CN116635418A - 抗igsf1抗体及其用途 - Google Patents
抗igsf1抗体及其用途 Download PDFInfo
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- CN116635418A CN116635418A CN202180048750.4A CN202180048750A CN116635418A CN 116635418 A CN116635418 A CN 116635418A CN 202180048750 A CN202180048750 A CN 202180048750A CN 116635418 A CN116635418 A CN 116635418A
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Abstract
本发明涉及与IGSF1特异性结合的新型抗体和用于预防或治疗癌症的包含该抗体作为活性成分的药物组合物。具体而言,本发明提供了与IGSF1的C端结合的抗体。根据本发明的抗IGSF1抗体对IGSF1表现出高特异性和高结合能力。当IGSF1过表达的肺癌细胞球体与人外周单个核细胞共培养时,根据本发明的抗IGSF1抗体增加了球体中免疫细胞的浸润。此外,根据本发明的抗IGSF1抗体在移植有IGSF1过表达的人肺癌细胞的人源化小鼠中抑制肿瘤生长,并增加肿瘤组织中细胞因子的表达。通过以上结果,证实了抗IGSF1抗体可通过增加免疫细胞向IGSF1表达增加的肺癌组织中的浸润以及免疫应答来抑制肿瘤生长。因此,抗IGSF1抗体可用作有效治疗IGSF1过表达的癌症的抗癌剂。
Description
技术领域
本发明涉及与IGSF1特异性结合的新型抗体和包含该抗体作为活性成分的用于预防或治疗癌症的药物组合物。
背景技术
尽管长期以来已经深入开展了对癌症的研究,但由于环境污染和不良饮食习惯,癌症的发病率不断上升。全世界每年出现超过1亿癌症患者,世界卫生组织(WHO)将癌症列为主要死因之一。因此,癌症是现代社会中死亡率居首位的重大疾病,尽管迄今已有许多研究,但尚无划时代的治疗方法。
在癌症的治疗中,诸如抗癌剂的化学疗法在一定程度上是有效的,但由于癌症的各种发病机制和对抗癌剂的耐药性,还需要进行许多研究。尽管近几十年来由于诊断和治疗技术的发展,癌症治疗率有所提高,但许多晚期癌症的5年生存率仍保持在5%至50%的范围内。此外,在一些癌症中,尽管进行了各种研究和治疗,但过去20年来的存活率并没有显著变化。
因此,癌症不易通过常规的癌症治疗方案进行治疗,会出现复发和转移到其他部位,因此需要更根本性的治疗方法。因此,人们越来越关注开发通过靶向生物标志物来治疗癌症的物质,这些生物标志物是癌细胞的特征,被确定为癌症的恶化、转移和复发的原因。
另一方面,韩国专利申请公开第2016-0014564号公开了IGSF1(免疫球蛋白超家族成员1)基因可用作预测对MET(间充质-上皮转化因子)抑制剂敏感性的生物标志物。在上述文件中,公开了在治疗癌症患者之前,可以通过使用生物标志物确定每个患者的敏感性来选择具有高治疗效果的抗癌剂。然而,尚未公开IGSF1特异性抗体可用作抗癌剂。
发明内容
技术问题
本发明人为了开发治疗效果高的抗癌剂、特别是用于有效治疗IGSF1过表达的癌症的治疗剂而进行了研究。结果,本发明人开发了与IGSF1的C端特异性结合的抗体,并发现该抗体有效地预防或治疗癌症。
解决方案
为了实现上述目的,在本发明的一个方面,提供一种抗癌剂,该抗癌剂包含与IGSF1的C端特异性结合的抗IGSF1抗体作为活性成分。
在本发明的另一个方面,提供了一种IGSF1特异性抗体或其片段,其包含重链可变区和轻链可变区,该重链可变区包含SEQ ID NO:1的H-CDR1、SEQ ID NO:2的H-CDR2和SEQID NO:3的H-CDR3,并且该轻链可变区包含SEQ ID NO:4的L-CDR1、SEQ ID NO:5的L-CDR2和SEQ ID NO:6的L-CDR3。
在本发明的另一个方面,提供了一种编码IGSF1特异性抗体或其片段的多核苷酸、一种包含该多核苷酸的表达运载体、以及一种导入了该表达运载体的转化细胞。
