CN113227143A - 抗c-Met激动剂抗体及其应用 - Google Patents
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- CN113227143A CN113227143A CN201980081085.1A CN201980081085A CN113227143A CN 113227143 A CN113227143 A CN 113227143A CN 201980081085 A CN201980081085 A CN 201980081085A CN 113227143 A CN113227143 A CN 113227143A
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Abstract
本发明涉及抗c‑Met激动剂抗体及其应用,更具体来说,涉及与人源c‑Met蛋白质特异性结合的激动剂抗体或其片段、其生产方法、使用其的c‑Met特异性检测方法、包含其的癌的预防或治疗用组合物、干细胞的分化诱导用组合物以及干细胞用培养基。本发明的方法可高效地用于c‑Met抗体的检测、利用抗体的干细胞分化的诱导、癌的治疗或预防。
Description
技术领域
本申请请求2018年12月7日提交的大韩民国专利申请第10-2018-0157325号的优先权,所述说明书全文通过引用并入本文。
本发明涉及抗c-Met激动剂抗体及其应用,具体地,涉及与人源c-Met蛋白质特异性结合的激动剂抗体或其片段、其生产方法、使用其的c-Met特异性检测方法、包含其的癌的预防或治疗用组合物、干细胞的分化诱导用组合物以及干细胞用培养基。
背景技术
c-Met作为存在于细胞表面的代表性的RTK(受体酪氨酸激酶),不仅与作为其配体的HGF/SF(肝细胞生长因子/离散因子)结合而促进细胞内信号传递,促进细胞的生长,而且在多种癌细胞中过表达,广泛地参与癌的发生、癌转移、癌细胞的迁移、癌细胞的浸润、血管生成。此外,如配体这一名称所指,介以HGF/SF的c-Met信号传递减弱几乎所有种类的上皮性肿瘤(epithelial tumor)的细胞间接触(cell-cell contact),是引发离散的代表性的癌转移初期的蛋白质(Nat Rev Cancer.2012Jan 24;12(2):89-103)。特别是,众所周知c-Met基因的上游(upstream)存在缺氧应答元件(hypoxiaresponse),该基因的表达在缺氧状况下增加(Oral Oncol.2006Jul;42(6):593-8)。此外,c-Met在从发生起经发展至转移为止的癌发生的各步骤均发挥作用,因此c-Met及作为其配体的HGF一直以来被视作用于癌靶向治疗的优先候选位点([Comoglio等2008Nat Rev Drug Discov 7:504];[Knudsen和VandeWoude 2008Curr Opin Genet Dev 18:87])。特别是已知目前人们所知的抗癌剂的作用机理涉及抗药性,所以c-Met在个性化治疗中的重要性进一步被认识,成为关于抗癌剂受到大量制药公司关注的靶分子。
最近,针对c-Met的抗体作为拮抗药(antagonist)在抗癌剂的开发中取得了少许进展,但是需要开发对于c-Met具有更高的亲和性而可特异性结合、由人源序列构成、给药至体内时诱发免疫反应的可能性低、显示更多样的活性的c-Met。
发明内容
技术课题
于是,本发明人努力进行靶向c-Met并显示多样的生理活性的抗体的开发后,确认为了靶向c-Met而由特异性结合c-Met的人源互补决定区(CDR)和骨架区(FR)形成的人抗体显示与HGF类似的活性,发挥与作为细胞表面分子的c-Met结合而诱导信号传递的激动剂抗体的功能,从而完成了本发明。
因此,本发明的目的是提供与人源c-Met蛋白质特异性结合的激动剂抗体或其片段。
本发明的另一目的是提供编码所述抗体或其片段的聚核苷酸、载体、以及被载体转化的细胞。
本发明的又另一目的是提供与人c-Met结合的激动剂抗体或其片段的生产方法、以及c-Met特异性检测方法。
本发明的又另一目的是提供包含所述抗体或其片段作为有效成分的癌的预防或治疗用药学组合物。
此外,本发明的又另一目的是提供由所述抗体或其片段形成的预防或治疗用药学组合物。
此外,本发明的又另一目的是提供以所述抗体或其片段必须的癌的预防或治疗用药学组合物。
本发明的又另一目的是提供包含所述抗体的干细胞的分化诱导用组合物以及包含其的干细胞用培养基。
此外,本发明的又另一目的是提供由所述抗体形成的干细胞的分化诱导用组合物以及包含其的干细胞用培养基。
此外,本发明的又另一目的是提供以所述抗体必须的干细胞的分化诱导用组合物以及包含其的干细胞用培养基。
本发明的又另一目的是提供所述抗体或其片段在癌的预防或治疗用制剂的制造中的用途。
本发明的又另一目的是提供癌的治疗方法,其中,包括将有效量的包含所述抗体或其片段作为有效成分的组合物给予有需要的个体的步骤。
本发明的又另一目的是提供所述抗体在干细胞的分化诱导用制剂的制造中的用途。
本发明的又另一目的是提供干细胞的分化诱导方法,其中,包括将有效量的包含所述抗体的组合物给予有需要的个体的步骤。
解决技术问题所采用的技术方案
为了实现如上所述的目的,本发明提供一种与人源c-Met蛋白质特异性结合的激动剂抗体或其片段,其中,所述抗体包含抗体轻链可变区(VL)和抗体重链可变区(VH),所述抗体轻链可变区(VL)包括含有如SEQ ID NO:1所示的氨基酸序列的互补决定区(CDR)L1、含有如SEQ ID NO:2所示的氨基酸序列的互补决定区(CDR)L2和含有如
SEQ ID NO:3所示的氨基酸序列的互补决定区(CDR)L3,所述抗体重链可变区(VH)包括含有如SEQ ID NO:4所示的氨基酸序列的互补决定区(CDR)H1、含有如SEQ ID NO:5所示的氨基酸序列的互补决定区(CDR)H2和含有如SEQ ID NO:6所示的氨基酸序列的互补决定区(CDR)H3。
为了实现本发明的另一目的,本发明提供一种编码所述抗体或其片段的聚核苷酸。
为了实现本发明的另一目的,本发明提供一种包含所述聚核苷酸的载体。
为了实现本发明的另一目的,本发明提供一种通过所述载体被转化的细胞。
为了实现本发明的另一目的,本发明提供一种与人c-Met结合的激动剂抗体或其片段的生产方法,其中,包括:在将所述细胞在表达聚核苷酸的条件下进行培养,生产包含轻链及重链可变区的多肽的步骤;以及从所述细胞或对其进行培养的培养基回收所述多肽的步骤。
为了实现本发明的另一目的,本发明提供一种c-Met特异性检测方法,其中,包括使所述抗体或其片段与试样接触的步骤以及检测所述激动剂抗体或其片段的步骤。
为了实现本发明的另一目的,本发明提供一种包含所述抗体或其片段作为有效成分的癌的预防或治疗用药学组合物。
此外,本发明提供一种由所述抗体或其片段形成的癌的预防或治疗用药学组合物。
此外,本发明提供一种以所述抗体或其片段为必要成分的癌的预防或治疗用药学组合物。
为了实现本发明的另一目的,本发明提供一种包含所述抗体的干细胞的分化诱导用组合物。
此外,本发明提供一种由所述抗体形成的干细胞的分化诱导用组合物。
此外,本发明提供一种为所述抗体必须的干细胞的分化诱导用组合物。
为了实现本发明的另一目的,本发明提供一种包含所述组合物的干细胞用培养基。
此外,本发明提供一种由所述组合物形成的干细胞用培养基。
此外,本发明提供一种为所述组合物必须的干细胞用培养基。
为了实现本发明的另一目的,本发明提供一种所述抗体或其片段在癌的预防或治疗用制剂的制造中的用途。
为了实现本发明的另一目的,本发明提供一种癌的治疗方法,其中,包括将有效量的包含所述抗体或其片段作为有效成分的组合物给予有需要的个体的步骤。
为了实现本发明的另一目的,本发明提供一种所述抗体在干细胞的分化诱导用制剂的制造中的用途。
为了实现本发明的另一目的,本发明提供一种干细胞的分化诱导方法,其中,包括将有效量的包含所述抗体的组合物给予有需要的个体的步骤。
以下,对本发明进行详细说明。
本发明提供一种与人源c-Met蛋白质特异性结合的激动剂抗体或其片段,其中,所述抗体包含抗体轻链可变区(VL)和抗体重链可变区(VH),所述抗体轻链可变区(VL)包括含有如SEQ ID NO:1所示的氨基酸序列的互补决定区(CDR)L1、含有如SEQ ID NO:2所示的氨基酸序列的互补决定区(CDR)L2和含有如SEQ ID NO:3所示的氨基酸序列的互补决定区(CDR)L3,所述抗体重链可变区(VH)包括含有如SEQ ID NO:4所示的氨基酸序列的互补决定区(CDR)H1、含有如SEQ ID NO:5所示的氨基酸序列的互补决定区(CDR)H2和含有如SEQ IDNO:6所示的氨基酸序列的互补决定区(CDR)H3。
本发明的“c-Met蛋白质”是肝细胞生长因子(HGF)的受体,HGF是与c-Met受体酪氨酸激酶的细胞外部位结合并在各种正常细胞和肿瘤细胞中诱发分裂、运动、形态发生、血管生成的细胞因子的一种。c-Met是存在于细胞表面的代表性的受体酪氨酸激酶(receptortyrosine kinase),其本身是致癌基因,有时与作为配体的HGF无关,是与癌的发生、癌转移、癌细胞的迁移、癌细胞浸润、血管生成等涉及肿瘤的各种机理相关的蛋白质。所述蛋白质包括由以序列编号7(NCBI参考序列:NM_001127500.2)表示的核苷酸序列(mRNA)编码的多肽或其细胞外结构域,也是具有以序列编号8(NCBI参考序列:NP_001120972.1)表示的氨基酸序列的多肽。
本发明的“抗体”、“抗c-Met抗体”、“人源化抗c-Met抗体”和“变形人源化抗c-Met抗体”、“anti-c-Met antibody”以本发明的最广义的含义使用,具体来说,单克隆性抗体(包括单克隆抗体、全长单克隆抗体)、多克隆性抗体(多克隆抗体)包括多重特异性抗体(例如,双重特异性抗体)、及抗体的片段(例如,可变区和显示作为目标的生物活性(例如,与c-Met的结合)的抗体的其他部分)。
本发明的抗体作为为了可与c-Met选择性结合而在轻链及重链CDR中包含特定的氨基酸序列的抗体,其中均包括单克隆抗体和多克隆抗体,较好是可以为单克隆抗体。此外,本发明的抗体均包括嵌合抗体、人源化抗体、人抗体,较好是可以为人抗体。
本发明的单克隆抗体表示由实质上同质的抗体的群体获得的抗体。即,除了可少量存在的尽可能天然存在的突变之外,构成群体的各抗体相同。单克隆抗体非常特异性地与单一性抗原的表位结合。
本发明中,“单克隆”一词是指抗体由实质上同源性的群体获得并表示抗体的特性,并不是必须通过特定的方法生产抗体。例如,本发明的单克隆抗体可通过最先记载于文献(Kohler等(1975)Nature 256:495)的杂交瘤法制造,或者可通过重组DNA方法(参照:美国专利第4,816,567号)制造。此外,例如可使用本领域公知的技术从噬菌体抗体文库中分离。
本发明的抗体具体包括嵌合抗体,嵌合抗体的情况下,重链和/或轻链的一部分源自特定的种,或者与特定抗体的相应序列一致或显示同源性,只要本发明的抗体显示所期望的生物学活性(例如,与NRS的选择性结合),其余部分可源自其他种,或者与其他抗体的相应序列一致或显示同源性(美国专利第4,816,567号)。
人源化抗体是人和非人(例如,小鼠、大鼠)抗体的序列全部包含在内的抗体,一般来说,除与表位结合的部位(CDR)以外的其余部分为人抗体的序列,与表位结合的部位(CDR)可包含非人源序列。全人抗体是指仅包含人免疫球蛋白的蛋白质序列的抗体,可由小鼠、小鼠细胞或来源于小鼠细胞的杂交瘤生产,或者通过噬菌体展示法生产。
由生物体生产的天然抗体通常是由2条同样的轻链(L)和2条同样的重链(H)构成的约150,000道尔顿的异源四聚体性糖蛋白。各轻链通过1个共有二硫键与重链连接,但二硫键数在不同的免疫球蛋白亚型的重链之间以不同的形式存在。各重链和轻链还具有规律地间隔的链内二硫键交联。各重链在一末端具有与可变结构域(VH)相连的多个恒定结构域。各轻链在一末端具有可变结构域(VL),在另一末端具有恒定结构域,轻链的恒定结构域与重链的第一恒定结构域对位,轻链的可变结构域与重链的可变结构域对位。被认为是特别的氨基酸残基在轻链可变结构域与重链可变结构域间形成界面。抗体的“可变区”或“可变结构域”是指抗体的重链或轻链的氨基酸末端结构域。重链的可变区记作“VH”,轻链的可变区记作“VL”。这些结构域一般来说是抗体的最具可变性的部分,包括抗原结合部位。
