括固体承载体。本发明的结合分子可附着至所述固体承载体,且所述固体承载体可以是多孔的或无孔的,或可以是平面的或非平面的。
此外,本发明提供了一种用于诊断狂犬病的方法,所述方法包括使受试者样品与所述结合分子接触;和b)分析步骤a)的结果以确定被狂犬病感染。
在本发明的诊断方法中,所述样品可以是但不限于选自由以下项组成的组的任一种样品:受试者的痰、唾沫、血液、汗液、肺细胞、肺组织的粘液、呼吸组织和唾液,所述样品可以使用本领域技术人员通常已知的方法来制备。
此外,本发明提供了一种用于预防或治疗狂犬病的方法,所述方法包括将所述结合分子以治疗有效量给药予受试者。
例如,当人们经过已知存在狂犬病毒的区域时,可以向其给药本发明的人单克隆抗体,从而在1天、2天、3天或若干天内赋予对狂犬病毒的免疫力。
此外,本发明提供了一种用于检测狂犬病毒的方法,所述方法包括a)使受试者样品与所述结合分子接触;和b)测量所述结合分子是否与所述受试者样品特异性结合。
在本发明的狂犬病毒检测方法中,所述受试者样品可包括但不限于,来自(潜在)被感染的受试者的血液、血清、唾液、痰、唾沫、汗液、组织或其它生物材料,且可以通过本领域技术人员已知的常规方法来制备。所述(潜在)被感染的受试者可以是人,但可以包括被怀疑是狂犬病毒携带者的动物。受试者样品可首先经操作以使其更适合于检测方法。优选地,在允许所述结合分子与存在于所述受试者样品中的狂犬病毒或其抗原成分之间形成免疫学复合物的条件下,使本发明的结合分子或免疫偶联物与受试者样品进行接触。通过适合的手段检测并测量免疫学复合物的形成,其中免疫学复合物的形成表明受试者样品中存在狂犬病毒。为此,可以进行免疫测定,如放射免疫测定(RIA)、ELISA、免疫荧光、免疫组织化学、FACS、BIACORE和Western印记分析,但本发明不限于此。
此外,本发明提供了一种用于诊断、预防或治疗狂犬病的药物组合物(下文称为“鸡尾酒组合物”),所述药物组合物包括:a)第一结合分子,所述第一结合分子与位于野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位结合,该野生型狂犬病毒G蛋白如SEQID NO:2所示;和b)第二结合分子,所述第二结合分子与位于野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位结合,该野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
在本发明的实施方式,鸡尾酒组合物可包括浓度比例为1:9~9:1的a)所述第一结合分子和b)所述第二结合分子。在另一实施方式中,所述鸡尾酒组合物的浓度比例可以在1:3~9:1的范围内。
在本发明的实施方式中,所述第一结合分子所结合的表位可以包括选自由野生型狂犬病毒G蛋白的第33、34、35、38、200、202和215位氨基酸残基所组成的组中的至少一个氨基酸残基,该野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
在本发明的实施方式中,所述第二结合分子所结合的表位可以包括选自由野生型狂犬病毒G蛋白的第331和333位氨基酸残基所组成的组中的至少一个氨基酸残基,该野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
在本发明的实施方式中,所述第一结合分子可具有小于1×10-8M的结合亲和力(KD)。在另一实施方式中,所述结合分子可具有小于5×10-9M的结合亲和力。在又一实施方式中,所述结合分子可具有小于1×10-9M的结合亲和力。在再一实施方式中,所述结合分子可具有小于5×10-10M的结合亲和力。在再又一实施方式中,所述结合分子可具有小于1×10-10M的结合亲和力。在进一步的实施方式中,所述结合分子可具有小于5×10-11M的结合亲和力。在又进一步的实施方式中,所述结合分子可具有小于1×10-11M的结合亲和力。在再进一步的实施方式中,所述结合分子可具有小于5×10-12M的结合亲和力。在又再进一步的实施方式中,所述结合分子可具有小于1×10-12M的结合亲和力。
在本发明的实施方式中,所述第二结合分子的结合亲和力(KD)可小于1×10-9M。在另一实施方式中,所述结合分子可具有小于3×10-10M的结合亲和力。在又一实施方式中,所述结合分子可具有小于1×10-10M的结合亲和力。在再一实施方式中,所述结合分子可具有小于3×10-11M的结合亲和力。在再又一实施方式中,所述结合分子可具有小于1×10-11M的结合亲和力。在进一步的实施方式中,所述结合分子可具有小于3×10-12M的结合亲和力。在又进一步的实施方式中,所述结合分子可具有小于1×10-12M的结合亲和力。在再进一步的实施方式中,所述结合分子可具有小于3×10-13M的结合亲和力。在又再进一步的实施方式中,所述结合分子可具有小于1×10-13M的结合亲和力。
在本发明的实施方式中,所述第一结合分子可以是包括以下项的结合分子:a)含SEQ ID NO:3的CDR1、SEQ ID NO:4的CDR2和SEQ ID NO:5的CDR3的可变区;和/或b)含SEQID NO:6的CDR1、SEQ ID NO:7的CDR2和SEQ ID NO:8的CDR3的可变区。在另一实施方式中,所述第一结合分子可以是包括以下项的结合分子:SEQ ID NO:15的可变区和/或SEQ IDNO:16的可变区。在又一实施方式中,所述第一结合分子可以是包括以下项的结合分子:SEQID NO:19的重链和/或SEQ ID NO:20的轻链。
在本发明的实施方式中,所述第二结合分子可以是包括以下项的结合分子:a)含SEQ ID NO:9的CDR1、SEQ ID NO:10的CDR2和SEQ ID NO:11的CDR3的可变区;和/或含SEQID NO:12的CDR1、SEQ ID NO:13的CDR2和SEQ ID NO:14的CDR3的可变区。在另一实施方式中,所述第二结合分子可以是包括以下项的结合分子:SEQ ID NO:17的可变区和/或SEQ IDNO:18的可变区。在又一实施方式中,所述第二结合分子可以是包括以下项的结合分子:SEQID NO:21的重链和/或SEQ ID NO:22的轻链。
在本发明的实施方式中,所述结合分子可以是抗体或抗原结合片段,且抗病毒药物可以进一步附着至所述抗体。
在本发明的实施方式中,所述鸡尾酒组合物可以以无菌注射溶液、冻干制剂、预填充注射溶液、口服制剂、外用制剂或栓剂的形式来提供。
此外,本发明提供了一种用于诊断、预防或治疗狂犬病的方法,所述方法包括:a)将上述鸡尾酒组合物以治疗有效量给药予受试者;b)将所述第一结合分子和所述第二结合分子以治疗有效量同时给药予受试者;或者c)将所述第一结合分子和所述第二结合分子以治疗有效量依次给药予受试者。
在本发明的预防或治疗方法中,可以将本领域技术人员已知的治疗剂一同给药。在本发明的预防或治疗方法中,给药方法可包括口服给药和胃肠外给药,且给药途径可以例如为静脉内给药,但不限于此。
在本发明的预防或治疗方法中,可进一步给药抗病毒的药物。所述抗病毒的药物可以是,但不限于抗狂犬病毒的单克隆抗体、抗狂犬病毒的多克隆抗体、DNA聚合酶抑制剂、siRNA制剂或治疗性疫苗。
此外,本发明提供了一种诊断、预防或治疗狂犬病的方法,所述方法包括:
a)将所述第一结合分子和所述第二结合分子以治疗有效量同时给药予受试者;
b)依次先将所述第一结合分子以治疗有效量给药予受试者,随后将所述第二结合分子以治疗有效量给药予受试者;或者c)依次先将所述第二结合分子以治疗有效量给药予受试者,随后将所述第一结合分子以治疗有效量给药予受试者。
此外,本发明提供了一种用于诊断、预防或治疗狂犬病的药物组合物,所述药物组合物包括:a)将所述第一结合分子和所述第二结合分子以治疗有效量同时给药予受试者;b)依次先将所述第一结合分子以治疗有效量给药予受试者,随后将所述第二结合分子以治疗有效量给药予受试者;或者c)依次先将所述第二结合分子以治疗有效量给药予受试者,随后将所述第一结合分子以治疗有效量给药予受试者。
此外,本发明提供了一种用于诊断、预防或治疗狂犬病的试剂盒,所述试剂盒包括:(1)含治疗有效量的所述第一结合分子和所述第二结合分子的上述药物组合物;和(2)表示出以下内容的包装说明书:a)将所述第一结合分子和所述第二结合分子以治疗有效量同时给药予受试者,b)依次先将所述第一结合分子以治疗有效量给药予受试者,随后将所述第二结合分子以治疗有效量给药予受试者,或者c)依次先将所述第二结合分子以治疗有效量给药予受试者,随后将所述第一结合分子以治疗有效量给药予受试者。
此外,本发明提供了一种多肽,该多肽包括位于野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位,该野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
该表位可以包括选自由野生型狂犬病毒G蛋白的第33、34、35、38、200、202和215位氨基酸残基所组成的组中的至少一个氨基酸残基。
此外,本发明提供了一种多肽,该多肽包括位于野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位,该野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
该表位可以包括选自由野生型狂犬病毒G蛋白的第331和333位氨基酸残基所组成的组中的至少一个氨基酸残基。
在本发明的多肽中,表位可以以与载剂连接的形式使用,以在用于疫苗组合物等时保持其三维结构或确保其效率。在本发明中,任何载剂只要是生物相容性的且适于实现本发明的效果的都可以使用,可以选自于但不限于:肽、血清白蛋白、免疫球蛋白、血蓝蛋白和多糖。
此外,本发明提供了编码上述表位的多核苷酸。编码上述表位的多核苷酸可以基因疫苗的形式单独使用,其中上述表位含根据本发明的上述氨基酸位置。此处,所述多核苷酸可以在不存在任何载体的情况下单独使用,且可以包埋于病毒或非病毒载体中,并随后转移到体内。病毒或非病毒载体只要已知在本发明所属技术领域中通常是有用的,则它的使用不存在限制。具体来说,病毒载体的实例可包括腺病毒、腺相关病毒、慢病毒、逆转录病毒等,而非病毒载体可包括阳离子聚合物、非离子聚合物、脂质体、脂质、磷脂、亲水聚合物、疏水聚合物以及从它们中选取的至少一种组合,但本发明不限于此。
此外,本发明提供了一种表达载体,所述表达载体含编码上述表位的多核苷酸。
此外,本发明提供了经所述表达载体转化的重组微生物或重组病毒。在一个实施方式中,所述重组微生物或重组病毒可以是重组大肠杆菌(E.coli)、重组酵母或重组噬菌体。