在本发明的另一个方面,提供了一种产生IGSF1特异性抗体或其片段的方法,该方法包括:培养转化细胞;以及回收抗IGSF1抗体或其片段。
在本发明的另一个方面,提供了一种用于预防或治疗癌症的药物组合物,该药物组合物包含IGSF1特异性抗体或其片段作为活性成分。
在本发明的另一个方面,提供了一种预防或治疗癌症的方法,该方法包括向对象施用IGSF1特异性抗体或其片段。
发明效果
根据本发明的抗IGSF1抗体对IGSF1表现出高特异性和高结合能力。当IGSF1过表达的肺癌细胞球体(lung cancer cell spheroids)与人外周单个核细胞共培养时,根据本发明的抗IGSF1抗体增加了球体中免疫细胞的浸润。此外,根据本发明的抗IGSF1抗体在移植有IGSF1过表达的人肺癌细胞的人源化小鼠中抑制肿瘤生长。此外,该抗体增加了肿瘤组织中存在的细胞毒性T淋巴细胞中细胞因子的表达。通过以上结果,证实了抗IGSF1抗体可通过增加免疫细胞向IGSF1表达增加的肿瘤组织中的浸润以及免疫应答来抑制肿瘤生长。因此,抗IGSF1抗体可用作有效治疗IGSF1过表达的癌症的抗癌剂。
附图说明
图1示出了通过蛋白质印迹和RT-PCR确认IGSF1过表达的人肺癌细胞(NCI-H292IGSF1O/E)和对照(NCI-H292空白(MOCK))中IGSF1的表达水平而获得的结果。
图2示出了当IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)和对照(NCI-H292空白)球体与人外周单个核细胞(PBMC)共培养时,通过确认球体中存在的肿瘤浸润淋巴细胞(TIL)而获得的结果。
图3是示出了为了确认移植了IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)或对照(NCI-H292空白)的小鼠的肿瘤组织中存在肿瘤浸润淋巴细胞,通过流式细胞术分析hCD45+细胞的分布程度而获得的结果的图。
图4示出了通过免疫组织化学染色法确认移植了IGSF1过表达的人肺癌细胞(NCI-H292IGSF1 O/E)或对照(NCI-H292空白)的小鼠的肿瘤组织中的IGSF1表达以及肿瘤浸润淋巴细胞存在而获得的结果。
图5是示出了通过使用ELISA分析对WM-A1-3389抗体与IGSF1抗原的结合亲和力进行分析而获得的结果的图。
图6是示出了通过使用FACS分析对WM-A1-3389抗体与细胞中的IGSF1抗原的结合亲和力进行分析而获得的结果的图。
图7是示出了通过使用FACS分析对过表达IGSF的人肺癌细胞(NCI-H292 IGSF1 O/E)和对照(NCI-H292空白)中WM-A1-3389抗体与在细胞中表达的IGSF1的结合能力进行分析而获得的结果的图。
图8是示出了通过对两种过表达IGSF的人肺癌细胞(NCI-H292 IGSF1 O/E和HEK293EIGSF1 O/E)和对照(NCI-H292空白和HEK293E空白)中WM-A1-3389抗体在经shIGSF1处理的IGSF1敲除(K/D)细胞系中的结合特异性进行分析而获得的结果的图。
图9示出了通过显微镜图像确认当IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1O/E)球体与人外周单个核细胞(PBMC)共培养时,在用IgG或WM-A1-3389抗体处理后球体中存在的肿瘤浸润淋巴细胞(TIL)而获得的结果。
图10是示出了当IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)球体与人外周单个核细胞(PBMC)共培养时,用IgG或WM-A1-3389抗体处理后球体中HMGB1和Hsp90表达的图。
图11是示出了通过测量移植了IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)的小鼠模型中施用了IgG或WM-A1-3389抗体的组的肿瘤大小而获得的结果的图。
图12是示出了移植了IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)的小鼠模型中施用了IgG或WM-A1-3389抗体的小鼠组的每个对象的肿瘤大小的图。