本发明中,“高变性(hypervariable)”是指所述可变区内的若干序列在抗体间的序列上大范围变化,包含与针对其特异性的抗原决定簇的各特定抗体的结合和特异性直接相关的残基。轻链及重链可变区这两者中,高变性的关注点集中于作为互补决定区(CDR)或高变环(HVL)公知的3个区段。CDR由基于文献(Kabat等、1991年、In:Sequences ofProteins of Immunological Interest、5th Ed.Public Health Service、NationalInstitutes of Health、Bethesda、MD)的序列比对限定,而HVL如文献(Chothia和Le、1987、J.Mol.Biol.196:901-917)所揭示基于所述可变区的三维结构在结构上限定。
分别在所述重链和轻链内的3个CDR被骨架区(FR)分隔,所述部位包含具有以下的可变倾向的序列。从所述重链及轻链可变区的氨基末端至羧基末端,所述FR和CDR以FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4的顺序排列。所述FR的较大的β折叠结构使所述各链内部的CDR不仅相互接近,也与其他链的CDR接近。所生成的形态有利于抗原结合部位,但不需要所有CDR残基都直接参与与抗原的结合。
本发明的所述片段的特征在于,选自双抗体、Fab、Fab'、F(ab)2、F(ab')2、Fv和scFv。
本发明的抗体的片段是指维持抗体整体的抗原特异性结合能力的抗体的片段,较好是所述片段保持母抗体的人源c-Met蛋白质亲和性的至少20%、50%、70%、80%、90%、95%或100%或其以上。具体来说,还可以是Fab、F(ab)2、Fab'、F(ab')2、Fv、双抗体、scFv等形态。
Fab(fragment antigen-binding)为抗体的抗原结合片段,由重链和轻链各自的一个可变结构域和恒定结构域构成。F(ab')2为将抗体用胃蛋白酶水解生成的片段,呈2个Fab介以重链铰链(hinge)通过二硫键(disulfide bond)连接的形态。F(ab')为将F(ab')2片段的二硫键还原而分离得到的Fab上附加有重链铰链的形态的单体的抗体片段。Fv(variable fragment,可变片段)为仅由重链和轻链各自的可变区构成的抗体片段。scFv(single chain variable fragment,单链可变片段)为重链可变区(VH)和轻链可变区(VL)通过柔软的肽接头连接的重组抗体的片段。双抗体(diabody)是指scFv的VH和VL以极短的接头连接而无法相互结合,与具有相同形态的其他scFv的VL和VH分别结合而形成二聚体的形态的片段。
本发明的目标抗体的片段只要维持针对人源c-Met蛋白质的结合特异性,结构和形态不受限制,但较好是可以为scFv。本发明所述的scFv只要具有对于所述人源c-Met蛋白质特异性的CDR的构成、或者VH和Vl的构成,VH的C末端与VL的N末端介以接头连接,其序列无特别限定。所述接头只要作为在本领域中适用于scFv的接头公知,其种类无特别限定。
本发明的抗体或其片段可包含实质上不改变其生物学活性的保守性氨基酸置换(也称为抗体的保守性变异体)。
此外,上述的本发明的抗体或其片段有时也与酶、荧光物质、放射性物质和蛋白质等结合,对其无限定。此外,抗体的结合所述物质的方法在本领域是公知的。
本发明的抗体可来源于包括包含人的哺乳动物、鸟类等的任意动物。所述抗体较好是人、小鼠、驴、绵羊、兔、山羊、豚鼠、骆驼、马或鸡的抗体,最好是人或小鼠。
人抗体还包括具有人免疫球蛋白的氨基酸序列,且从人免疫球蛋白文库分离的抗体,或者从针对一种以上人免疫球蛋白进行转化移植而不表达内源性免疫球蛋白的动物分离的抗体(参照美国专利第5,939,598号)。
本发明的抗体有时也可以是与酶、荧光物质、放射性物质和蛋白质等结合的抗体,对其无限定。此外,抗体的结合所述物质的方法在本领域是公知的。
本发明提供一种编码所述抗体或其片段的聚核苷酸。
本发明中,“聚核苷酸”也可记载为寡聚核苷酸或核酸,包括DNA分子(例如,cDNA或基因组(基因组DNA))、RNA分子(例如,mRNA)、使用核苷酸类似物生成的所述DNA或RNA的类似物(例如,肽核酸和非自然产生的核苷酸类似物)和它们的杂合体。所述聚核苷酸可以是单链(single-stranded)或双链(double-stranded)。所述聚核苷酸是指编码由具有对所述KRS的N末端区域特异性的CDR的构成、或者VH和VL的构成的重链和轻链形成的抗体的碱基序列。
本发明的聚核苷酸只要编码本发明的抗体或其片段,其序列无特别限定,编码以上说明的本发明所述的抗体中所述的CDR序列的聚核苷酸的序列无特别限定,较好是包含如SEQ ID NO:1(重链CDR1)、如SEQ ID NO:2(重链CDR2)、如SEQ ID NO:3(重链CDR3)、如SEQID NO:4(轻链CDR1)、如SEQ ID NO:5(轻链CDR2)、如SEQ ID NO:6(轻链CDR3))表示的碱基序列。此外,本发明所述的抗体中,编码上述的VH和VL的聚核苷酸的序列无特别限定。
编码本发明的述抗体或其片段的聚核苷酸可通过本领域公知的方法获得。例如,可基于编码所述抗体的重链和轻链的部分或全部的DNA序列或其氨基酸序列,使用本领域熟知的寡核苷酸合成方法、例如聚合酶链式反应(PCR)法等合成。
本发明提供一种含有所述多聚核苷酸的载体。
本发明的“载体(vector)”用于为了本发明的抗体或其片段的重组生产而进行的本发明的聚核苷酸的复制或表达,一般来说,包含信号序列、复制起点、1个以上的标记物基因、增强子元件、启动子和转录终止序列中的一种以上。本发明的载体较好是可以为表达载体,更好是可以为包含以可作用的方式与调节序列、例如启动子的本发明的聚核苷酸的载体。
作为载体的一种的质粒是指可结合外源聚核苷酸片段的线性或环形的双螺旋DNA分子。载体的其他形态为病毒载体(viral vector,例如复制缺陷型逆转录病毒(replication defective retroviruses)、腺病毒和腺伴随病毒(adeno associatedviruses)),在此附加的DNA片段可引入所述病毒基因组(viral genome)内。特定的载体可在其中导入这些载体的宿主细胞(例如,包括来源于细菌(bacterial origin)的载体和附加型哺乳类载体(episomal mammalian vectors)的细菌性载体(bacterial vectors))内进行自我复制。其他载体(例如,非附加型哺乳类载体(non-episomal mammalianvectors))通过导入宿主细胞内,被整合至宿主细胞的基因组内,并且由此与所述宿主细胞基因组一起被复制。
本发明中,“表达载体(expression vector)”为可表达所选择的聚核苷酸的载体的一种形态。一种聚核苷酸序列在调节序列对所述聚核苷酸序列的表达(例如,水平、时机或表达的位置)产生影响的情况下,“以可作用的方式连接于”所述调节序列(regulatorysequence)。所述调节序列是以其可作用的方式连接的对核酸的表达(例如,水平、时机或表达的位置)产生影响的序列。所述调节序列例如可对于所调节的核酸直接或通过一种以上的其他分子(例如,与所述调节序列和/或所述核酸结合的多肽)的作用,产生影响。所述调节序列包括启动子、增强子、和其他表达条件元件。本发明的载体较好是可以为pOptiVECTM-TOPO和pcDNATM3.3-TOPO。
本发明提供一种通过所述载体被转化的细胞。
本发明的细胞只要是可用于本发明的表达载体所含的编码所述抗体或其片段的聚核苷酸的表达的细胞,其种类无特别限定。通过本发明所述的表达载体转化的细胞(宿主细胞)可以是原核细胞(例如,大肠杆菌)、真核细胞(例如,酵母或其他菌类)、植物细胞(例如,烟草或西红柿植物细胞)、动物细胞(例如,人细胞、猴细胞、仓鼠细胞、大鼠细胞、小鼠细胞、昆虫细胞)、或者来源于它们的杂交瘤。较好是来源于包含人的哺乳类的细胞。
适合于本目的的原核生物包括革兰氏阴性或革兰氏阳性的有机体,例如肠道细菌科(Enterobacteriaceae)、例如埃希氏菌属(Escherichia)、例如大肠杆菌(E.coli)、肠杆菌属(Enterobacter)、欧文氏菌属(Erwinia)、克雷伯氏菌属(Klebsiella)、变形杆菌属(Proteus)、沙门氏菌属(Salmonella)、例如鼠伤寒沙门氏菌(Salmonella typhimurium)、沙雷氏菌属(Serratia)、例如粘质沙雷氏菌(Serratia marcescans)、和痢疾志贺氏菌(Shigella)、和芽孢杆菌属(Bacilli)、例如枯草芽孢杆菌(B.subtilis)及地衣芽孢杆菌(B.licheniformis)、假单胞菌属(Pseudomonas)、例如绿脓杆菌(P.aeruginosa)、和链霉菌属(Streptomyces)。本发明的细胞只要可以表达本发明的载体,无特别限定,较好是大肠杆菌。
作为本发明的细胞,真核细胞最常采用酵母(酿酒酵母(Saccharomycescerevisiae))。另一方面,还可使用多种其他属、种和菌株,例如粟酒裂殖酵母(Schizosaccharomyces pombe)、克鲁维酵母宿主、例如乳酸克鲁维酵母(K.lactis)、脆壁克鲁维酵母(K.fragilis,ATCC 12,424)、保加利亚克鲁维酵母(K.bulgaricus)(ATCC16,045)、威克拉姆氏克鲁维酵母(K.wickeramii)(ATCC24,178)、瓦特氏克鲁维酵母(K.waltii)(ATCC56,500)、果蝇克鲁维酵母(K.drosophilarum)(ATCC36,906)、耐热克鲁维酵母(K.thermotoIerans)及马克斯克鲁维酵母(K.marxianus),耶氏酵母属(Yarrowia)(EP402,226),巴斯德毕赤酵母(Pichia pastoris)(EP183,070),念珠菌属,瑞氏木霉菌(Trichoderma reesia)(EP244,234),粗糖脉抱菌(Neurospora crasssa),许旺氏酵母属(Schwann1myces)、例如西方许旺氏酵母(Schwann1myces occidentalis)和丝状真菌、例如脉孢属(Neurospora)、青霉属(Penicillium)、弯颈霉属(Tolypocladium),和曲霉属(Aspergillus)宿主、例如小巢状曲霉(A.nidulans)及黑曲霉(A.niger),但并不仅限于。
所述术语“转化(transformation)”是指基于外源性聚核苷酸的引入的宿主细胞的基因型的变化,无关用于该转化的方法,均指外源性聚核苷酸被引入宿主细胞内。被引入宿主细胞内的外源性聚核苷酸可整合于宿主细胞的基因组内并维持,或者不整合的情况下维持,本发明同时包含两者。
本发明涉及的可表达与人源c-Met蛋白质特异性结合的抗体或片段的重组表达载体可为了生产抗体或其片段而通过本领域公知的方法引入细胞内部而进行转化,所述方法可例举例如瞬时转染(transient transfection)、微注射、转导(transduction)、细胞融合、磷酸钙沉淀法、脂质体介导转染(liposome-mediated transfection)、DEAE葡聚糖介导转染(DEAE dextran-mediated transfection)、聚凝胺介导转染(polybrene-mediatedtransfection)、电穿孔法、基因枪(gene gun)和用于将核酸导入细胞内的公知的方法,但并不仅限于此。
此外,本发明的细胞为可通过本发明的聚核苷酸或包含其的载体转化或转染的培养细胞,该细胞可持续在所述宿主细胞内表达。重组细胞是指被要表达的聚核苷酸转化或转染的细胞。本发明的细胞还可以是包含本发明的聚核苷酸,但只要调节序列以与所述聚核苷酸通过可作用的形式连接的方式导入所述细胞内,不会表达该聚核苷酸至所期望的水平的细胞。
本发明的细胞可通过各种培养基进行培养。商业上可采用的培养基、例如汉姆氏
(Ham's)F10(西格玛奥德里奇公司,圣路易斯,密苏里州)、伊格尔最低必需培养基
(MEM,西格玛奥德里奇公司)、RPMI-1640(西格玛奥德里奇公司)、和达尔伯克改良伊格尔培养基(DMEM,西格玛奥德里奇公司)适合于细胞的培养。所述培养基可根据需要追加激素和/或其他生长因子、盐、缓冲液、核苷酸、抗生素、微量元素和葡萄糖、或者同等的能量源。