在本发明的实施方式中,本发明提供了一种在微生物或病毒表面上表达以下表位的方法:位于如SEQ ID NO:2所示的野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位,或者位于如SEQ ID NO:2所示的野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位。此处,可使用含编码诱导型启动子或信号蛋白的序列的重组载体,以及含该重组载体的任何微生物或病毒。具体来说,适合的微生物或病毒可以包括,但不限于:重组E.coli、重组酵母或重组噬菌体。为了在微生物或病毒表面上表达含上述氨基酸位置的表位,可利用本发明所属领域公知的展示技术。具体来说,本发明的表达方法可按以下方式进行:其中,编码含上述氨基酸位置的表位的多核苷酸序列可结合至编码诱导在微生物细胞或病毒表面上表达的启动子或信号蛋白的序列;或者其中,可缺失编码最初在表面上表达的蛋白的基因位点,随后可将编码含上述氨基酸位置的表位的多核苷酸序列***到其中,但本发明不限于此。当使用本发明的表达方法时,在微生物或病毒表面上表达的含上述氨基酸位置的表位可被分离和纯化,因此可应用与本发明的某些目的中,并且此外,在表面上表达的情况中,可以选择性地得到与含上述氨基酸位置的表位特异性结合的抗体。
此外,本发明提供了一种用于生产上述表位的方法,该方法包括孵育所述重组微生物或重组病毒。
此外,本发明提供了一种用于检测狂犬病毒的组合物,所述组合物包括上述表位或编码该表位的多核苷酸。
此外,本发明提供了一种筛选中和狂犬病毒的中和分子的方法,其中,该中和狂犬病毒的中和分子与上述多肽特异性结合,该方法包括将该结合分子与该多肽接触。
在本发明的实施方式中,该结合分子可以是抗体或抗原结合片段。
根据本发明的筛选方法可通过任何免疫测定法,例如ELISA、组织或细胞(经转染的细胞)染色、中和测定或本领域已知的其它方法来进行,以验证所需的特异性或功能性,但本发明不限于此。
此外,本发明提供了一种含上述多核苷酸的狂犬病毒疫苗组合物。
本发明的疫苗组合物可以进一步包括药学上可接受的佐剂。佐剂的功能是在注射至体内时增加抗体的形成,任何佐剂只要能够实现本发明的效果都可以使用,佐剂的实例可包括,但不限于:铝盐(Al(OH)3、AlPO4)、角鲨烯、山梨糖醇、聚山梨醇酯80、CpG、脂质体、胆固醇、MPL(单磷酰脂质A)和GLA(吡喃葡萄糖基脂质A)。
本发明中所使用的术语定义如下。
如本文所使用的,术语“结合分子”是指完整的免疫球蛋白,包括单克隆抗体,如嵌合抗体、人源化抗体或人单克隆抗体;或是指与抗原结合的免疫球蛋白,如可变区,其中可变区包括与完整的免疫球蛋白竞争以与狂犬病毒、病毒外面的G蛋白(糖蛋白)或它们的片段结合的免疫球蛋白片段。不管结构如何,抗原结合片段与完整的免疫球蛋白所识别的同一抗原结合。抗原结合片段可以包括肽或多肽,该肽或多肽包括由所述结合分子的氨基酸序列的至少2个连续氨基酸残基、至少5个连续氨基酸残基、至少10个连续氨基酸残基、至少15个连续氨基酸残基、至少20个连续氨基酸残基、至少25个连续氨基酸残基,至少30个连续氨基酸残基、至少35个连续氨基酸残基、至少40个连续氨基酸残基、至少50个连续氨基酸残基、至少60个连续氨基酸残基、至少70个连续氨基酸残基、至少80个连续氨基酸残基、至少90个连续氨基酸残基、至少100个连续氨基酸残基、至少125个连续氨基酸残基、至少150个连续氨基酸残基、至少175个连续氨基酸残基、至少200个连续氨基酸残基或至少250个连续氨基酸残基所组成的氨基酸序列。
如本文所使用的,术语“抗原结合片段”是指Fab、F(ab')、F(ab')2、Fv、dAb、Fd、互补决定区(CDR)片段、单链抗体(scFv)、二价单链抗体、单链噬菌体抗体、双价抗体、三价抗体、四价抗体、含免疫球蛋白中足以赋予多肽特异性抗原结合的至少一个片段的多肽,等等。上述片段可以通过合成来产生或通过对完整的免疫球蛋白进行酶促或化学切割来生产,或者它们可以通过重组DNA技术进行遗传工程处理。这样的生产方法是本领域所公知的。
如本文所使用的,术语“表位”是指对应于抗原中被抗体识别的一部分的抗原决定簇,且是指含本说明书和权利要求书中所使用的单种或多种肽的肽物质,且表位具有如本文所述的SEQ ID NO:2所示的氨基酸序列数据及其变体,还包括具有在本说明书和权利要求书中所描述的活性谱的肽。因此,即使是显示出几乎相同的活性或改变的活性的蛋白质,也应从这个意义上来理解。这样的变体可以通过定点诱变有目的地获得,或者可以通过复合体或宿主(是其指定亚基的生产者)的突变而意外获得。作为形成并检验肽变体的方法是本领域技术人员公知的,其中肽变体包括含变体,定点诱变和随机诱变的表位。
如本文所使用的,术语“药学上可接受的赋形剂”是指与活性分子(如药物、试剂或结合分子)组合用于制备适合或方便的剂型的任何惰性物质。药学上可接受的赋形剂是在所用剂量和浓度下对受体无毒或至少减毒的赋形剂,并且与包括药物、试剂或结合分子的制剂的其它成分相容。
如本文所使用的,术语“治疗有效量”是指本发明的结合分子的量对于暴露于狂犬病毒之前或之后的预防或治疗是有效的。
本发明人已经确定了:当使用鸟枪诱变法将除信号肽外的狂犬病毒G蛋白的氨基酸第33、34、35、38、200、202和215位替换为其它氨基酸残基时,可显著降低与根据本发明的抗体的结合活性,由此验证出对应位点是狂犬病毒G蛋白的表位。另外,当使用鸟枪诱变法将狂犬病毒G蛋白的氨基酸第331和333位替换为其它氨基酸残基时,可显著降低与根据本发明的另一抗体的结合活性,由此验证出对应位点是狂犬病毒G蛋白的表位。另外,在含有混合的上述两种抗体的抗体鸡尾酒中,可确认对狂犬病毒的中和活性,而不存在与不同表位结合所引起的任何干扰。因此,发现本发明的表位,与其结合的抗体及其抗体鸡尾酒可有效地用于治疗感染源自于广泛个体的狂犬病毒的患者。
有益效果
根据本发明,鉴定出了狂犬病毒G蛋白的不同表位位点,并且还确认了与其结合的结合分子及结合分子鸡尾酒具有对多种狂犬病毒的中和活性。因此,狂犬病毒G蛋白的表位及与其特异性结合的中和狂犬病毒的结合分子在狂犬病的诊断、预防或治疗中是有用的。
附图说明
图1示出了在动物试验中对SV2病毒的小鼠存活率。
具体实施方式
通过以下实施例可以更好地理解本发明,这些实施例是出于说明的目的,不应该被解释为对本发明范围的限制。本文所引用的文件通过引用的方式并入到本申请中。
实施例1:抗体的表位鉴定
为了鉴定出在韩国专利申请号10-2014-0178030所公开的实施例4中最终选择的四个抗体中的两个抗体(下文称为“抗体1”或“抗体2”)的表位,诱导了狂犬病毒G蛋白(SEQID NO:1)中的单个突变,并且评估抗体1和抗体2与各突变体的结合活性。使用美国Integral Molecular的鸟枪诱变法(J Am Chem Xoc.2009;131(20):6952-6954)来制备各突变体,并分析抗体1和抗体2与各突变体的结合活性。
鸟枪诱变法使突变的靶蛋白文库能在真核细胞中表达并进行分析。具体来说,可以用不同的氨基酸来突变靶蛋白的所有残基,并可以在哺乳动物细胞系中表达,以分析单克隆抗体(MAb)结合或功能的变化。
鸟枪诱变法分两步进行,其中,制备野生型狂犬病毒CVS-11毒株的G蛋白表达质粒,并在哺乳动物细胞系中进行表达,然后优化了用于抗体1和抗体2的结合活性分析的抗体浓度。
之后,使用鸟枪诱变法制备了突变体文库(下文称为“单突变体文库”),其中狂犬病毒CVS-11毒株的G蛋白中的各个氨基酸残基被替换成其它氨基酸,分析其与抗体的结合活性,从而确定了抗体1和抗体2的表位。
实施例1-1:制备表达狂犬病毒G蛋白的质粒
使用表达狂犬病毒CVS-11毒株的G蛋白的基因(Genbank Ref#AAC34683.1)来制备质粒,其中G蛋白的C末端带有V5/HIS6标签以便验证其表达。接下来,在HEK293细胞中表达质粒。将相应的质粒瞬时转染到HEK293细胞中,随后将质粒在384孔板中孵育一天,其中质粒包括仅含载体的阴性对照组,和为表达狂犬病毒G蛋白质组的结构(WT RABV)的阳性对照组。
实施例1-2:制备狂犬病毒G蛋白的单突变体文库
使用鸟枪诱变法制备单突变体文库,在单突变体文库中,除信号肽外的狂犬病毒G蛋白(SEQ ID NO:2)的第1~505位氨基酸残基中中的每一个被替换为不同的氨基酸。实施例1-1中制备的质粒被用作亲本质粒。进行丙氨酸扫描诱变,作为产生505个突变体克隆(下文中称为“丙氨酸扫描突变体”)的诱变策略。丙氨酸扫描诱变是以下的方法:它将蛋白质氨基酸替换为丙氨酸,以评估特定氨基酸位点对整个蛋白的功能、稳定性或外部响应的贡献。另外,使用逃逸突变病毒(escape mutant virus)试验法(韩国专利申请号10-2014-0178030),使狂犬病毒G蛋白的第34、210、331、336和413位不被替换为丙氨酸,而被替换为其它氨基酸残基以产生单突变体克隆(下文中称为“定制的突变体”)。因此,总文库大小由512个突变体克隆组成,如下表1所示。
[表1]用于表位鉴定的文库的性质
*除了狂犬病毒G蛋白的信号肽外,对氨基酸位置进行编号。
实施例1-3:抗体的表位鉴定
实施例1-3-1:使用丙氨酸扫描突变体进行抗体的表位鉴定
为了鉴定抗体1和抗体2的表位,使用实施例1-2中制备的丙氨酸扫描突变体文库来分析与抗体1和抗体2的结合活性。
为了评估实施例1-2的丙氨酸扫描突变体文库与抗体1和抗体2的结合,进行了两次免疫荧光FACS,从而对突变体进行选择。
在将抗体1和抗体2的整个抗体用于表位分析试验时,降低了相应的分析识别度。因此,使用木瓜蛋白酶处理抗体1和抗体2,由此从抗体中去除Fc部分且仅留下Fab部分,从而确定抗体1的Fab和抗体2的Fab的使用。通过使用不含Fc的Fab的试验,用于分析检测的二抗是Fab特异性的偶联Alexa Fluor 488的二抗(Jackson Immunoresearch Alexafluor488山羊抗人F(ab')2片段)。
另外,在抗体1的Fab的最佳浓度0.33μg/ml和抗体2的Fab的最佳浓度0.33μg/ml的条件下,进行表位分析试验。作为对照抗体,使用了Abcam 1C5(Abcam Inc.)和QED 20501(QED Bioscience Inc.)抗体,并且在对照抗体Abcam 1C5的最佳浓度0.25μg/ml和对照抗体QED 20501的最佳浓度0.5μg/ml的条件下,进行分析。
在文库选择中,选择与对实施例1-1的阳性对照组的结合反应性相比,表达超过对照抗体Abcam 1C5或QED 20501的80%,同时小于抗体1的Fab或抗体2的Fab的15%的丙氨酸扫描突变体。
[表2]
从表2的结果明显看出,在抗体1的情况下,总共选择出了七种丙氨酸扫描突变体,通过所选择的突变体鉴定出了抗体1的表位位点位于狂犬病毒G蛋白的氨基酸第33、34、35、38、200、202和215位。
在抗体2的情况下,总共选择出了一种丙氨酸扫描突变体,通过所选择的突变体鉴定出了抗体2的表位位点位于狂犬病毒G蛋白的氨基酸第333位。
实施例1-3-2:使用定制的突变体进行抗体的表位鉴定
为了鉴定抗体1和抗体2的表位,使用实施例1-2中制备的定制的突变体文库分析与抗体1和抗体2的结合活性。
为了评估实施例1-2的定制的突变体文库与抗体1和抗体2的结合,如实施例1-3-1那样进行免疫荧光FACS,并且对突变体进行选择。选择结果示于下表3中。此处,抗V5用作分析对照组,来证实狂犬病毒G蛋白经表达载体的表达。
[表3]
从表3的结果明显看出,在抗体1的情况下,选择出了三种定制的突变体,通过所选择的突变体鉴定出了抗体1的表位位点位于狂犬病毒G蛋白的氨基酸第34位。