图13示出了通过分析IGSF1在高加索人种(Caucasian)肺癌患者组织中的表达水平而获得的结果。
本发明的最佳实施方式
在本发明的一个方面,提供一种抗癌剂,该抗癌剂包含与IGSF1的C端特异性结合的抗IGSF1抗体作为活性成分。
如本文所用,术语“IGSF1”是由在人和其他哺乳动物物种的X染色体上发现的IGSF1基因编码的膜蛋白。虽然IGSF1在正常细胞中的功能尚不清楚,但已知IGSF1突变会导致IGSF1缺乏综合征或中枢性甲状腺功能减退症等疾病。
可以包括在在本发明中的IGSF1没有限定,只要是哺乳动物的IGSF1即可,但优选可以指人IGSF1。此外,在本发明中,IGSF1蛋白包括所有的天然IGSF1蛋白或其变体,但不限于此。天然IGSF1蛋白一般是指包含天然IGSF1蛋白的氨基酸序列的多肽,并且天然IGSF1蛋白的氨基酸序列一般是指天然存在的IGSF1中发现的氨基酸序列。IGSF1的信息可以从美国国立卫生研究院的Genebank等公知的数据库中获得,例如IGSF1可以具有Genebank登录号NP_001164433.1的氨基酸序列或SEQ ID NO:19的氨基酸序列,但不限于此。
如本文所用,术语“抗IGSF1抗体”是指能够与IGSF1结合的抗体,并且在本发明中可以与“IGSF1特异性抗体”互换使用。特别地,抗IGSF1抗体可以与IGSF1的C端特异性结合。抗体的形式可以包括完整抗体及其抗体片段。
如本文所用,术语“抗癌剂”可包括对癌症表现出预防或治疗作用的任何组合物或药物。
在本发明中,与IGSF1的C端结合的抗IGSF1抗体可以有效消灭IGSF1过表达的癌症。在这种情况下,癌症可以是选自由以下组成的组中的任何一种癌症:胃癌、肝癌、肺癌、非小细胞肺癌、结直肠癌、膀胱癌、骨癌、血液癌、乳腺癌、黑色素瘤、甲状腺癌、甲状旁腺癌、骨髓癌、直肠癌、咽喉癌、喉癌、食道癌、胰腺癌、舌癌、皮肤癌、脑肿瘤、子宫癌、头颈癌、胆囊癌、口腔癌、肛周癌、结肠癌和中枢神经系统肿瘤,但不限于此,只要它是IGSF1过表达的癌症即可。
抗IGSF1抗体
在本发明的另一个方面,提供了一种IGSF1特异性抗体或其片段,其包含重链可变区和轻链可变区,该重链可变区包含SEQ ID NO:1的H-CDR1、SEQ ID NO:2的H-CDR2和SEQID NO:3的H-CDR3,并且该轻链可变区包含SEQ ID NO:4的L-CDR1、SEQ ID NO:5的L-CDR2和SEQ ID NO:6的L-CDR3。
如本文所用,术语“抗体”是指与特定抗原发生免疫反应的免疫球蛋白分子,并且是指特异性识别抗原的蛋白质分子。抗体包括完整抗体、单克隆抗体、多克隆抗体、单结构域抗体、单链抗体、多特异性抗体、人抗体、人源化抗体、嵌合抗体、胞内抗体、scFv、Fab片段、F(ab')片段、通过二硫键连接的Fv(sdFv)以及上述任意者的表位结合片段,但不限于此。
免疫球蛋白的重链和轻链可以各自包括恒定区和可变区。
免疫球蛋白的轻链和重链可变区包括三个称为互补决定区(CDR)的可变区和四个框架区(FR)。CDR主要用于与抗原的表位结合。每条链的CDR从N端开始通常依次称为CDR1、CDR2和CDR3,并通过特异性CDR所在的链进行识别。本发明的IGSF1特异性抗体及其片段可以包括包含SEQ ID NO:1的H-CDR1、SEQ ID NO:2的H-CDR2和SEQ ID NO:3的H-CDR3的重链可变区(VH)。此外,本发明的IGSF1特异性抗体及其片段可以包括包含SEQ ID NO:4的L-CDR1、SEQ ID NO:5的L-CDR2和SEQ ID NO:6的L-CDR3的轻链可变区(VL)。在这种情况下,重链可变区可以具有SEQ ID NO:7的氨基酸序列,轻链可变区可以具有SEQ ID NO:8的氨基酸序列。本文中该抗体可称为WM-A1-3389。
抗体的重链可变区可包含以下或由以下组成:与SEQ ID NO:7的氨基酸序列具有约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或约100%的同一性的氨基酸序列。此外,抗体的轻链可变区可包含以下或由以下组成:与SEQID NO:8的氨基酸序列具有约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或约100%的同一性的氨基酸序列。