本发明提供一种与人c-Met结合的激动剂抗体或其片段的生产方法,其中,包括:在将所述细胞在表达聚核苷酸的条件下进行培养,生产包含轻链及重链可变区的多肽的步骤;以及从所述细胞或对其进行培养的培养基回收所述多肽的步骤。
本发明中,关于生产方法中的细胞如前所述,包含编码本发明的抗体的聚核苷酸。所述生产方法的多肽可以是本发明的抗体或其片段本身,也可另外结合有除本发明的抗体或其片段以外的其他氨基酸序列。
该情况下,可利用本领域一般技术人员熟知的方法,从本发明的抗体或其片段除去。所述培养的培养基组成和培养条件可根据所述细胞的种类而变化,这可由本领域一般技术人员适当地进行选择和调节。
所述抗体分子可积聚于细胞的细胞质内、或者从细胞分泌、或者通过适当的信号序列以周质或细胞外培养基(supernatant)靶向化,较好是靶向周质或细胞外培养基。此外,较好是利用本领域一般技术人员熟知的方法使所生产的抗体分子折叠,使其具有功能性构象(conformation)。所述多肽的回收可根据所生产的多肽的特性和细胞的特性而不同,其可由具有本领域常识的人适当地进行选择和调整。
所述多肽可生产至细胞内、周边细胞质的空间,或者直接分泌至培养基内。多肽在细胞内生产的情况下,该细胞可作为第一步骤被破坏而释放蛋白质。粒子型碎片、宿主细胞或被溶解的片段可通过例如离心分离或超滤被除去。抗体被分泌至培养基内的情况下,来自这样的表达系统的上清液通常最初用可商业化利用的蛋白质浓缩过滤器、例如Amicon或Millipore Pellicon超滤单元进行浓缩。可为了抑制蛋白质分解在任意的在先步骤包含蛋白酶抑制剂、例如PMSF,也可为了防止偶发的污染物质的增长而包含抗生素。由细胞制造的抗体可使用例如羟磷灰石层析、凝胶电泳、透析和亲和层析进行纯化,本发明的抗体较好是通过亲和层析进行纯化。
本发明提供一种c-Met特异性检测方法,其中,包括使所述抗体或其片段与试样接触的步骤以及检测所述激动剂抗体或其片段的步骤。
本发明的所述检测方法在使本发明所述的抗体或其片段与试样接触之前,可包括使用本发明所述的抗体或其片段准备用于测定KRS(或暴露于细胞外膜的KRS的N末端肽)的有无和浓度的试样的步骤((1)步骤)。
一般技术人员可适当选择利用抗体检测蛋白质的公知方法,根据选择的方法准备试样。此外,试样可以是以从诊断癌或癌转移的程度的被检测体采集的活体标本等得到的细胞或组织、血液、全血、血清、血浆、唾液、脑脊液等。使用所述抗体检测蛋白质的方法无限定,有例如蛋白质印迹、免疫印迹、斑点印迹法、免疫组化学染色(immunohistochemistry)、酶联免疫测定(ELISA)、放射免疫测定法(radioimmunoassay)、竞争性结合分析、免疫沉淀等。例如,为了实施蛋白质印迹,可通过向试样或细胞的溶解产物添加适合于电泳的缓冲液并煮沸等方法进行准备,为了免疫组化学染色,进行固定细胞或组织的切片并封闭(blocking)等预处理。
接着,实施使本发明所述的抗体或其片段与上述的步骤中准备的试样接触的步骤((2)步骤)。
本发明所述的抗体是具有以上所述的CDR、或VH和VL的构成且与人源c-Met蛋白质特异性结合的抗体或其片段,关于其具体的种类和序列的构成如上所述。
为了上述检测,所述抗体或其片段一般可通过能够检测的部分(moiety)进行标记。例如,可使用本领域公知的技术通过放射性同位素或荧光标记进行标记。此外,可利用各种各样的酶-底物标记,作为所述酶标记的例子,包括如果蝇荧光素酶和细菌荧光素酶(美国专利第4,737,456号)等荧光素酶、荧光素(luciferin)、2,3-二氢酞嗪二酮、苹果酸脱氢酶、脲酶、如辣根过氧化物酶(HRPO)等过氧化物酶、碱性磷酸酶、β-半乳糖苷酶、糖化酶、溶菌酶、糖氧化酶(例如,葡萄糖氧化酶、半乳糖氧化酶、和葡萄糖-6-磷酸脱氢酶)、杂环氧化酶(例如,尿酸酶和黄嘌呤氧化酶)、乳过氧化物酶、微过氧化物酶等。例如,使酶与抗体结合的技术在本领域是公知的。标记可利用各种公知的技术,与抗体直接或间接结合。例如,抗体可与生物素(biotin)结合,属于所述3大类的任意标记可与亲和素(avidin)结合,或者相反地与其结合。生物素与亲和素选择性结合,所以该标记可通过这样的间接方法结合于抗体。或者,为了实现抗体的标记的间接结合,抗体可与较小的半抗原(hapten)(例如,地高辛[digoxin])结合,所述的不同类型的标记之一可与抗半抗原抗体结合(例如,抗地高辛抗体)。因此,可实现标记对于抗体的间接结合。
本发明中,“接触(contacting)”以其通常的含义使用,是指将2种以上的物质混合、结合、或相互连接。所述接触可在试管内(in vitro)或其他容器中实施,还可在原位(insitu)、生物体内、个体内、组织内、细胞内进行。
接着,通过实施所述(2)步骤后的试样检测本发明所述的抗体或其片段的步骤((3)步骤)。
所述“检测”以试样内形成的本发明所述的抗体或其片段与抗原的复合物为对象,感知人c-Met的肽(或包含其的蛋白质)是否存在或测定所述肽的水平(定性或定量的测定均包含在内)。因此,在进行所述(2)步骤之后、后述的检测步骤((3)步骤)之前,还包括除去未与人源c-Met蛋白质形成复合物的剩余抗体或其片段的步骤。
在上述的(2)步骤所使用的抗体或其片段包含以荧光、放射性同位素、酶等直接标记等的可检测的部分(moiety)的情况下,可通过检测该部分的本领域公知的方法进行。作为一例,放射能例如可通过闪烁计数(scintillation counting)进行测定,荧光可用荧光计进行定量。
此外,在上述的(2)步骤所使用的抗体或其片段不包含以上单独说明的检测部分情况下,如本领域所知,可使用以荧光、放射能、酶等标记的二级抗体间接地进行感知。所述二级抗体与基于本发明的抗体或其片段(一级抗体)结合。
最近的研究中,报道有关于HGF/SF也作用于神经系统,特别是涉及运动神经细胞的保护功能的大量研究(Novak等、Journal of Neuroscience 20:326-337、2000)。此外,还提示在心脏的损伤恢复(Nakamura等、J Clin Invest.106:1511-1519、2000)等通常的脏器损伤后的防御、生理学机理也有重要的作用,实际上已证明HGF/MET路径与脑梗塞、进行性肾炎、肝硬化和肺纤维化的过程相关,HGF在这些变性疾病的病变中过表达,通过组织损伤的生理学防御机制显示保护活性(Comoglio等、Nature Review Drug Discovery 7:504-516、2008)。此外,HGF/c-Met信号传递的过度活性与内皮系统的各种细胞的恶性肿瘤化和血管生成相关,基于这样的观点,提示了靶向c-Met的拮抗性c-Met抗体可用作抗癌剂的可能性(Comoglio等、Nature Review Drug Discovery.7:504-516、2008)。例如,报道了具有一个分支的c-Met抗体对HGF的基于c-Met二聚体化的激活进行负调节,移植小鼠模型中有效地抑制肿瘤的生长(Jin等,Cancer Research 68(11):4360-4368、2008;Comoglio等、Nature Review Drug Discovery.7:504-516、2008)。此外,T细胞治疗法中,对于选择性识别癌细胞的表面抗原的T细胞的基因操作,针对癌细胞所过表达的抗原的抗体也被应用至用于连接T细胞的肿瘤靶向化(Sadelain、The Cancer Journal 15(6):451-455、2009)。
本发明提供一种包含所述抗体或其片段作为有效成分的癌的预防或治疗用药学组合物。
本发明的所述抗体及其片段的与所述c-Met蛋白质特异性结合的能力良好,c-Met抗体或其片段具有对HGF的激活进行负调节而抑制肿瘤生长的效果,因此可用作癌治疗剂。此外,所述抗体或其片段组合癌治疗药,可用于癌的预防和治疗,可将所述抗体或片段与药学上可接受的载体一起制成合适的形态而用于癌的预防或治疗。
本发明的所述“癌(cancer)”可包括膀胱癌、乳腺癌、宫颈癌、胆管癌、结肠/直肠癌、大肠癌、子宫内膜癌、食道癌、胃癌、头颈癌、肾癌、肝癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、胆囊癌、前列腺癌、甲状腺癌、骨肉瘤、横纹肌肉瘤、滑膜肉瘤、卡波西肉瘤、平滑肌肉瘤、恶性纤维组织细胞瘤、纤维肉瘤、急性骨髓性白血病、成人T细胞白血病、慢性骨髓性白血病、淋巴瘤、多发性骨髓瘤、胶质母细胞瘤、星形细胞瘤、黑色素瘤、间皮细胞瘤、维尔姆斯瘤、和透明细胞肉瘤(CCS)、腺泡状软组织肉瘤(ASPS)和电位相关肾细胞癌,但并不仅限于此。
本发明所述的药学组合物可单独含有与c-Met蛋白质特异性结合的激动剂抗体或其片段,也可与药学上可接受的载体一起制剂化成适当的形式,可追加含有赋形剂或稀释剂。上述中,“药学上可接受”是指生理学上允许,向人给药时,通常不会引发肠胃障碍、头晕等过敏反应或与之类似的反应的无毒性的组合物。
作为药学上可接受的载体,例如可还包含口服用载体或非口服用载体。口服用载体可包括乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。同时,可包含用于肽制剂的口服的各种药物递送物质。此外,非口服用载体可包含水、适当的油、食盐水、水性葡萄糖和二醇等,可还包含稳定剂和保存剂。作为合适的稳定剂,有亚硫酸氢钠、亚硫酸钠、或如抗坏血酸等抗氧化剂。作为合适的保存剂,有苯扎氯铵、对羟基苯甲酸甲酯或丙酯和氯丁醇。除上述成分之外,本发明的药学组合物可还包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、悬浮剂等。其他药学上可接受的载体和制剂可参照本领域公知的载体或制剂。
本发明的组合物可通过任意的方法给予人等哺乳动物。例如,可通过口服或非口服的方式给药。作为非口服的给药方法,可以是静脉内、肌肉内、动脉内、髓内、硬脑膜内、心脏内、经皮、皮下、腹腔内、鼻腔内、肠道、局部、舌下或直肠内的给药,但并不仅限于此。
本发明的药学组合物可根据如上所述的给药路径制成口服用或非口服用的制剂。
口服用制剂的情况下,本发明的组合物为粉末、颗粒、片剂、丸剂、糖衣片剂、胶囊剂、液剂、凝胶剂、糖浆剂、膏剂、悬浮液等,可使用本领域公知的方法剂型化。例如,口服用制剂可将活性成分与固体赋形剂掺合,将其粉碎并添加合适的助剂后,用颗粒的混合物进行处理,从而获得片剂或糖衣片剂。作为合适的赋形剂的例子,可包括包含乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藻糖醇和麦芽糖醇等的糖类,包含玉米淀粉、小麦淀粉、米淀粉和马铃薯淀粉等的淀粉类,包含纤维素、甲基纤维素、羧甲基纤维素钠和羟丙基甲基纤维素等的纤维素类,明胶、聚乙烯基吡咯烷酮等填充剂。此外,可根据情况添加交联聚乙烯吡咯烷酮、琼脂、海藻酸或海藻酸钠作为崩解剂。另外,本发明的药学组合物可还包含抗凝剂、润滑剂、湿润剂、香料、乳化剂和防腐剂等。
非口服用制剂的情况下,可以注射剂、霜剂、洗剂、外用软膏剂、油剂、保湿剂、凝胶剂、气溶胶和鼻腔吸入剂的形式,通过本领域公知的方法制剂化。这些剂型在任何制药化学上一般公知的处方书中有记载。
本发明的组合物的总有效量可按照单次给药量(single dose)给予患者,也可通过按照多次给药量(multiple dose)长期给药的分次治疗方法(fractionated treatmentprotocol)进行给药。本发明的药学组合物可根据疾病的程度改变有效成分的含量。优选地,本发明的药学组合物的优选的整体容量每天每1kg患者体重为约0.01μg至10,000mg,最好是0.1μg至500mg。但是,关于所述药学组合物的容量,考虑给药途径和治疗次数以及患者的年龄、体重、健康状态、性别、疾病的严重程度、饮食和排泄率等各种因素确定患者的有效给药量,所以考虑这一点时,如果是拥有本领域常识的人,应可确定本发明的组合物的合适的有效给药量。本发明所述的药学组合物只要显示本发明的效果,对其剂型、给药途径和给药方法无特别限定。
本发明提供一种包含所述抗体的干细胞的分化诱导用组合物。
本发明的所述“干细胞”是具有可分化为各种各样的细胞的干性(stemness)的未分化细胞的总称,干细胞根据特定的分化因子和/或环境进行向特定细胞的分化。干细胞的种类有胚胎干细胞(embryonic stem cell)、胚生殖细胞、成体干细胞、癌干细胞等。可利用干细胞治疗损伤组织的再生、糖尿病、白血病、帕金森氏症、心脏病、脊髓外伤等各种疾病,本发明中最好是可以为来源于脂肪的间充质干细胞。
本发明提供一种包含所述干细胞的分化诱导用组合物的干细胞用培养基。