在抗体2的情况下,选择出了一种定制的突变体,通过所选择的突变体鉴定出了抗体2的表位位点位于狂犬病毒G蛋白的氨基酸第331位。
实施例1-3-3:抗体的表位鉴定的结果
基于实施例1-3-1和1-3-2的结果,发现抗体1的表位位于狂犬病毒G蛋白(SEQ IDNO:2)的氨基酸第33、34、35、38、200、202和215位,且发现抗体2的表位位于狂犬病毒G蛋白的氨基酸第331和333位,如下表4所示。
狂犬病毒结合位点被表示为狂犬病毒表面糖蛋白的抗原位点,并且每一位点的狂犬病糖蛋白的抗原结构最初由Lafon等(J.Gen.Virol.64:843-8451 1983)定义。目前将鉴定出的狂犬病毒结合位点分类为抗原位点I、II、III、IV和a,并由Marissen等(JVirol.2005 Apr;79(8):4672-8.)定义。
[表4]
*除了狂犬病毒G蛋白的信号肽外,对氨基酸位置进行编号。
实施例2:使用表面等离子共振技术确定抗原-抗体结合亲和力
使用表面等离子共振测定(Biacore Inc.),通过正向和反向反应速率常数的流行病学测量来确定抗体的结合亲和力。因此,使用表面等离子共振技术确定了抗体1和抗体2的抗原-抗体结合亲和力。
具体来说,在25℃下,使用分析缓冲液HBS-EP(10mM HEPES[pH 7.4]、150mM NaCl、3mM EDTA和0.005%表面活性剂P20),利用Biacore T200(GE Healthcare),通过表面等离子共振测定,来确定经纯化的狂犬病毒G蛋白与抗体1和抗体2的结合亲和力。按照制造商的指南和程序,使用胺偶联试剂盒,将稀释于10mM乙酸钠(pH 5.0)的50μg/ml狂犬病毒G蛋白,以约500RU的量直接固定在CM5生物传感器芯片上。生物传感器表面未反应的部分用乙醇胺封闭。使用Biacore T200控制软件和Biacore T200评估软件进行反应分析。将抗体1和抗体2稀释于HBS-EP缓冲液中。在测定过程中,所有的测量都使用没有固定的狂犬病毒G蛋白的生物传感器表面作为对照组来进行。以30μl/min的流速来测定结合速率常数Ka(M-1s-1)和解离速率常数Kd(s-1)。通过三倍系列稀释,测量抗体浓度范围为2.46至200nM的结合,并使用缓冲液作为对照组,来获得速率常数。随后,由反应速率常数使用以下等式计算出抗体与靶抗原之间的反应的平衡解离常数KD(M):KD=Kd/Ka。结合通过计算时间与反应速率常数的函数来记录。
基于其结果,如下表5所示,测定了抗体1和抗体2与经纯化的狂犬病毒G蛋白的结合亲和力。抗体1和抗体2均显示出与狂犬病毒G蛋白的高亲和力。
[表5]使用狂犬病毒G蛋白测量结合亲和力
实施例3:评估抗体针对由CR4098抗体所产生的逃逸病毒的中和活性
实施例3-1:产生CR4098抗体的逃逸病毒
参照专利US7579446和NCBI(国家生物技术信息中心)数据库验证了CR4098抗体(Crucell)的DNA序列,在Enzynomics Co.Ltd.(位于大田,儒城区)合成了该DNA序列,克隆至pCT146表达载体中(根据韩国专利申请号10-2014-0178030),并随后运送到CelltrionInc。通过限制性酶切分析和DNA测序确定了合成部分的序列。通过瞬时转导法,在F2N78细胞系中产生CR4098抗体。
对于细胞内瞬时转导,使用阳离子聚合物FreeStyleTMMAX(Invitrogen,16447-100),并按照生产商的手册进行转导。在转导前的一天,将生长在EX-CELL 293无血清培养基(Sigma,14571C:下文中称为“EX-CELL 293培养基”)上的F2N78细胞(韩国专利号10-1005967,专利权人:赛特瑞恩(Celltrion))离心,将培养基替换为FreeStyle293无血清培养基(Gibco,12338),并且使用两个250ml摇瓶,以各50ml的量(总共100ml)、每毫升0.8×106的细胞浓度接种细胞。在转导当天,使用OptiPRO SFM II培养基(Invitrogen,12309)将125μg含抗体基因的pCT178DNA和125μl FreeStyleTM Max试剂分别稀释成2ml的体积,并轻轻混合。立即将稀释的FreeStyleTM Max试剂溶液与稀释的DNA溶液混合,然后在室温下反应17分钟。在室温下反应17分钟期间,对用于转导的接种的F2N细胞的数量进行计数,并使用FreeStyle293培养基将细胞浓度稀释至1.0×106。17分钟后,通过DNA与FreeStyleTM Max试剂的混合溶液处理F2N细胞来实施传导。转导后的一天,将相同量的EX-CELL 293培养基加入至经转导的细胞并孵育7天,从而产生CR4098抗体。
此后,使用CR4098来进行产生相应抗体的逃逸突变病毒的试验。
具有106感染性/毫升的狂犬病毒CVS-11毒株在96孔细胞培养板中进行1.5倍的系列稀释,随后在37℃下与10~40IU/ml的CR4098抗体反应1小时。在反应1小时后,加入2×105细胞/ml的BHK细胞并孵育3天。3天后,获得病毒,固定细胞,通过染色测量狂犬病核衣壳蛋白的表达,以评价细胞是否感染了CVS-11毒株(JENO Biotech,9061)。在第二次传代中,向第一次传代获得的病毒加入增加量的CR4098抗体,并重复上述的相同试验。在第一次或第二次传代中,对病毒的4~5个克隆进行扩增,之后用QIAamp Viral RNA Mini试剂盒(QIAGEN,52904)分离RNA,在该病毒的4~5个克隆中,证实了获自还未感染或几乎未感染狂犬病毒CVS-11毒株的孔的病毒,尽管CR4098抗体的添加量逐渐增加,仍引起了感染或增加了感染的程度。
使用RNA作为模板,利用用于RT-PCR的SuperScriptIII第一链合成***(Invitrogen,18080-051)合成cDNA,随后通过Takara ExTaq(Takara,RR001A)扩增,然后测序。基于测序结果,CR4098抗体的逃逸突变病毒的改变的序列显示了N336K。
实施例3-2:评估抗体针对由CR4098抗体所产生的逃逸病毒的中和活性
评估了抗体1和抗体2是否具有针对实施例3-1中由CR4098抗体产生的逃逸病毒(N336K)的中和活性。
使用FAVNT法进行中和活性的试验。荧光抗体病毒中和试验(FAVNT)是一种通过细胞培养法,测定人或动物血清中狂犬病毒抗体水平的试验方法。
在FAVNT试验方法中,将稀释试验抗体(或HRIG)和预定量的狂犬病毒[100TCID50/0.1ml]放入96孔板中,并反应60分钟,将幼仓鼠肾细胞与含10%牛血清的培养基(Eagle's最低基础培养基)一同孵育36~48小时。孵育后,将细胞固定,随后用抗狂犬病的抗体、ABC试剂盒(VECTASTAIN)和DAB试剂盒(VECTASTAIN)对感染狂犬病毒的细胞进行染色。最后,对染色细胞的数量进行计数,并计算了试验抗体相对于HRIG(其中和活性明确已知)的中和活性。
结果如下表6所示,抗体1和抗体2均表现出针对CR4098抗体逃逸病毒(N336K)的中和活性,而仅CR4098没有中和活性。
[表6]评估抗体针对由CR4098抗体所产生的逃逸病毒的中和活性的结果
实施例4:评估抗体针对不同类型的狂犬病毒的中和活性
通过RFFIT,体外测试了抗体1和抗体2对来自世界各地的约50个狂犬病毒变种的体外中和活性。结果示于下表7中。
在中和活性试验中,进行快速荧光聚焦抑制试验(RFFIT)以测量暴露于狂犬病毒抗原的抗体的活性。中和抗体由病毒外表面上的糖蛋白诱导。疾病控制中心采用了快速、经济、灵敏且可重复的RFFIT方法。
与FAVNT类似,RFFIT是一种通过细胞培养法,测定人或动物血清中狂犬病毒抗体水平的试验方法。免疫荧光染色被用来评估病毒扩增,并需要约20小时。
RFFIT使用混合稀释试验血清和预定量的狂犬病毒[50-50%荧光灶剂量(Fluorescing Foci Dose)(50FFD50)/0.1ml],在多孔载玻片上进行。将含有成神经细胞瘤和培养基(Eagle's最低基础培养基)和10%牛血清的混合载玻片,于37℃二氧化碳培养箱中孵育90分钟。将血清-病毒-细胞的形态在37℃二氧化碳培养箱中孵育20小时。此后,对偶联有标签的狂犬病毒进行孵育、洗涤、固定和染色,并使用荧光显微镜进行观察。
[表7]评估针对不同类型狂犬病毒的抗体的中和活性的结果
实施例5:评估针对在印度分离的狂犬病毒的抗体的中和活性
实施例5-1:体外试验
使用抗体1、抗体2和抗体鸡尾酒(抗体1+抗体2),将盛行于印度的下表8的野生型病毒进行如实施例4中那样的RFFIT。该试验是在印度国家心理健康和神经科学研究所(NIMHANS)进行的。各抗体的浓度为约1μg,用100FFD50的下表8中的各病毒在Neuro-2a细胞中进行试验。RFFIT的结果在三种抗体中都显示出针对每种病毒的中和活性。
[表8]在印度分离的狂犬病毒
病毒缩写 | 分离病毒的动物 | 分离病毒的地区 |
SV1 | 狗 | 印度,喀拉拉邦 |
SV2 | 狗 | 印度,喀拉拉邦 |
SV3 | 人 | 印度,卡纳塔克邦 |
SV4 | 人 | 印度,卡纳塔克邦 |
SV5 | 狗 | 印度,泰米尔纳依邦,金奈 |
SV6 | 狗 | 印度,泰米尔纳依邦,金奈 |
实施例5-2:体内试验
实施例5-1的体外试验之后,在小鼠中进行了体内试验。如下表9所示,所有的抗体在动物试验组中都表现出高的中和活性。每个动物试验组使用10只小鼠,所用病毒为100LD50(0.1mL中)。在病毒接种(肌肉注射)后3小时,在相同位置接种(肌肉注射)各抗体(约1μg),然后观察存活率30天。图1是显示了在动物试验中,针对总共六种病毒(SV1~SV6)中的SV2病毒的小鼠存活率的曲线图。
在本发明的动物试验中,针对SV1至SV6病毒中的每一种的存活率示于下表9中。
[表9]通过动物试验评估针对在印度分离的狂犬病毒的抗体的中和活性的结果
实施例6:评估抗体1和抗体2的鸡尾酒的干扰效应
实施例6-1:使用测量针对野生型狂犬病毒和狂犬病毒CVS-11毒株的中和活性的试验,来评估抗体1和抗体2的鸡尾酒的干扰效应。
使用抗体1、抗体2和抗体鸡尾酒(抗体1+抗体2),将十二种野生型病毒和狂犬病毒CVS-11毒株进行如实施例4中那样的RFFIT。
如下表10所示,抗体1、抗体2及含以相同比例混合的抗体1和抗体2的鸡尾酒都表现出针对十二种野生型狂犬病毒和狂犬病毒CVS-11毒株的优异的中和活性,由此证实了鸡尾酒中的抗体1和抗体2在生物中和活性评估时不存在干扰效应。
[表10]评估针对不同类型狂犬病毒的抗体鸡尾酒的中和活性的结果
实施例6-2:用摩尔过剩试验评估抗体1和抗体2鸡尾酒的干扰效应
还通过摩尔过剩试验,评估了抗体1和抗体2是否表现出干扰效应。为此,对于实施例6-1中试验的狂犬病毒CVS-11毒株,将两种抗体的浓度比例设定在1/9至9/1的范围内,并且进行三次如实施例4中那样的REFIT。结果示于下表11和表12中。
通过以不同浓度比例的抗体1和抗体2进行的试验,即使将抗体1与抗体2的比例调整为1:9至9:1时,抗体1、抗体2及抗体1和抗体2鸡尾酒均表现出如下表11和表12中所示的中和狂犬病毒的活性。