免疫球蛋白的重链恒定区(CH)表现出不同的氨基酸组成和序列,因此具有不同类型的抗原性。因此,免疫球蛋白可分为五类并可称为免疫球蛋白同种型,即IgM、IgD、IgG、IgA和IgE。相应的重链分别为μ链、δ链、γ链、α链和ε链。此外,根据铰链区的氨基酸组成和重链二硫键的数目和位置,同一类型的Ig可分为不同的亚型。例如,IgG可以分为IgG1、IgG2、IgG3和IgG4。轻链根据恒定区的不同可分为κ链或λ链。五种IgG中的每一种都可具有κ或λ链。
当本发明的IGSF1特异性抗体包括恒定区时,它可以包括来源自IgG、IgA、IgD、IgE、IgM或其部分杂合体的恒定区。
如本文所用,术语“杂合体”是指在单链免疫球蛋白重链恒定区内存在对应于具有两个或更多个不同来源的免疫球蛋白重链恒定区的序列。例如,由选自由IgG、IgA、IgD、IgE和IgM的CH1、CH2和CH3组成的组中的1至4个结构域组成的结构域的杂交是可能的。
此外,当本发明的IGSF1特异性抗体包含轻链恒定区(LC)时,该轻链恒定区可以来源于λ轻链或κ轻链。
如本文所用,术语“抗体片段”是指具有抗原结合活性的Fab片段、Fab'片段、F(ab')2片段,以及scFv片段(其是与IGSF1结合的Fv片段),并且包含本发明所述抗体的CDR区。Fv片段是抗体的最小片段,包含重链可变区和轻链可变区,没有恒定区,并且具有所有的抗原结合位点。
编码抗IGSF1抗体的多核苷酸
在本发明的另一个方面,提供了编码IGSF1特异性抗体或其片段的多核苷酸。抗IGSF1抗体及其片段如上所述。在这种情况下,多核苷酸的重链区可以包含SEQ ID NO:9的核苷酸序列,轻链区可以包含SEQ ID NO:10的核苷酸序列。
如果多核苷酸编码相同的多肽,一个或多个碱基可通过取代、缺失、插入或其组合来进行突变。当通过化学合成制备多核苷酸序列时,可以使用本领域公知的合成方法,例如文件(Engels and Uhlmann,Angew Chem IntEd Engl.,37:73-127,1988)中描述的方法,并且可以包括三酯法、亚磷酸酯法、亚磷酰胺法和H-磷酸酯法、PCR和其他自引物法、寡核苷酸在固体支撑物上的合成法等。
根据一个实施方式,多核苷酸可以包含分别与SEQ ID NO:9或SEQ ID NO:10的核苷酸序列具有至少约70%、至少约75%、至少约80%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%或至少约100%同一性的核苷酸序列。
多核苷酸还可以包含信号序列或前导序列。如本文所用,术语“信号序列”是指编码引导目标蛋白分泌的信号肽的核酸。信号肽在宿主细胞中被翻译然后被切割。具体地,本发明的信号序列是编码起始蛋白质穿过ER(内质网)膜转运的氨基酸序列的核苷酸。
信号序列的特性在本领域中是众所周知的。此类信号序列通常包含16至30个氨基酸残基,并且可以包含比16至30个氨基酸残基更多或更少的氨基酸残基。常规的信号肽由三个区域组成,即碱性N端区域、中心疏水区域和更具极性的C端区域。中心疏水区域包含4至12个疏水残基,这些疏水残残基导致信号序列在未成熟多肽通过膜脂双层转运期间被固定。
起始后,信号序列在ER腔内被胞内酶(通常称为信号肽酶)切割。在这种情况下,信号序列可以是tPa(组织纤溶酶原激活)、HSV gDs(单纯疱疹病毒糖蛋白D的信号序列)、IgG信号序列或生长激素的分泌信号序列。优选地,可以使用在包括哺乳动物等在内的高等真核细胞中使用的分泌信号序列。
可用于本发明的信号序列包括:抗体轻链信号序列,例如抗体14.18(Gillies etal.,J.Immunol.Methods,1989.125:191-202);抗体重链信号序列,例如MOPC141抗体重链信号序列(Sakano et al.,Nature,1980.286:676-683);和本领域已知的其他信号序列(参见例如Watson et al.,Nucleic Acid Research,1984.12:5145-5164)。
负载有多核苷酸的运载体