本发明的“干细胞用培养基”是包含含有所述c-Met抗体的干细胞的分化诱导用组合物的培养基,是包含培养干细胞或使其分化的成分的培养基。所述培养基包括可使干细胞分化为脂肪、软骨、骨、神经等所有细胞的培养基,较好是可以为使干细胞分化为脂肪细胞、软骨细胞或骨细胞的培养基。
本发明的一个实施例中,使用人重组c-Met抗体进行人scFv文库筛选,获得扩增的样品后,通过ELISA方法确认结合能力,筛选显示结合信号的样品进行碱基序列分析。接着,选择其中具有不同序列的候选(hit),通过ELISA方法确认结合能力,筛选最强力结合的10个候选并转换为人IgG形态(参照实施例1、图1a、图1b和图2)。
本发明的另一实施例中,为了确认人IgG与天然c-Met结合而通过质粒转染293F细胞后,回收细胞,用蛋白质A珠粒纯化抗体并进行SDS-PAGE,结果确认所述10个候选(hit)转换为人IgG形态在细胞中表达,并且确认了轻链和重链的尺寸。接着,使用c-Met阳性细胞进行了流式细胞分析后,筛选了抗体的结合图案(binding pattern)在细胞上呈现的最大变化与c-Met的表达水平一致的4种抗体(参照实施例2、图3、图4a和图4b)。
本发明的又另一实施例中,使作为抗原的人c-Met重组蛋白质固定于生物表面(biosurface)后,使抗体(A8、A11和C8)流过而与抗原反应后,测定结合系数,以Octet平台进行分析后,结果确认与所有以往的c-Met抗体相比,3种抗体均具有高亲和性和解离值(参照实施例3和图5)。
本发明的又另一实施例中,培养c-Met阳性的细胞株而获得蛋白质后,通过蛋白质印迹法确认了c-Met的信号图案,结果确认仅H596细胞株中未发生c-Met催化的磷酸化,对H596细胞用HGF用不同浓度处理后进行了蛋白质印迹,结果确认Tyr1234和Tyr1349的表达量依赖于浓度而增加。然后,对H596细胞用HGF和作为c-Met抗体的A8、A11、B10、C8按照不同浓度处理并进行了蛋白质印迹,结果确认HGF、A8、A11诱导包括如p-Erk和p-Akt等主要的下游信号的磷酸化信号(参照实施例4和图6a~图6c)。
本发明的又另一实施例中,对H596细胞改变HGF、A8或A11的浓度以WST测试法分析了细胞增殖,结果确认以抗体处理的情况呈现与以HGF处理的情况不同的细胞增殖速度,但饱和点更高(参照实施例5和图7)。
本发明的又另一实施例中,使用没有HGF的培养基和分别含有不同浓度的HGF、A8或A11的培养基培养间充质干细胞,培养的同时对培养时间、生存力和细胞形态进行了观察,结果确认所有组均显示细胞的平均生存率在90%以上,由此c-Met抗体对干细胞的培养形态不造成影响(参照实施例6-1、图8a和图8b)。
本发明的又另一实施例中,以HGF、A8或A11处理培养来源于脂肪的间充质干细胞后,诱导脂肪、软骨和骨的分化。根据分化的细胞系分别以不同的培养基条件诱导干细胞的分化,对各细胞进行染色并观察后,结果确认干细胞在所有的培养条件下分化为脂肪细胞,无HGF的培养基中未显示软骨和骨的分化,A8或A11显示与HGF类似的结果。由此,确认干细胞中A8或A11具有与HGF同样的作用(参照实施例6-2和图a~图9d)。
此外,本发明还提供一种所述抗体或其片段在癌的预防或治疗用制剂的制造中的用途。
此外,本发明还提供一种癌的治疗方法,其中,包括将有效量的包含所述抗体或其片段作为有效成分的组合物给予有需要的个体的步骤。
本发明提供所述抗体在干细胞的分化诱导用制剂的制造中的用途。
本发明提供一种干细胞的分化诱导方法,其中,包括将有效量的包含所述抗体的组合物给予有需要的个体的步骤。
本发明的所述“有效量”是指向个体给药时显示癌的改善、治疗、预防、检测、诊断或者癌的抑制或减少效果的量,是指显示诱导干细胞的分化的效果的量。所述“个体”可以是动物,较好是哺乳动物,特别是包括人的动物,可以是来源于动物的细胞、组织、器官等。所述个体可以是需要所述效果的患者。
本发明的所述“治疗”概括性地表示改善癌或癌的症状,其可包括癌的治愈和实质上的预防、或状态的改善,包括缓解和治疗、或预防源自癌的一种症状或几乎所有症状,但并不仅限于此。
本发明的术语“包括(comprising)~”与“含有”或“以~为特征”同样地使用,在组合物或方法中,不排除未记载的追加成分、要素或方法步骤等。术语“由~形成(consistingof)”是指排除未另行记载的追加要素、步骤或成分等。术语“必须由~形成(essentiallyconsisting of)”是指在组合物或方法的范围内,除了所记载的成分要素或步骤之外,包括对其基本特性不造成实质上的影响的成分要素或步骤。
发明的效果
因此,本发明提供抗c-Met激动剂抗体及其应用。本发明的方法可用于c-Met抗体的检测、利用抗体的干细胞分化的诱导、癌的治疗或预防。
附图说明
图1a和图1b表示使用人c-Met重组蛋白质作为抗原(antigen)的基于噬菌体展示(图1a)和ELISA的筛选结果(图1b)。
图2表示基于ELISA的结果选择的候选(hit)的结合程度的确认结果。
图3表示为了确认纯化的抗体的重链和轻链的尺寸而进行SDS-PAGE的结果。
图4a和图4b表示使用A549细胞和MDA-MB-231细胞通过流式细胞分析确认10种c-Met抗体的结合能力的结果(图4a)、以及利用A549、H596和SKBR-3细胞通过流式细胞分析确认c-Met抗体(A8、A11、B10、C8)的结合能力的结果(图4b)。
图5表示使用Octet分析确认c-Met抗体(A8、A11、B10、C8)的结合亲和性的结果。
图6a~图6c表示使用蛋白质印迹法以c-Met阳性细胞株确认c-Met信号图案的结果(图6a)、对H596细胞分别以不同浓度的HGF处理确认c-Met信号图案的结果(图6b)以及对H596细胞以HGF和c-Met抗体(A8、A11、B10、C8)处理确认c-Met信号图案的结果(图6c)。
图7表示使用WST分析方法确认c-Met抗体和HGF对细胞增殖造成的影响的结果。
图8a和图8b表示确认HGF或c-Met抗体(A8)对间充质干细胞的群体倍增时间(图8a)和生存力(图8b)造成的影响的结果。
图9a~图9d表示确认HGF或c-Met抗体(A8)对间充质干细胞的基于培养条件的培养形态(图9a)和脂肪分化(图9b)、软骨分化(图9c)和骨分化(图9d)造成的影响的结果。
具体实施方式
以下,对本发明进行详细说明。
但是,下述的实施例示例本发明,本发明并不受到下述的实施例的限定。
实验方法
试剂
A549细胞株和MDA-MB231细胞株从ATCC(美国典型培养物保藏中心,AmericanType Culture Collection,USA)购入,H596细胞、SKBR-3细胞从韩国细胞株银行(KoreanCell Line Bank,KCLB)购入。来源于脂肪的间充质干细胞由Xcell Therapeutics(首尔)提供。此外,间充质干细胞培养用培养基从Xcell Therapeutics购入。用于筛选的抗原为受体的包含1~932个氨基酸(amino acid,aa)的人c-Met重组蛋白质,从北京义翘神州生物技术有限公司(中国)购入。此外,作为对照组,使用从艾博抗(Abcam,美国)购入的抗c-Met抗体。
噬菌体展示
使用人重组c-Met蛋白质作为抗原,人scFv文库用于与c-Met的细胞外区域结合的候选(hits)筛选。将抗原被覆于浓度10μg/μl的免疫管(Nunc,USA),以O/N培养并使其结合。对于免疫管和噬菌体用封闭缓冲液(PBST内3%牛乳)抑制活性。将噬菌体加入被覆有抗原的免疫管并使其结合,1小时后,用PBST清洗4次,用PBS清洗1次。用7~8分钟使噬菌体溶出至100mM TEA后,用Tris-HCl(pH8)溶液中和。使溶出的噬菌体感染大肠杆菌,一部分在固体LA平板中以O/N培养而确认输出效价(output titer)。残留噬菌体用辅助噬菌体(helperphage)再生,同样的实验重复3次。
ELISA筛选
第4次围栏培养(penning)后,将单一群落分别注入96孔板的150μl的含氨苄青霉素的SB。接着,用37℃振荡培养器培养至培养基白浊。培养后,将培养液加入圆板并用1nMIPTG诱导后,在30℃过夜培养。使用c-Met重组蛋白质作为抗原,在ELISA(康宁3690)以1μg/ml的浓度溶于PBS进行被覆,在4℃过夜培养。第二天,将注入了克隆的平板以3000rpm离心分离15分钟。除去上清液并将颗粒在37℃用1×TES缓冲液再悬浮5~7分钟后,添加0.2×TES缓冲液在4℃反应30分钟而溶解细胞。将被覆有抗原的平板用150μl的TBST清洗3次,用3%脱脂奶抑制反应。从被溶解的细胞回收周质(periplasmic)提取物,在新的平板中用6%脱脂奶抑制反应1小时。接着,将溶液添加于被覆有抗原的平板,在室温下恒温培养1小时后,用TBST清洗3次。然后,添加抗HA Hrp二级抗体培养1小时后,用TBST清洗3次。然后,以30μl的TMB处理而开始反应后,使用1N H2SO4抑制反应,在450nm进行检测。
碱基序列分析和IgG转换
对所述ELISA筛选中所选的候选的序列进行分析(Cosmogenetech,韩国)。使序列分析和ELISA筛选后所选的最终候选转换为人IgG。将scFv序列转换为人轻链和重链的序列,使其与基于克隆的pOptiVECTM-TOPO和pcDNATM3.3-TOPO(赛默飞世尔科技公司,USA)载体融合。然后,用midi prep(Macherey Nagel,德国))扩增质粒。
过表达和抗体纯化
将扩增的质粒用Freestyle Expression System(英杰公司,USA)进行瞬时表达。在三角烧瓶(康宁,USA)中用Freestyle表达培养基(Freestyle Expression Medium)解冻Freestyle细胞(Freestyle cell)并进行培养。培养至细胞达到3.0×106细胞/ml的浓度,每2~3天传代培养,4次传代培养后,用FreeStyleTM MAX Transfection试剂(英杰公司,USA)转染重链和轻链质粒。然后,在8%CO2、37℃的条件下用振荡机培养细胞。转染后第7天回收细胞,获得上清液并过滤。过滤后,在色谱柱(Bio-rad,USA)上将上清液适用于MabSelect SuRe蛋白质A珠粒(GE healthcare,USA)。接着,通过SDS-PAGE和考马斯蓝(coomassie blue)染色确认了尺寸。
流式细胞分析
利用A549、MDA-MP231、H596和SKBR-3细胞进行了流式细胞分析(flow cytometricanalysis)。对于细胞,用细胞解离用试剂(cell dissociation buffer,Hyclone,USA)提取细胞后,用PBS清洗后,分离2.0×105个细胞加入管中。将抗体以1μg/管的浓度用含2%FBS的DBPS(Wellgene)溶液稀释并添加于细胞,反应1小时。作为对照组,使用了商业用抗c-Met抗体。接着,清洗细胞2次,用结合有FITC的二级抗体反应40分钟。清洗3次后,用FACS BDCalibur(BD、USA)进行了分析。
Octet分析
Octet服务由PALL corp,Fortebio提供。使用带有His标签的人重组c-Met蛋白质(北京义翘神州生物技术有限公司,中国)作为抗原。靶在生物表面被浓度20μg/ml的12个Ni-NTA传感器捕获。使用PBS作为配体缓冲液,使用1×Fortebio Kinetic缓冲液作为分析物缓冲液。配体固定后,使c-Met、A8、A11和C8的抗体结合,分析Kon和Koff的值并评价了结合能力。
细胞培养和抗体治疗
对H596细胞用含10%FBS和1%青霉素/链霉素(Hyclone)的RPMI(Wellgene)进行了培养。为了观察抗体是否能够诱导磷酸化信号,在6孔板中培养细胞。接着,为了去除FBS产生的信号干扰,用不含FBS的RPMI培养基过夜培养。第二天,除去培养基,用以不同浓度含有抗体或HGF的溶液处理1小时。
蛋白质印迹
如上所述培养细胞后,用含有RIPA(Biosesang)、蛋白质分解酶抑制剂(Roche)和磷酸化酶抑制剂(Roche)的溶解缓冲液回收细胞,用1ml注射器使细胞溶解。溶解后,将细胞以14000rpm离心分离15分钟。然后,回收上清液并通过BCA分析(赛默飞世尔科技公司)对蛋白质进行了定量。将上清液与5×样品上样缓冲液混合后,加热10分钟。接着,进行SDS-PAGE后,将蛋白质转移至激活的PVDF(聚偏二氟乙烯,polyvinylidene difluoride)膜(Bio-rad)。用5%BSA抑制膜的活性并用一级抗体反应后,用结合有Hrp的二级抗体反应。然后,在暗室中用ECL(安玛西亚公司)进行了确认。