[表11]评估针对狂犬病毒CVS-11毒株的抗体鸡尾酒的中和活性
[表12]评估针对狂犬病毒CVS-11毒株的抗体鸡尾酒的中和活性
用多重比较检验法之一的邓奈特检验(Dunnett's test)作为统计分析方法,来评价试验组和对照组之间的中和活性差异的显著性,以确认干扰效应。具体来说,如果在邓奈特检验中经校正的p值大于显著性阈值0.05,则不显著,表明在比较的组之间不存在差异。另一方面,如果经校正的p值小于0.05,则表明在比较的组之间存在显著差异。基于表11和表12的邓奈特分析的结果分别示于下表13和表14中。
如下表13和表14所示,在表13中,只有在抗体1的比例为90%或更高时,经校正的p值为0.05或更低,这表明除抗体1的含量为90%的情况外,不存在干扰效应。然而,在抗体1的比例为90%或更高时,在统计学上可能存在干扰效应,但这被认为是由于抗体1的非常强的中和活性导致的,而不能被当做是干扰效应。在表14中,即使当抗体2的比例增加时,经校正的p值也为0.05或更多,这证实了不存在干扰效应。因此,可以得出在所有浓度下两种抗体之间都不存在干扰效应的结论。
[表13]在抗体1的浓度下,狂犬病毒CVS-11毒株的多重比较检验的结果
[表14]在抗体2的浓度下,狂犬病毒CVS-11毒株的多重比较检验的结果
尽管出于说明的目的已公开了本发明的优选实施方式,但是本领域技术人员应理解,可以提供能够对其进行替代的各种修改和等同物,而不脱离权利要求书中所述的本发明的范围和精神。因此,本发明并不限于仅作为实施本发明的最佳形式所公开的特定实施方式,而应解释为包括落入所附权利要求书范围内的所有实施方式。
<110> 赛特瑞恩股份有限公司
<120> 狂犬病毒糖蛋白的表位及能与其表位特异性结合的中和狂犬病毒的结合分子
<130> CPD2016011KR
<150> 2015/0082284
<151> 2015-06-10
<160> 42
<170> KoPatentIn 3.0
<210> 1
<211> 524
<212> PRT
<213> 人工序列
<220>
<223> CVS-11毒株G蛋白
<400> 1
Met Val Pro Gln Val Leu Leu Phe Val Pro Leu Leu Gly Phe Ser Leu
1 5 10 15
Cys Phe Gly Lys Phe Pro Ile Tyr Thr Ile Pro Asp Lys Leu Gly Pro
20 25 30
Trp Ser Pro Ile Asp Ile His His Leu Ser Cys Pro Asn Asn Leu Val
35 40 45
Val Glu Asp Glu Gly Cys Thr Asn Leu Ser Glu Phe Ser Tyr Met Glu
50 55 60
Leu Lys Val Gly Tyr Ile Ser Ala Ile Lys Val Asn Gly Phe Thr Cys
65 70 75 80
Thr Gly Val Val Thr Glu Ala Glu Thr Tyr Thr Asn Phe Val Gly Tyr
85 90 95
Val Thr Thr Thr Phe Lys Arg Lys His Phe Arg Pro Thr Pro Asp Ala
100 105 110
Cys Arg Ala Ala Tyr Asn Trp Lys Met Ala Gly Asp Pro Arg Tyr Glu
115 120 125
Glu Ser Leu His Asn Pro Tyr Pro Asp Tyr His Trp Leu Arg Thr Val
130 135 140
Arg Thr Thr Lys Glu Ser Leu Ile Ile Ile Ser Pro Ser Val Thr Asp
145 150 155 160
Leu Asp Pro Tyr Asp Lys Ser Leu His Ser Arg Val Phe Pro Gly Gly
165 170 175
Lys Cys Ser Gly Ile Thr Val Ser Ser Thr Tyr Cys Ser Thr Asn His
180 185 190
Asp Tyr Thr Ile Trp Met Pro Glu Asn Pro Arg Pro Arg Thr Pro Cys
195 200 205
Asp Ile Phe Thr Asn Ser Arg Gly Lys Arg Ala Ser Lys Gly Asn Lys
210 215 220
Thr Cys Gly Phe Val Asp Glu Arg Gly Leu Tyr Lys Ser Leu Lys Gly
225 230 235 240
Ala Cys Arg Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met Asp
245 250 255
Gly Thr Trp Val Ala Met Gln Thr Ser Asp Glu Thr Lys Trp Cys Pro
260 265 270
Pro Asp Gln Leu Val Asn Leu His Asp Phe Arg Ser Asp Glu Ile Glu
275 280 285
His Leu Val Val Glu Glu Leu Val Lys Lys Arg Glu Glu Cys Leu Asp
290 295 300
Ala Leu Glu Ser Ile Met Thr Thr Lys Ser Val Ser Phe Arg Arg Leu
305 310 315 320
Ser His Leu Arg Lys Leu Val Pro Gly Phe Gly Lys Ala Tyr Thr Ile
325 330 335
Phe Asn Lys Thr Leu Met Glu Ala Asp Ala His Tyr Lys Ser Val Arg
340 345 350
Thr Trp Asn Glu Ile Ile Pro Ser Lys Gly Cys Leu Lys Val Gly Gly
355 360 365
Arg Cys His Pro His Val Asn Gly Val Phe Phe Asn Gly Ile Ile Leu
370 375 380
Gly Pro Asp Gly His Val Leu Ile Pro Glu Met Gln Ser Ser Leu Leu
385 390 395 400
Gln Gln His Met Glu Leu Leu Lys Ser Ser Val Ile Pro Leu Met His
405 410 415
Pro Leu Ala Asp Pro Ser Thr Val Phe Lys Glu Gly Asp Glu Ala Glu
420 425 430
Asp Phe Val Glu Val His Leu Pro Asp Val Tyr Lys Gln Ile Ser Gly
435 440 445
Val Asp Leu Gly Leu Pro Asn Trp Gly Lys Tyr Val Leu Met Thr Ala
450 455 460
Gly Ala Met Ile Gly Leu Val Leu Ile Phe Ser Leu Met Thr Trp Cys
465 470 475 480
Arg Arg Ala Asn Arg Pro Glu Ser Lys Gln Arg Ser Phe Gly Gly Thr
485 490 495
Gly Arg Asn Val Ser Val Thr Ser Gln Ser Gly Lys Val Ile Pro Ser
500 505 510
Trp Glu Ser Tyr Lys Ser Gly Gly Glu Ile Arg Leu
515 520
<210> 2
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> CVS-11毒株G蛋白
<400> 2
Lys Phe Pro Ile Tyr Thr Ile Pro Asp Lys Leu Gly Pro Trp Ser Pro
1 5 10 15
Ile Asp Ile His His Leu Ser Cys Pro Asn Asn Leu Val Val Glu Asp
20 25 30
Glu Gly Cys Thr Asn Leu Ser Glu Phe Ser Tyr Met Glu Leu Lys Val
35 40 45
Gly Tyr Ile Ser Ala Ile Lys Val Asn Gly Phe Thr Cys Thr Gly Val
50 55 60
Val Thr Glu Ala Glu Thr Tyr Thr Asn Phe Val Gly Tyr Val Thr Thr
65 70 75 80
Thr Phe Lys Arg Lys His Phe Arg Pro Thr Pro Asp Ala Cys Arg Ala
85 90 95
Ala Tyr Asn Trp Lys Met Ala Gly Asp Pro Arg Tyr Glu Glu Ser Leu
100 105 110
His Asn Pro Tyr Pro Asp Tyr His Trp Leu Arg Thr Val Arg Thr Thr
115 120 125
Lys Glu Ser Leu Ile Ile Ile Ser Pro Ser Val Thr Asp Leu Asp Pro
130 135 140
Tyr Asp Lys Ser Leu His Ser Arg Val Phe Pro Gly Gly Lys Cys Ser
145 150 155 160
Gly Ile Thr Val Ser Ser Thr Tyr Cys Ser Thr Asn His Asp Tyr Thr
165 170 175
Ile Trp Met Pro Glu Asn Pro Arg Pro Arg Thr Pro Cys Asp Ile Phe
180 185 190
Thr Asn Ser Arg Gly Lys Arg Ala Ser Lys Gly Asn Lys Thr Cys Gly
195 200 205
Phe Val Asp Glu Arg Gly Leu Tyr Lys Ser Leu Lys Gly Ala Cys Arg
210 215 220
Leu Lys Leu Cys Gly Val Leu Gly Leu Arg Leu Met Asp Gly Thr Trp
225 230 235 240
Val Ala Met Gln Thr Ser Asp Glu Thr Lys Trp Cys Pro Pro Asp Gln
245 250 255
Leu Val Asn Leu His Asp Phe Arg Ser Asp Glu Ile Glu His Leu Val
260 265 270
Val Glu Glu Leu Val Lys Lys Arg Glu Glu Cys Leu Asp Ala Leu Glu
275 280 285
Ser Ile Met Thr Thr Lys Ser Val Ser Phe Arg Arg Leu Ser His Leu
290 295 300
Arg Lys Leu Val Pro Gly Phe Gly Lys Ala Tyr Thr Ile Phe Asn Lys
305 310 315 320
Thr Leu Met Glu Ala Asp Ala His Tyr Lys Ser Val Arg Thr Trp Asn
325 330 335
Glu Ile Ile Pro Ser Lys Gly Cys Leu Lys Val Gly Gly Arg Cys His
340 345 350
Pro His Val Asn Gly Val Phe Phe Asn Gly Ile Ile Leu Gly Pro Asp
355 360 365
Gly His Val Leu Ile Pro Glu Met Gln Ser Ser Leu Leu Gln Gln His
370 375 380
Met Glu Leu Leu Lys Ser Ser Val Ile Pro Leu Met His Pro Leu Ala
385 390 395 400
Asp Pro Ser Thr Val Phe Lys Glu Gly Asp Glu Ala Glu Asp Phe Val
405 410 415
Glu Val His Leu Pro Asp Val Tyr Lys Gln Ile Ser Gly Val Asp Leu
420 425 430
Gly Leu Pro Asn Trp Gly Lys Tyr Val Leu Met Thr Ala Gly Ala Met
435 440 445
Ile Gly Leu Val Leu Ile Phe Ser Leu Met Thr Trp Cys Arg Arg Ala
450 455 460
Asn Arg Pro Glu Ser Lys Gln Arg Ser Phe Gly Gly Thr Gly Arg Asn
465 470 475 480
Val Ser Val Thr Ser Gln Ser Gly Lys Val Ile Pro Ser Trp Glu Ser
485 490 495
Tyr Lys Ser Gly Gly Glu Ile Arg Leu
500 505
<210> 3
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的重链CDR1
<400> 3
Arg Arg Arg Asp Tyr Trp Gly
1 5
<210> 4
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的重链CDR2
<400> 4
Ser Phe Phe His Arg Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Glu Ser
1 5 10 15
<210> 5
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的重链CDR3
<400> 5
His Pro Ser Thr Pro Phe Ala Glu Tyr Leu Leu Leu Pro Asp Ala Phe
1 5 10 15
Asp Ser
<210> 6
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的轻链CDR1
<400> 6
Arg Ala Ser Gln Ser Val Arg Ser Ser Leu Ala
1 5 10
<210> 7
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的轻链CDR2
<400> 7
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的轻链CDR3
<400> 8
Gln Gln Tyr Ser Asp Trp Pro Leu Thr
1 5
<210> 9
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的重链CDR1
<400> 9
Ser Tyr Asp Ile Ser
1 5
<210> 10
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的重链CDR2
<400> 10
Trp Ile Ser Thr Tyr Lys Gly Asn Thr Asn Phe Ala Gln Lys Phe Gln
1 5 10 15
Asp
<210> 11
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的重链CDR3
<400> 11
Ala Lys Ser His Pro Phe Tyr Asp Phe Trp Ser Ala Tyr Tyr Val Pro
1 5 10 15
Gly Ala Phe Asp Ile
20
<210> 12
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的轻链CDR1
<400> 12
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 13
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的轻链CDR2
<400> 13
Asp Ala Ser Asn Leu Glu Thr
1 5
<210> 14
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的轻链CDR3
<400> 14
Gln Gln Tyr Asp Asn Leu Pro Leu Thr
1 5
<210> 15
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的重链可变区
<400> 15
Glu Val Gln Leu Leu Gln Glu Ser Gly Pro Gly Leu Ala Lys Pro Ser
1 5 10 15
Glu Thr Leu Ser Leu Ile Cys Thr Val Ser Gly Gly Ser Ile Ser Arg
20 25 30
Arg Arg Asp Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Arg Gly Leu
35 40 45
Glu Trp Ile Gly Ser Phe Phe His Arg Gly Ser Thr Tyr Tyr Asn Pro
50 55 60
Ser Leu Glu Ser Arg Val Ser Ile Ser Val Asp Pro Ser Lys Asn Gln
65 70 75 80
Phe Ser Leu His Leu Ser Ser Val Thr Val Ala Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg His Pro Ser Thr Pro Phe Ala Glu Tyr Leu Leu Leu
100 105 110
Pro Asp Ala Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 16
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的轻链可变区
<400> 16
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Ser Thr Arg Ala Thr Asp Ile Pro Ala Arg Leu Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asp Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 17
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的重链可变区
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Thr Tyr Lys Gly Asn Thr Asn Phe Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Leu Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Lys Ser His Pro Phe Tyr Asp Phe Trp Ser Ala Tyr Tyr
100 105 110
Val Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Val Val Thr Val
115 120 125
Ser Ser
130
<210> 18
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的轻链可变区
<400> 18
Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 19
<211> 459
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的重链
<400> 19
Glu Val Gln Leu Leu Gln Glu Ser Gly Pro Gly Leu Ala Lys Pro Ser
1 5 10 15
Glu Thr Leu Ser Leu Ile Cys Thr Val Ser Gly Gly Ser Ile Ser Arg
20 25 30
Arg Arg Asp Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Arg Gly Leu
35 40 45
Glu Trp Ile Gly Ser Phe Phe His Arg Gly Ser Thr Tyr Tyr Asn Pro
50 55 60
Ser Leu Glu Ser Arg Val Ser Ile Ser Val Asp Pro Ser Lys Asn Gln
65 70 75 80
Phe Ser Leu His Leu Ser Ser Val Thr Val Ala Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg His Pro Ser Thr Pro Phe Ala Glu Tyr Leu Leu Leu