细胞增殖分析
将H596细胞在96孔板中以1.0×104细胞/孔的浓度过夜培养。第二天,除去培养基,用以39pM~10nM的浓度含HGF或抗c-Met抗体的溶液进行了处理。接着,培养细胞72小时,将培养基置换为WST溶液(DoGen)培养2~3小时。接着,用多功能读板仪(Tecan)在450nm进行了测定。
实施例1:与c-Met结合的scFv的筛选和鉴定
为了确认与c-Met结合的抗体,使用仅含细胞外结构域(aa,1-932)的人重组c-Met抗体作为抗原,基于所述的方法进行了人scFv文库筛选。使抗原结合于免疫管(immunotube)后,重复进行4个循环。
其结果如图1a所示,在第3个和第4个的循环中显示输出(output)增加,第3个和第4个的循环中得到的样品通过ELISA法确认结合力,其结果示于图1b。此外,选择与对照组板相比显示信号的样品后,分析碱基序列(sequencing),选择其中具有不同序列的31个候选(hit),再进行ELISa确认结合力,选择最强力结合的10个候选(hit)。各候选基于ELISA的结果命名为A8、A9、A11、B8、B10、C8、C9、D7、D12、E10。接着,将10个候选转换为人IgG形态(图2)。
实施例2:人IgG形态的天然c-Met结合程度的确认
为了确认所述实施例1中制成的人IgG与天然c-Met的结合,如下进行了实验。
首先,按照所述实验方法以质粒转染293F细胞并培养7天。然后,回收细胞并用蛋白质A珠粒纯化抗体,进行SDS-PAGE。
其结果如图3所示,确认所述实施例1中最强力结合的10个候选被转换为人IgG形态并在细胞中表达,确认了轻链和重链的尺寸。
确认转换IgG后,基于CCLE的信息选择对于c-Met呈阳性的细胞,按照所述实验方法进行了流式细胞分析(flow cytometry)。
其结果如图4a所示,抗体的结合图案显示在A549细胞上呈现的最大变化与c-Met的表达水平一致,筛选其中最相似的4种抗体并使用其他细胞株进行了相同的实验。此时,H596细胞株为中间表达细胞株,SKBR-3细胞株被用作阴性对照组。
其结果如图4b所示,显示4种抗体(A8、A11、B10、C8)的结合图案与c-Met表达水平相关,作为c-Met阴性细胞株的SKBR-3细胞株中显示并未明显呈现结合迁移。其中,A11中,确认A549和H596细胞株与作为对照组的抗c-Met抗体的表达图案类似,SKBR-3细胞株与作为对照组的抗c-Met抗体的表达率一致。
由此,确认所选的4种先导抗体(leads)对c-Met受体具有特异性。
实施例3:先导抗体(lead antibody)的结合亲和性的分析
基于确认所述实施例2中的抗体与天然c-Met结合的结果使用显示最高迁移的先导抗体(A8、A11和C8),如下进行了实验。
通过所述实验方法,使作为抗原的人c-Met重组蛋白质固定于生物表面(biosurface)后,使抗体流过而与抗原反应。接着,使用结合系数Kon和解离常数Koff计算作为亲和性的定量值的KD。分析通过Octet平台进行。Kon值越高,则抗体与配体结合越快,Koff值越低,则解离越慢。KD值以Kon与Koff的比计算。
其结果如图5所示,显示与3种抗体与现有的c-Met抗体相比,3种抗体均具有更高的亲和性和解离值。其中,A8具有0.326nM的KD值,显示与抗c-Met抗体相比更高的亲和性。
由此可确认,与以往的c-Met抗体相比,A8抗体与受体更快结合,更慢解离。
实施例4:c-Met抗体的效果
上述实施例中,确认筛选的c-Met抗体对信号传递造成影响,因此使用c-Met阳性且依赖于HGF信号活性的细胞株,进行了如下的实验。
首先,对c-Met阳性的各种细胞株(Hs746T、H596、AsPC1、MKN45、SNU620、SNU5)分别进行培养后回收蛋白质。然后,如上述实验方法所述,进行蛋白质印迹,确认了c-Met信号图案。
其结果如图6a所示,显示仅H596细胞株未发生c-Met催化的磷酸化。
在此,向H596细胞添加50、100、200、500ng/ml的HGF并通过相同的方法进行了蛋白质印迹。其结果如图6b所示,显示添加HGF后,Tyr1234和Tyr1349的表达量依赖于浓度增加。
此外,在6孔板中用RPMI培养基(无血清)过夜培养H596细胞后,以纳摩尔浓度用HGF和作为c-Met抗体的A8、A11、B10、C8处理1小时。然后,回收细胞并如上所述进行了蛋白质印迹。
其结果如图6c所示,显示HGF、A8、A11诱导包括如p-Erk和p-Akt等主要的下游信号的磷酸化信号,但B10和C8不会诱导。此外,以A8处理的情况下,显示Tyr1234、Tyr1349的表达量依赖于浓度增加,诱导p-Erk和p-Akt的表达。
实施例5:c-Met抗体对细胞增殖产生的效果
为了确认在所述实施例4中确认的c-Met抗体的信号诱导对细胞直接造成的影响,如下进行了实验。
首先,在96孔板中培养H596细胞,将实施例4中诱导信号活性的HGF、A8或A11以0.039~10nM的浓度进行了处理。接着,将细胞再培养72小时,通过WST测试法分析了细胞增殖。数值与对照组(未处理,Untreated)的细胞增加率成比例地计算。
其结果如图7所示,确认已HGF、A8或A11处理的情况下细胞增殖,显示以A8抗体处理的情况下不同的细胞增殖速度,但饱和点更高。
实施例6:间充质干细胞的c-Met抗体的效果
为了确认作为c-Met抗体的A8和A11在间充质干细胞中显示与HGF同样的效果,进行了如下的实验。
向6孔板中加入含生长因子的化学稳定的培养基并接种间充质干细胞。此时,使用无HGF的培养基和分别含有不同浓度的HGF、A8或A11的培养基。
6-1:c-Met抗体的细胞毒性效果
通过所述实验方法,对来源于脂肪的间充质干细胞以不同浓度的HGF、A8或A11进行处理,以除去了HGF的培养基进行了培养。培养的同时对培养时间、生存力和细胞形态进行评价,使用Cedex细胞计数装置(Roche,USA),台盼蓝染色(trypan blue staining)后使用计数法对群体倍增时间和生存力进行评价,细胞形态使用光学显微镜拍摄图像并观察。
其结果如图8a和8b所示,群体倍增时间在未处理HGF的情况与以HGF和c-Met抗体A8进行处理的情况下未显示显著差异。此外,所有组中,显示细胞的平均生存率在90%以上。
由此,可确认作为c-Met抗体的A8对干细胞的培养形态不造成影响,具有与HGF同样的效果。
6-2:c-Met抗体对干细胞的分化产生的效果
通过所述实验方法,对来源于脂肪的间充质干细胞以各种调整用培养基培养至第9次传代。第9次传代后将细胞接种于6孔板,使其根据分化的细胞系统生长。将细胞诱导为脂肪、软骨和骨的分化。
首先,通过如下的方法分化为脂肪细胞。第10次传代的细胞生长至约90~100%,将培养基替换为细胞分化用培养基。使用StemPro脂肪生成分化试剂盒(赛默飞世尔科技公司,USA)作为分化培养基,每2~3天更换培养基并维持2~3周。在分化为脂肪后,为了观察细胞,以油红O染色进行观察。
此外,通过如下的方法使干细胞分化为软骨细胞。第10次传代的细胞生长至约50%,将培养基替换为细胞分化用培养基。使用含FBS(Hyclone,USA)、1%ITS-X、50μg/ml抗坏血酸、100nM地塞米松(dexamethasone)和10ng/ml TGF-β1的DMEM低葡萄糖培养基(Wellgene,韩国)作为分化培养基,每2~3天更换培养基并维持2~3周。3周后,固定细胞并用阿尔辛蓝(Alcian blue)染色观察。
此外,通过如下的方法使干细胞分化为骨细胞。将细胞培养至第10次传代,将培养基替换为细胞分化用培养基。使用含FBS、100nM地塞米松(dexamethasone)、10nM甘油-2-磷酸(glycerol-2-phosphate)、50μg/ml抗坏血酸和1%谷氨酰胺(Glutamax)的DMEM低葡萄糖培养基(Wellgene,韩国)作为分化培养基,每2~3天更换培养基并维持3周。3周后,固定细胞,用茜素红染色观察。
其结果如图9a~图9d所示,显示干细胞在所有培养基条件下分化为脂肪细胞,但软骨和骨分化在无HGF的培养基中未分化。此外,显示用含有A8的培养基培养的细胞以与HGF对照组类似的密度被染色。
由此可确认,为了维持干细胞的多分化能力,HGF发挥重要作用,A8在干细胞中发挥与HGF同样的作用。
工业上利用的可能性
如上所述,本发明提供抗c-Met激动剂抗体及其应用。本发明的方法可有效地用于c-Met抗体的检测、利用抗体的干细胞分化的诱导、癌的治疗或预防。
SEQUENCE LISTING
<110> 首尔大学校产学协力团
瑷备恩有限公司
<120> 抗c-Met激动剂抗体及其应用
<130> P21115126WP
<150> KR 10-2018-0157325
<151> 2018-12-07
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> VL-CDR1 of c-Met A8
<400> 1
Thr Gly Ser Ser Ser Asn Ile Gly Asn Asn Asn Val Tyr
1 5 10
<210> 2
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> VL-CDR2 of c-Met A8
<400> 2
Ala Asn Ser His Arg Pro Ser
1 5
<210> 3
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> VL-CDR3 of c-Met A8
<400> 3
Gly Ser Trp Asp Tyr Ser Leu Asn Gly
1 5
<210> 4
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> VH-CDR1 of c-Met A8
<400> 4
Asp Tyr Tyr Met Ser
1 5
<210> 5
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> VH-CDR2 of c-Met A8
<400> 5
Ala Ile Ser His Asp Asp Ser Ser Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 6
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> VH-CDR3 of c-Met A8
<400> 6
Asp Leu Leu Gln Cys Asn Ser Glu Gln Cys Tyr Ser Asp Asn Gly Met
1 5 10 15
Asp Val
<210> 7
<211> 1408
<212> PRT
<213> Artificial Sequence
<220>
<223> Homo sapiens c-Met Protein
<400> 7
Met Lys Ala Pro Ala Val Leu Ala Pro Gly Ile Leu Val Leu Leu Phe
1 5 10 15
Thr Leu Val Gln Arg Ser Asn Gly Glu Cys Lys Glu Ala Leu Ala Lys
20 25 30
Ser Glu Met Asn Val Asn Met Lys Tyr Gln Leu Pro Asn Phe Thr Ala
35 40 45
Glu Thr Pro Ile Gln Asn Val Ile Leu His Glu His His Ile Phe Leu
50 55 60
Gly Ala Thr Asn Tyr Ile Tyr Val Leu Asn Glu Glu Asp Leu Gln Lys
65 70 75 80
Val Ala Glu Tyr Lys Thr Gly Pro Val Leu Glu His Pro Asp Cys Phe
85 90 95
Pro Cys Gln Asp Cys Ser Ser Lys Ala Asn Leu Ser Gly Gly Val Trp
100 105 110
Lys Asp Asn Ile Asn Met Ala Leu Val Val Asp Thr Tyr Tyr Asp Asp