100 105 110
Pro Asp Ala Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
130 135 140
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
145 150 155 160
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
165 170 175
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
180 185 190
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
195 200 205
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
210 215 220
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
225 230 235 240
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
245 250 255
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
260 265 270
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
275 280 285
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
290 295 300
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
305 310 315 320
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
325 330 335
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
340 345 350
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
355 360 365
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
370 375 380
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
385 390 395 400
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
405 410 415
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
420 425 430
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
435 440 445
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 20
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体1的轻链
<400> 20
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Ser Gly Ala Ser Thr Arg Ala Thr Asp Ile Pro Ala Arg Leu Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Asp Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 21
<211> 460
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的重链
<400> 21
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Thr Tyr Lys Gly Asn Thr Asn Phe Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Leu Thr Thr Asp Thr Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Lys Ser His Pro Phe Tyr Asp Phe Trp Ser Ala Tyr Tyr
100 105 110
Val Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Val Val Thr Val
115 120 125
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
130 135 140
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
145 150 155 160
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
165 170 175
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
180 185 190
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
195 200 205
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
210 215 220
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
225 230 235 240
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
245 250 255
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
275 280 285
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
290 295 300
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
305 310 315 320
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
325 330 335
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
340 345 350
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
355 360 365
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
370 375 380
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
385 390 395 400
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
405 410 415
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
435 440 445
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460
<210> 22
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体2的轻链
<400> 22
Glu Leu Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Leu
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 23
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的重链CDR1
<400> 23
cggcggagag actactgggg c 21
<210> 24
<211> 48
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的重链CDR2
<400> 24
agcttcttcc accggggcag cacctactac aaccccagcc tggaaagc 48
<210> 25
<211> 54
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的重链CDR3
<400> 25
caccccagca cccccttcgc cgagtacctg ctgctgcccg acgccttcga tagc 54
<210> 26
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的轻链CDR1
<400> 26
agagccagcc agagcgtgcg gagcagcctg gcc 33
<210> 27
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的轻链CDR2
<400> 27
ggcgccagca ccagagccac c 21
<210> 28
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的轻链CDR3
<400> 28
cagcagtaca gcgactggcc cctgacc 27
<210> 29
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的重链CDR1
<400> 29
agctatgata tcagc 15
<210> 30
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的重链CDR2
<400> 30
tggatcagca cttacaaggg taacacaaac tttgcacaaa agttccagga c 51
<210> 31
<211> 63
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的重链CDR3
<400> 31
gccaaatccc acccgtttta cgatttttgg agtgcttact atgtccccgg tgcttttgat 60