115 120 125
Gln Leu Ile Ser Cys Gly Ser Val Asn Arg Gly Thr Cys Gln Arg His
130 135 140
Val Phe Pro His Asn His Thr Ala Asp Ile Gln Ser Glu Val His Cys
145 150 155 160
Ile Phe Ser Pro Gln Ile Glu Glu Pro Ser Gln Cys Pro Asp Cys Val
165 170 175
Val Ser Ala Leu Gly Ala Lys Val Leu Ser Ser Val Lys Asp Arg Phe
180 185 190
Ile Asn Phe Phe Val Gly Asn Thr Ile Asn Ser Ser Tyr Phe Pro Asp
195 200 205
His Pro Leu His Ser Ile Ser Val Arg Arg Leu Lys Glu Thr Lys Asp
210 215 220
Gly Phe Met Phe Leu Thr Asp Gln Ser Tyr Ile Asp Val Leu Pro Glu
225 230 235 240
Phe Arg Asp Ser Tyr Pro Ile Lys Tyr Val His Ala Phe Glu Ser Asn
245 250 255
Asn Phe Ile Tyr Phe Leu Thr Val Gln Arg Glu Thr Leu Asp Ala Gln
260 265 270
Thr Phe His Thr Arg Ile Ile Arg Phe Cys Ser Ile Asn Ser Gly Leu
275 280 285
His Ser Tyr Met Glu Met Pro Leu Glu Cys Ile Leu Thr Glu Lys Arg
290 295 300
Lys Lys Arg Ser Thr Lys Lys Glu Val Phe Asn Ile Leu Gln Ala Ala
305 310 315 320
Tyr Val Ser Lys Pro Gly Ala Gln Leu Ala Arg Gln Ile Gly Ala Ser
325 330 335
Leu Asn Asp Asp Ile Leu Phe Gly Val Phe Ala Gln Ser Lys Pro Asp
340 345 350
Ser Ala Glu Pro Met Asp Arg Ser Ala Met Cys Ala Phe Pro Ile Lys
355 360 365
Tyr Val Asn Asp Phe Phe Asn Lys Ile Val Asn Lys Asn Asn Val Arg
370 375 380
Cys Leu Gln His Phe Tyr Gly Pro Asn His Glu His Cys Phe Asn Arg
385 390 395 400
Thr Leu Leu Arg Asn Ser Ser Gly Cys Glu Ala Arg Arg Asp Glu Tyr
405 410 415
Arg Thr Glu Phe Thr Thr Ala Leu Gln Arg Val Asp Leu Phe Met Gly
420 425 430
Gln Phe Ser Glu Val Leu Leu Thr Ser Ile Ser Thr Phe Ile Lys Gly
435 440 445
Asp Leu Thr Ile Ala Asn Leu Gly Thr Ser Glu Gly Arg Phe Met Gln
450 455 460
Val Val Val Ser Arg Ser Gly Pro Ser Thr Pro His Val Asn Phe Leu
465 470 475 480
Leu Asp Ser His Pro Val Ser Pro Glu Val Ile Val Glu His Thr Leu
485 490 495
Asn Gln Asn Gly Tyr Thr Leu Val Ile Thr Gly Lys Lys Ile Thr Lys
500 505 510
Ile Pro Leu Asn Gly Leu Gly Cys Arg His Phe Gln Ser Cys Ser Gln
515 520 525
Cys Leu Ser Ala Pro Pro Phe Val Gln Cys Gly Trp Cys His Asp Lys
530 535 540
Cys Val Arg Ser Glu Glu Cys Leu Ser Gly Thr Trp Thr Gln Gln Ile
545 550 555 560
Cys Leu Pro Ala Ile Tyr Lys Val Phe Pro Asn Ser Ala Pro Leu Glu
565 570 575
Gly Gly Thr Arg Leu Thr Ile Cys Gly Trp Asp Phe Gly Phe Arg Arg
580 585 590
Asn Asn Lys Phe Asp Leu Lys Lys Thr Arg Val Leu Leu Gly Asn Glu
595 600 605
Ser Cys Thr Leu Thr Leu Ser Glu Ser Thr Met Asn Thr Leu Lys Cys
610 615 620
Thr Val Gly Pro Ala Met Asn Lys His Phe Asn Met Ser Ile Ile Ile
625 630 635 640
Ser Asn Gly His Gly Thr Thr Gln Tyr Ser Thr Phe Ser Tyr Val Asp
645 650 655
Pro Val Ile Thr Ser Ile Ser Pro Lys Tyr Gly Pro Met Ala Gly Gly
660 665 670
Thr Leu Leu Thr Leu Thr Gly Asn Tyr Leu Asn Ser Gly Asn Ser Arg
675 680 685
His Ile Ser Ile Gly Gly Lys Thr Cys Thr Leu Lys Ser Val Ser Asn
690 695 700
Ser Ile Leu Glu Cys Tyr Thr Pro Ala Gln Thr Ile Ser Thr Glu Phe
705 710 715 720
Ala Val Lys Leu Lys Ile Asp Leu Ala Asn Arg Glu Thr Ser Ile Phe
725 730 735
Ser Tyr Arg Glu Asp Pro Ile Val Tyr Glu Ile His Pro Thr Lys Ser
740 745 750
Phe Ile Ser Thr Trp Trp Lys Glu Pro Leu Asn Ile Val Ser Phe Leu
755 760 765
Phe Cys Phe Ala Ser Gly Gly Ser Thr Ile Thr Gly Val Gly Lys Asn
770 775 780
Leu Asn Ser Val Ser Val Pro Arg Met Val Ile Asn Val His Glu Ala
785 790 795 800
Gly Arg Asn Phe Thr Val Ala Cys Gln His Arg Ser Asn Ser Glu Ile
805 810 815
Ile Cys Cys Thr Thr Pro Ser Leu Gln Gln Leu Asn Leu Gln Leu Pro
820 825 830
Leu Lys Thr Lys Ala Phe Phe Met Leu Asp Gly Ile Leu Ser Lys Tyr
835 840 845
Phe Asp Leu Ile Tyr Val His Asn Pro Val Phe Lys Pro Phe Glu Lys
850 855 860
Pro Val Met Ile Ser Met Gly Asn Glu Asn Val Leu Glu Ile Lys Gly
865 870 875 880
Asn Asp Ile Asp Pro Glu Ala Val Lys Gly Glu Val Leu Lys Val Gly
885 890 895
Asn Lys Ser Cys Glu Asn Ile His Leu His Ser Glu Ala Val Leu Cys
900 905 910
Thr Val Pro Asn Asp Leu Leu Lys Leu Asn Ser Glu Leu Asn Ile Glu
915 920 925
Trp Lys Gln Ala Ile Ser Ser Thr Val Leu Gly Lys Val Ile Val Gln
930 935 940
Pro Asp Gln Asn Phe Thr Gly Leu Ile Ala Gly Val Val Ser Ile Ser
945 950 955 960
Thr Ala Leu Leu Leu Leu Leu Gly Phe Phe Leu Trp Leu Lys Lys Arg
965 970 975
Lys Gln Ile Lys Asp Leu Gly Ser Glu Leu Val Arg Tyr Asp Ala Arg
980 985 990
Val His Thr Pro His Leu Asp Arg Leu Val Ser Ala Arg Ser Val Ser
995 1000 1005
Pro Thr Thr Glu Met Val Ser Asn Glu Ser Val Asp Tyr Arg Ala
1010 1015 1020
Thr Phe Pro Glu Asp Gln Phe Pro Asn Ser Ser Gln Asn Gly Ser
1025 1030 1035
Cys Arg Gln Val Gln Tyr Pro Leu Thr Asp Met Ser Pro Ile Leu
1040 1045 1050
Thr Ser Gly Asp Ser Asp Ile Ser Ser Pro Leu Leu Gln Asn Thr
1055 1060 1065
Val His Ile Asp Leu Ser Ala Leu Asn Pro Glu Leu Val Gln Ala
1070 1075 1080
Val Gln His Val Val Ile Gly Pro Ser Ser Leu Ile Val His Phe
1085 1090 1095
Asn Glu Val Ile Gly Arg Gly His Phe Gly Cys Val Tyr His Gly
1100 1105 1110
Thr Leu Leu Asp Asn Asp Gly Lys Lys Ile His Cys Ala Val Lys
1115 1120 1125
Ser Leu Asn Arg Ile Thr Asp Ile Gly Glu Val Ser Gln Phe Leu
1130 1135 1140
Thr Glu Gly Ile Ile Met Lys Asp Phe Ser His Pro Asn Val Leu
1145 1150 1155
Ser Leu Leu Gly Ile Cys Leu Arg Ser Glu Gly Ser Pro Leu Val
1160 1165 1170
Val Leu Pro Tyr Met Lys His Gly Asp Leu Arg Asn Phe Ile Arg
1175 1180 1185
Asn Glu Thr His Asn Pro Thr Val Lys Asp Leu Ile Gly Phe Gly
1190 1195 1200
Leu Gln Val Ala Lys Gly Met Lys Tyr Leu Ala Ser Lys Lys Phe
1205 1210 1215
Val His Arg Asp Leu Ala Ala Arg Asn Cys Met Leu Asp Glu Lys
1220 1225 1230