atc 63
<210> 32
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的轻链CDR1
<400> 32
caggcgagtc aggacattag caactattta aat 33
<210> 33
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的轻链CDR2
<400> 33
gatgcatcca atttggaaac a 21
<210> 34
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的轻链CDR3
<400> 34
caacagtatg ataatctccc ccttact 27
<210> 35
<211> 387
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的重链可变区
<400> 35
gaagtgcagc tgctgcagga aagcggccct ggcctggcca agcccagcga gacactgagc 60
ctgatctgca ccgtgtccgg cggcagcatc agccggcgga gagactactg gggctggatc 120
agacagcccc ctggcagagg cctggaatgg atcggcagct tcttccaccg gggcagcacc 180
tactacaacc ccagcctgga aagccgggtg tccatcagcg tggaccccag caagaaccag 240
ttcagcctgc acctgagcag cgtgaccgtg gccgacaccg ccgtgtacta ctgcgccaga 300
caccccagca cccccttcgc cgagtacctg ctgctgcccg acgccttcga tagctggggc 360
cagggcaccc tggtgacagt gtccagc 387
<210> 36
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的轻链可变区
<400> 36
gacatcgtga tgacccagag ccccgccacc ctgagcgtgt ccccaggcga gagagccacc 60
ctgtcctgca gagccagcca gagcgtgcgg agcagcctgg cctggtatca gcagaggcca 120
ggccaggccc ccagactgct gatcagcggc gccagcacca gagccaccga catccctgcc 180
agactgagcg gcagcggctc cggcaccgag ttcaccctga cagtgtccag cctgcagagc 240
gaggacttcg ccgtgtacta ctgccagcag tacagcgact ggcccctgac cttcggcgga 300
ggcaccaagg tggaaatcaa g 321
<210> 37
<211> 390
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的重链可变区
<400> 37
gaggtgcagc tggtggagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatgata tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcactt acaagggtaa cacaaacttt 180
gcacaaaagt tccaggacag agtcaccctt accacagaca catccacgac cacagcctac 240
atggagctga ggagcctgac atctgacgac acggccgtgt attactgtgc gagagccaaa 300
tcccacccgt tttacgattt ttggagtgct tactatgtcc ccggtgcttt tgatatctgg 360
ggccaaggga cagtggtcac cgtctcttca 390
<210> 38
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的轻链可变区
<400> 38
gagctcgtga tgacgcagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatatta ctgtcaacag tatgataatc tcccccttac tttcggccct 300
gggaccaaag tggatatcaa a 321
<210> 39
<211> 1380
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的重链
<400> 39
gaagtgcagc tgctgcagga aagcggccct ggcctggcca agcccagcga gacactgagc 60
ctgatctgca ccgtgtccgg cggcagcatc agccggcgga gagactactg gggctggatc 120
agacagcccc ctggcagagg cctggaatgg atcggcagct tcttccaccg gggcagcacc 180
tactacaacc ccagcctgga aagccgggtg tccatcagcg tggaccccag caagaaccag 240
ttcagcctgc acctgagcag cgtgaccgtg gccgacaccg ccgtgtacta ctgcgccaga 300
caccccagca cccccttcgc cgagtacctg ctgctgcccg acgccttcga tagctggggc 360
cagggcaccc tggtgacagt gtccagcgcc agcaccaagg gccccagcgt gttccctctg 420
gcccccagca gcaagagcac atctggcgga acagccgccc tgggctgcct ggtgaaagac 480
tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 540
accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 600
ccctccagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 660
accaaggtgg acaagaaagt tgagcccaaa tcttgtgaca aaactcacac atgcccaccg 720
tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 780
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 840
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 900
acaaagccgc gggaggagca gtacaacagc acgtaccggg tggtcagcgt cctcaccgtc 960
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 1020
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1080
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 1140
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1200
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1260
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1320
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaatga 1380
1380
<210> 40
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> 抗体1的轻链
<400> 40
gacatcgtga tgacccagag ccccgccacc ctgagcgtgt ccccaggcga gagagccacc 60
ctgtcctgca gagccagcca gagcgtgcgg agcagcctgg cctggtatca gcagaggcca 120
ggccaggccc ccagactgct gatcagcggc gccagcacca gagccaccga catccctgcc 180
agactgagcg gcagcggctc cggcaccgag ttcaccctga cagtgtccag cctgcagagc 240
gaggacttcg ccgtgtacta ctgccagcag tacagcgact ggcccctgac cttcggcgga 300
ggcaccaagg tggaaatcaa gcggaccgtg gccgctccca gcgtgttcat cttcccaccc 360
agcgacgagc agctgaagtc cggcacagcc agcgtggtgt gcctgctgaa caacttctac 420
ccccgcgagg ccaaggtgca gtggaaggtg gacaacgccc tgcagtccgg caactcccag 480
gaaagcgtga ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc 540
ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaagtgac ccaccagggc 600
ctgtccagcc ccgtgaccaa gagcttcaac cggggcgagt gctga 645
<210> 41
<211> 1383
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的重链
<400> 41
gaggtgcagc tggtggagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agctatgata tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcactt acaagggtaa cacaaacttt 180
gcacaaaagt tccaggacag agtcaccctt accacagaca catccacgac cacagcctac 240
atggagctga ggagcctgac atctgacgac acggccgtgt attactgtgc gagagccaaa 300
tcccacccgt tttacgattt ttggagtgct tactatgtcc ccggtgcttt tgatatctgg 360
ggccaaggga cagtggtcac cgtctcttca gcttccacca agggcccatc ggtcttcccc 420
ctggcaccct cctccaagag cacctctggg ggcacagcag ccctgggctg cctggtcaag 480
gactacttcc ccgaaccggt gacggtgtcg tggaactcag gcgccctgac cagcggcgtg 540
cacaccttcc cggctgtcct acagtcctca ggactctact ccctcagcag cgtggtgacc 600
gtgccctcca gcagcttggg cacccagacc tacatctgca acgtgaatca caagcccagc 660
aacaccaagg tggacaagaa agttgagccc aaatcttgtg acaaaactca cacatgccca 720
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 780
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 840
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 900
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 960
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1020
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1080
gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 1140
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1200
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1260
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1320
atgcatgagg ctctgcacaa ccactacaca cagaagagcc tctccctgtc tccgggtaaa 1380
tga 1383
<210> 42
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> 抗体2的轻链
<400> 42
gagctcgtga tgacgcagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180
aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagcag cctgcagcct 240
gaagatattg caacatatta ctgtcaacag tatgataatc tcccccttac tttcggccct 300
gggaccaaag tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
Claims (21)
1.一种中和狂犬病毒的结合分子,所述结合分子与位于野生型狂犬病毒G蛋白的第33至333位氨基酸残基的表位结合,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
2.根据权利要求1所述的结合分子,其中,所述表位是位于野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
3.根据权利要求2所述的结合分子,其中,所述表位是包括选自由野生型狂犬病毒G蛋白的第33、34、35、38、200、202和215位氨基酸残基所组成的组中的至少一个氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
4.权利要求2或3所述的结合分子,其中,所述结合分子具有小于1×10-8M的结合亲和力(KD)。
5.根据权利要求2或3所述的结合分子,其中,所述结合分子包括:
a)包含SEQ ID NO:3的CDR1、SEQ ID NO:4的CDR2和SEQ ID NO:5的CDR3的可变区;或
b)包含SEQ ID NO:6的CDR1、SEQ ID NO:7的CDR2和SEQ ID NO:8的CDR3的可变区。
6.根据权利要求1所述的结合分子,其中,所述表位是位于野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
7.根据权利要求6所述的结合分子,其中,所述表位是包括选自由野生型狂犬病毒G蛋白的第331和333位氨基酸残基所组成的组中的至少一个氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
8.权利要求6或7所述的结合分子,其中,所述结合分子具有小于1×10-9M的结合亲和力(KD)。
9.根据权利要求6或7所述的结合分子,其中,所述结合分子包括:
a)包含SEQ ID NO:9的CDR1、SEQ ID NO:10的CDR2和SEQ ID NO:11的CDR3的可变区;或
b)包含SEQ ID NO:12的CDR1、SEQ ID NO:13的CDR2和SEQ ID NO:14的CDR3的可变区。
10.根据权利要求1至9中任一项所述的结合分子,其中,所述结合分子是抗体或抗体片段。
11.一种用于诊断、预防或治疗狂犬病的药物组合物,所述药物组合物包括权利要求1至9中任一项所述的结合分子。
12.一种用于诊断、预防或治疗狂犬病的药物组合物,所述药物组合物含至少两种中和狂犬病毒的结合分子,所述两种中和狂犬病毒的结合分子包括:a)权利要求2至5中任一项所述的第一结合分子;和b)权利要求6至9中任一项所述的第二结合分子,所述第一结合分子与所述第二结合分子彼此不同。
13.根据权利要求12所述的药物组合物,其中,a)所述第一结合分子:b)所述第二结合分子的浓度比例为1:9~9:1。
14.一种用于诊断、预防或治疗狂犬病的方法,所述方法包括:
a)将权利要求12所述的第一结合分子和所述第二结合分子以治疗有效量同时给药予受试者;
b)依次先将权利要求12所述的第一结合分子以治疗有效量给药予受试者,随后将权利要求12所述的第二结合分子以治疗有效量给药予受试者;或者
c)依次先将权利要求12所述的第二结合分子以治疗有效量给药予受试者,随后将权利要求12所述的第一结合分子以治疗有效量给药予受试者。
15.一种用于诊断、预防或治疗狂犬病的试剂盒,所述试剂盒包括:
1)权利要求12所述的药物组合物,所述药物组合物含治疗有效量的所述第一结合分子和所述第二结合分子;和
(2)表示出以下内容的包装说明书:
a)将权利要求12所述的第一结合分子和所述第二结合分子以治疗有效量同时给药予受试者,
b)依次先将权利要求12所述的第一结合分子以治疗有效量给药予受试者,随后将权利要求12所述的第二结合分子以治疗有效量给药予受试者,或者
c)依次先将权利要求12所述的第二结合分子以治疗有效量给药予受试者,随后将权利要求12所述的第一结合分子以治疗有效量给药予受试者。
16.一种多肽,所述多肽包括位于野生型狂犬病毒G蛋白的第33至215位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
17.根据权利要求16所述的多肽,其中,所述表位是包括选自由野生型狂犬病毒G蛋白的第33、34、35、38、200、202和215位氨基酸残基所组成的组中的至少一个氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
18.一种多肽,所述多肽包括位于野生型狂犬病毒G蛋白的第331至333位氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
19.根据权利要求18所述的多肽,其中,所述表位是包括选自由野生型狂犬病毒G蛋白的第331和333位氨基酸残基所组成的组中的至少一个氨基酸残基的表位,所述野生型狂犬病毒G蛋白如SEQ ID NO:2所示。
20.一种筛选中和狂犬病毒的结合分子的方法,所述中和狂犬病毒的结合分子与权利要求16至19中任一项所述的多肽特异性结合,
所述方法包括使所述结合分子与权利要求16至19中任一项所述的多肽接触。
21.一种狂犬病毒疫苗组合物,所述狂犬病毒疫苗组合物包括权利要求16至19中任一项所述的多肽。
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CN111333723A (zh) * | 2018-08-09 | 2020-06-26 | 北京智仁美博生物科技有限公司 | 针对狂犬病病毒g蛋白的单克隆抗体及其用途 |
CN113501873A (zh) * | 2021-07-07 | 2021-10-15 | 高光 | Rbv的蛋白结合分子及其用途 |
CN117298263A (zh) * | 2023-09-27 | 2023-12-29 | 成都迈科康生物科技有限公司 | 一种重组狂犬病疫苗及其制备方法和应用 |
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CN115785281B (zh) * | 2022-09-27 | 2024-07-19 | 兴盟生物医药(苏州)有限公司 | 含有狂犬病病毒g蛋白的融合蛋白的制备方法及应用 |
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Also Published As
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HK1244018A1 (zh) | 2018-07-27 |
WO2016200189A1 (ko) | 2016-12-15 |
KR101969626B1 (ko) | 2019-04-16 |
US20190022211A1 (en) | 2019-01-24 |
KR20160145508A (ko) | 2016-12-20 |
CN107709360B (zh) | 2021-10-19 |
US10722571B2 (en) | 2020-07-28 |
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