Phe Thr Val Lys Val Ala Asp Phe Gly Leu Ala Arg Asp Met Tyr
1235 1240 1245
Asp Lys Glu Tyr Tyr Ser Val His Asn Lys Thr Gly Ala Lys Leu
1250 1255 1260
Pro Val Lys Trp Met Ala Leu Glu Ser Leu Gln Thr Gln Lys Phe
1265 1270 1275
Thr Thr Lys Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu
1280 1285 1290
Leu Met Thr Arg Gly Ala Pro Pro Tyr Pro Asp Val Asn Thr Phe
1295 1300 1305
Asp Ile Thr Val Tyr Leu Leu Gln Gly Arg Arg Leu Leu Gln Pro
1310 1315 1320
Glu Tyr Cys Pro Asp Pro Leu Tyr Glu Val Met Leu Lys Cys Trp
1325 1330 1335
His Pro Lys Ala Glu Met Arg Pro Ser Phe Ser Glu Leu Val Ser
1340 1345 1350
Arg Ile Ser Ala Ile Phe Ser Thr Phe Ile Gly Glu His Tyr Val
1355 1360 1365
His Val Asn Ala Thr Tyr Val Asn Val Lys Cys Val Ala Pro Tyr
1370 1375 1380
Pro Ser Leu Leu Ser Ser Glu Asp Asn Ala Asp Asp Glu Val Asp
1385 1390 1395
Thr Arg Pro Ala Ser Phe Trp Glu Thr Ser
1400 1405
<210> 8
<211> 6710
<212> DNA
<213> Artificial Sequence
<220>
<223> Homo sapiens c-Met mRNA
<400> 8
gcaggtgacc cggaggccct cgccgcccgc ggcgccccga gcgctttgtg agcagatgcg 60
gagccgagtg gagggcgcga gccagatgcg gggcgacagc tgacttgctg agaggaggcg 120
gggaggcgcg gagcgcgcgt gtggtccttg cgccgctgac ttctccactg gttcctgggc 180
accgaaagat aaacctctca taatgaaggc ccccgctgtg cttgcacctg gcatcctcgt 240
gctcctgttt accttggtgc agaggagcaa tggggagtgt aaagaggcac tagcaaagtc 300
cgagatgaat gtgaatatga agtatcagct tcccaacttc accgcggaaa cacccatcca 360
gaatgtcatt ctacatgagc atcacatttt ccttggtgcc actaactaca tttatgtttt 420
aaatgaggaa gaccttcaga aggttgctga gtacaagact gggcctgtgc tggaacaccc 480
agattgtttc ccatgtcagg actgcagcag caaagccaat ttatcaggag gtgtttggaa 540
agataacatc aacatggctc tagttgtcga cacctactat gatgatcaac tcattagctg 600
tggcagcgtc aacagaggga cctgccagcg acatgtcttt ccccacaatc atactgctga 660
catacagtcg gaggttcact gcatattctc cccacagata gaagagccca gccagtgtcc 720
tgactgtgtg gtgagcgccc tgggagccaa agtcctttca tctgtaaagg accggttcat 780
caacttcttt gtaggcaata ccataaattc ttcttatttc ccagatcatc cattgcattc 840
gatatcagtg agaaggctaa aggaaacgaa agatggtttt atgtttttga cggaccagtc 900
ctacattgat gttttacctg agttcagaga ttcttacccc attaagtatg tccatgcctt 960
tgaaagcaac aattttattt acttcttgac ggtccaaagg gaaactctag atgctcagac 1020
ttttcacaca agaataatca ggttctgttc cataaactct ggattgcatt cctacatgga 1080
aatgcctctg gagtgtattc tcacagaaaa gagaaaaaag agatccacaa agaaggaagt 1140
gtttaatata cttcaggctg cgtatgtcag caagcctggg gcccagcttg ctagacaaat 1200
aggagccagc ctgaatgatg acattctttt cggggtgttc gcacaaagca agccagattc 1260
tgccgaacca atggatcgat ctgccatgtg tgcattccct atcaaatatg tcaacgactt 1320
cttcaacaag atcgtcaaca aaaacaatgt gagatgtctc cagcattttt acggacccaa 1380
tcatgagcac tgctttaata ggacacttct gagaaattca tcaggctgtg aagcgcgccg 1440
tgatgaatat cgaacagagt ttaccacagc tttgcagcgc gttgacttat tcatgggtca 1500
attcagcgaa gtcctcttaa catctatatc caccttcatt aaaggagacc tcaccatagc 1560
taatcttggg acatcagagg gtcgcttcat gcaggttgtg gtttctcgat caggaccatc 1620
aacccctcat gtgaattttc tcctggactc ccatccagtg tctccagaag tgattgtgga 1680
gcatacatta aaccaaaatg gctacacact ggttatcact gggaagaaga tcacgaagat 1740
cccattgaat ggcttgggct gcagacattt ccagtcctgc agtcaatgcc tctctgcccc 1800
accctttgtt cagtgtggct ggtgccacga caaatgtgtg cgatcggagg aatgcctgag 1860
cgggacatgg actcaacaga tctgtctgcc tgcaatctac aaggttttcc caaatagtgc 1920
accccttgaa ggagggacaa ggctgaccat atgtggctgg gactttggat ttcggaggaa 1980
taataaattt gatttaaaga aaactagagt tctccttgga aatgagagct gcaccttgac 2040
tttaagtgag agcacgatga atacattgaa atgcacagtt ggtcctgcca tgaataagca 2100
tttcaatatg tccataatta tttcaaatgg ccacgggaca acacaataca gtacattctc 2160
ctatgtggat cctgtaataa caagtatttc gccgaaatac ggtcctatgg ctggtggcac 2220
tttacttact ttaactggaa attacctaaa cagtgggaat tctagacaca tttcaattgg 2280
tggaaaaaca tgtactttaa aaagtgtgtc aaacagtatt cttgaatgtt ataccccagc 2340
ccaaaccatt tcaactgagt ttgctgttaa attgaaaatt gacttagcca accgagagac 2400
aagcatcttc agttaccgtg aagatcccat tgtctatgaa attcatccaa ccaaatcttt 2460
tattagtact tggtggaaag aacctctcaa cattgtcagt tttctatttt gctttgccag 2520
tggtgggagc acaataacag gtgttgggaa aaacctgaat tcagttagtg tcccgagaat 2580
ggtcataaat gtgcatgaag caggaaggaa ctttacagtg gcatgtcaac atcgctctaa 2640
ttcagagata atctgttgta ccactccttc cctgcaacag ctgaatctgc aactccccct 2700
gaaaaccaaa gcctttttca tgttagatgg gatcctttcc aaatactttg atctcattta 2760
tgtacataat cctgtgttta agccttttga aaagccagtg atgatctcaa tgggcaatga 2820
aaatgtactg gaaattaagg gaaatgatat tgaccctgaa gcagttaaag gtgaagtgtt 2880
aaaagttgga aataagagct gtgagaatat acacttacat tctgaagccg ttttatgcac 2940
ggtccccaat gacctgctga aattgaacag cgagctaaat atagagtgga agcaagcaat 3000
ttcttcaacc gtccttggaa aagtaatagt tcaaccagat cagaatttca caggattgat 3060
tgctggtgtt gtctcaatat caacagcact gttattacta cttgggtttt tcctgtggct 3120
gaaaaagaga aagcaaatta aagatctggg cagtgaatta gttcgctacg atgcaagagt 3180
acacactcct catttggata ggcttgtaag tgcccgaagt gtaagcccaa ctacagaaat 3240
ggtttcaaat gaatctgtag actaccgagc tacttttcca gaagatcagt ttcctaattc 3300
atctcagaac ggttcatgcc gacaagtgca gtatcctctg acagacatgt cccccatcct 3360
aactagtggg gactctgata tatccagtcc attactgcaa aatactgtcc acattgacct 3420
cagtgctcta aatccagagc tggtccaggc agtgcagcat gtagtgattg ggcccagtag 3480
cctgattgtg catttcaatg aagtcatagg aagagggcat tttggttgtg tatatcatgg 3540
gactttgttg gacaatgatg gcaagaaaat tcactgtgct gtgaaatcct tgaacagaat 3600
cactgacata ggagaagttt cccaatttct gaccgaggga atcatcatga aagattttag 3660
tcatcccaat gtcctctcgc tcctgggaat ctgcctgcga agtgaagggt ctccgctggt 3720
ggtcctacca tacatgaaac atggagatct tcgaaatttc attcgaaatg agactcataa 3780
tccaactgta aaagatctta ttggctttgg tcttcaagta gccaaaggca tgaaatatct 3840
tgcaagcaaa aagtttgtcc acagagactt ggctgcaaga aactgtatgc tggatgaaaa 3900
attcacagtc aaggttgctg attttggtct tgccagagac atgtatgata aagaatacta 3960
tagtgtacac aacaaaacag gtgcaaagct gccagtgaag tggatggctt tggaaagtct 4020
gcaaactcaa aagtttacca ccaagtcaga tgtgtggtcc tttggcgtgc tcctctggga 4080
gctgatgaca agaggagccc caccttatcc tgacgtaaac acctttgata taactgttta 4140
cttgttgcaa gggagaagac tcctacaacc cgaatactgc ccagacccct tatatgaagt 4200
aatgctaaaa tgctggcacc ctaaagccga aatgcgccca tccttttctg aactggtgtc 4260
ccggatatca gcgatcttct ctactttcat tggggagcac tatgtccatg tgaacgctac 4320
ttatgtgaac gtaaaatgtg tcgctccgta tccttctctg ttgtcatcag aagataacgc 4380
tgatgatgag gtggacacac gaccagcctc cttctgggag acatcatagt gctagtacta 4440
tgtcaaagca acagtccaca ctttgtccaa tggttttttc actgcctgac ctttaaaagg 4500
ccatcgatat tctttgctct tgccaaaatt gcactattat aggacttgta ttgttattta 4560
aattactgga ttctaaggaa tttcttatct gacagagcat cagaaccaga ggcttggtcc 4620
cacaggccac ggaccaatgg cctgcagccg tgacaacact cctgtcatat tggagtccaa 4680
aacttgaatt ctgggttgaa ttttttaaaa atcaggtacc acttgatttc atatgggaaa 4740
ttgaagcagg aaatattgag ggcttcttga tcacagaaaa ctcagaagag atagtaatgc 4800
tcaggacagg agcggcagcc ccagaacagg ccactcattt agaattctag tgtttcaaaa 4860
cacttttgtg tgttgtatgg tcaataacat ttttcattac tgatggtgtc attcacccat 4920
taggtaaaca ttccctttta aatgtttgtt tgttttttga gacaggatct cactctgttg 4980
ccagggctgt agtgcagtgg tgtgatcata gctcactgca acctccacct cccaggctca 5040
agcctcccga atagctggga ctacaggcgc acaccaccat ccccggctaa tttttgtatt 5100
ttttgtagag acggggtttt gccatgttgc caaggctggt ttcaaactcc tggactcaag 5160
aaatccaccc acctcagcct cccaaagtgc taggattaca ggcatgagcc actgcgccca 5220
gcccttataa atttttgtat agacattcct ttggttggaa gaatatttat aggcaataca 5280
gtcaaagttt caaaatagca tcacacaaaa catgtttata aatgaacagg atgtaatgta 5340
catagatgac attaagaaaa tttgtatgaa ataatttagt catcatgaaa tatttagttg 5400
tcatataaaa acccactgtt tgagaatgat gctactctga tctaatgaat gtgaacatgt 5460
agatgttttg tgtgtatttt tttaaatgaa aactcaaaat aagacaagta atttgttgat 5520
aaatattttt aaagataact cagcatgttt gtaaagcagg atacatttta ctaaaaggtt 5580
cattggttcc aatcacagct cataggtaga gcaaagaaag ggtggatgga ttgaaaagat 5640
tagcctctgt ctcggtggca ggttcccacc tcgcaagcaa ttggaaacaa aacttttggg 5700
gagttttatt ttgcattagg gtgtgtttta tgttaagcaa aacatacttt agaaacaaat 5760
gaaaaaggca attgaaaatc ccagctattt cacctagatg gaatagccac cctgagcaga 5820
actttgtgat gcttcattct gtggaatttt gtgcttgcta ctgtatagtg catgtggtgt 5880
aggttactct aactggtttt gtcgacgtaa acatttaaag tgttatattt tttataaaaa 5940
tgtttatttt taatgatatg agaaaaattt tgttaggcca caaaaacact gcactgtgaa 6000
cattttagaa aaggtatgtc agactgggat taatgacagc atgattttca atgactgtaa 6060
attgcgataa ggaaatgtac tgattgccaa tacaccccac cctcattaca tcatcaggac 6120
ttgaagccaa gggttaaccc agcaagctac aaagagggtg tgtcacactg aaactcaata 6180
gttgagtttg gctgttgttg caggaaaatg attataacta aaagctctct gatagtgcag 6240
agacttacca gaagacacaa ggaattgtac tgaagagcta ttacaatcca aatattgccg 6300
tttcataaat gtaataagta atactaattc acagagtatt gtaaatggtg gatgacaaaa 6360
gaaaatctgc tctgtggaaa gaaagaactg tctctaccag ggtcaagagc atgaacgcat 6420
caatagaaag aactcgggga aacatcccat caacaggact acacacttgt atatacattc 6480
ttgagaacac tgcaatgtga aaatcacgtt tgctatttat aaacttgtcc ttagattaat 6540
gtgtctggac agattgtggg agtaagtgat tcttctaaga attagatact tgtcactgcc 6600
tatacctgca gctgaactga atggtacttc gtatgttaat agttgttctg ataaatcatg 6660
caattaaagt aaagtgatgc aacatcttgt aaaaaaaaaa aaaaaaaaaa 6710
Claims (16)
1.一种与人源c-Met蛋白质特异性结合的激动剂抗体或其片段,其中,所述抗体包含抗体轻链可变区(VL)和抗体重链可变区(VH),所述抗体轻链可变区(VL)包括含有如SEQ IDNO:1所示的氨基酸序列的互补决定区(CDR)L1、含有如SEQ ID NO:2所示的氨基酸序列的互补决定区(CDR)L2和含有如SEQ ID NO:3所示的氨基酸序列的互补决定区(CDR)L3,所述抗体重链可变区(VH)包括含有如SEQ ID NO:4所示的氨基酸序列的互补决定区(CDR)H1、含有如SEQ ID NO:5所示的氨基酸序列的互补决定区(CDR)H2和含有如SEQ ID NO:6所示的氨基酸序列的互补决定区(CDR)H3。
2.如权利要求1所述的激动剂抗体或其片段,其中,所述片段为选自双抗体、Fab、Fab'、F(ab)2、F(ab')2、Fv和scFv的片段。
3.一种聚核苷酸,其中,所述聚核苷酸编码如权利要求1所述的抗体或其片段。
4.一种表达载体,其中,所述表达载体包含如权利要求3所述的聚核苷酸。
5.一种细胞,其中,所述细胞通过如权利要求4所述的表达载体进行转化。
6.一种与人c-Met结合的激动剂抗体或其片段的生产方法,其中,包括:在将如权利要求5所述的细胞在表达聚核苷酸的条件下进行培养,生产包含轻链及重链可变区的多肽的步骤;以及从所述细胞或对其进行培养的培养基回收所述多肽的步骤。
7.一种c-Met特异性检测方法,其中,包括使如权利要求1所述的抗体或其片段与试样接触的步骤以及检测所述激动剂抗体或其片段的步骤。
8.一种癌的预防或治疗用药学组合物,其中,包含如权利要求1所述的抗体或其片段作为有效成分。
9.如权利要求8所述的癌的预防或治疗用药学组合物,其中,所述癌选自膀胱癌、乳腺癌、宫颈癌、胆管癌、结肠/直肠癌、大肠癌、子宫内膜癌、食道癌、胃癌、头颈癌、肾癌、肝癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、胆囊癌、前列腺癌、甲状腺癌、骨肉瘤、横纹肌肉瘤、滑膜肉瘤、卡波西肉瘤、平滑肌肉瘤、恶性纤维组织细胞瘤、纤维肉瘤、急性骨髓性白血病、成人T细胞白血病、慢性骨髓性白血病、淋巴瘤、多发性骨髓瘤、胶质母细胞瘤、星形细胞瘤、黑色素瘤、间皮细胞瘤、维尔姆斯瘤、和透明细胞肉瘤(CCS)、腺泡状软组织肉瘤(ASPS)和包括电位相关肾细胞癌的Mit肿瘤。
10.一种干细胞的分化诱导用组合物,其中,包含如权利要求1所述的抗体。
11.如权利要求10所述的诱导用组合物,其中,所述干细胞为来源于脂肪的间充质干细胞。
12.一种干细胞用培养基,其中,包含如权利要求10所述的组合物。
13.一种如权利要求1所述的抗体或其片段在癌的预防或治疗用制剂的制造中的用途。
14.一种癌的治疗方法,其中,包括将有效量的包含如权利要求1所述的抗体或其片段作为有效成分的组合物给予有需要的个体的步骤。
15.一种如权利要求1所述的抗体在干细胞的分化诱导用制剂的制造中的用途。
16.一种干细胞的分化诱导方法,其中,包括将有效量的包含如权利要求1所述的抗体的组合物给予有需要的个体的步骤。
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KR1020180157325A KR102396194B1 (ko) | 2018-12-07 | 2018-12-07 | 항 c-Met 아고니스트 항체 및 이의 용도 |
KR10-2018-0157325 | 2018-12-07 | ||
PCT/KR2019/017242 WO2020117017A1 (ko) | 2018-12-07 | 2019-12-06 | 항 c-met 아고니스트 항체 및 이의 용도 |
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KR102396194B1 (ko) | 2022-05-10 |
EP3892635A4 (en) | 2022-08-17 |
AU2022235579A1 (en) | 2022-10-13 |
US20220220207A1 (en) | 2022-07-14 |
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