在本发明的另一个方面,提供了一种包含编码IGSF1特异性抗体或其片段的多核苷酸的运载体。多核苷酸的重链区可以包含SEQ ID NO:9的核苷酸序列,轻链区可以包含SEQ IDNO:10的核苷酸序列。此外,该多核苷酸可以进一步包括信号序列或前导序列。这里,IGSF1特异性抗体及其片段、以及信号序列如上所述。
在这种情况下,运载体可以是分别含有重链和轻链的多核苷酸的两种运载体,或者是含有这两种多核苷酸的双顺反子运载体。
如本文所用的,术语“运载体”可以被导入宿主细胞以便与宿主细胞的基因组重组并插入宿主细胞的基因组中。此外,运载体被理解为含有可作为游离基因(episome)自主复制的核苷酸序列的核酸工具。运载体包括线性核酸、质粒、噬菌粒、粘粒、RNA运载体、病毒运载体、微型染色体及其类似物。病毒运载体的实例包括但不限于逆转录病毒、腺病毒和腺相关病毒。
具体地,运载体可以包括质粒DNA、噬菌体DNA等;和商业开发的质粒(pUC18、pBAD、pIDTSAMRT-AMP等)、大肠杆菌来源的质粒(pYG601BR322、pBR325、pUC118、pUC119等)、枯草芽孢杆菌(Bacillus subtilis)来源的质粒(pUB110、pTP5等)、酵母来源的质粒(YEp13、YEp24、YCp50等)、噬菌体DNA(Charon4A、Charon21A、EMBL3、EMBL4、λgt10、λgt11、λZAP等)、动物病毒运载体(逆转录病毒、腺病毒、牛痘病毒等)、昆虫病毒运载体(杆状病毒等)等。由于运载体取决于宿主细胞而表现出不同的蛋白质表达水平和修饰等,因此优选选择和使用最适合该目的的宿主细胞。
此外,质粒可以含有选择标记,例如抗生素抗性基因,并且保留该质粒的宿主细胞可以在选择性条件下培养。
如本文所用,术语“基因表达”或目标蛋白的“表达”应理解为指DNA序列的转录、mRNA转录物的翻译和融合蛋白产物或其片段的分泌。有用的表达运载体可以是RcCMV(Invitrogen,Carlsbad)或其变体。表达运载体可以包含用于促进目标基因在哺乳动物细胞中连续转录的人巨细胞病毒(CMV)启动子,以及用于增加转录后RNA的稳定性水平的牛生长激素多腺苷酸化信号序列。
表达抗IGSF1抗体的转化细胞
在本发明的另一个方面,提供了一种导入了表达运载体的转化细胞,该表达运载体包含编码IGSF1特异性抗体或其片段的多核苷酸。IGSF1特异性抗体及其片段如上所述。
如本文所用,术语“转化细胞”是指可以导入重组表达载体的原核细胞和真核细胞。可以通过将运载体导入宿主细胞并对转化运载体来构建转化细胞。此外,本发明的融合蛋白可以通过使运载体中包含的多核苷酸表达来制备。
可以通过各种方法进行转化。只要可以产生本发明的融合蛋白,就没有特别限制。具体地,可以使用例如以下的转化方法:CaCl2沉淀法、在CaCl2沉淀法中通过使用还原剂如二甲亚砜(DMSO)而提高了效率的Hanahan方法、电穿孔、磷酸钙沉淀法、原生质体融合法、使用碳化硅纤维的搅拌法、农杆菌属介导的转化法、使用PEG的转化法、硫酸葡聚糖介导的转化法、脂质体介导的转化法或干燥/抑制介导的转化法。此外,通过以感染为手段,可以使用病毒颗粒将目标对象递送到细胞中。另外,也可以通过基因轰击等将运载体导入宿主细胞中。
此外,只要用于构建转化细胞的宿主细胞也可以产生本发明的融合蛋白,就不对其特别限。具体而言,宿主细胞可以包括但不限于原核细胞、真核细胞和哺乳动物、植物、昆虫、真菌或细菌来源的细胞。作为原核细胞的例子,可以使用大肠杆菌。此外,作为真核细胞的例子,可以使用酵母。此外,对于哺乳动物细胞,可以使用CHO细胞、F2N细胞、CSO细胞、BHK细胞、Bowes黑色素瘤细胞、HeLa细胞、911细胞、AT1080细胞、A549细胞、SP2/0细胞、人淋巴母细胞、NSO细胞、HT-1080细胞、PERC.6细胞、HEK293细胞、HEK293T细胞等,但不限于此。可以使用本领域普通技术人员已知可用作哺乳动物宿主细胞的任何细胞。
如上所述,为了优化抗IGSF1抗体及其片段作为治疗剂的性质或为了任何其他目的,可以通过本领域技术人员已知的方法通过操纵宿主细胞所具有的糖基化相关基因来调节融合蛋白的糖基化模式(例如,唾液酸、岩藻糖基化、糖基化)。
产生抗IGSF1抗体的方法
在本发明的另一个方面,提供了一种产生IGSF1特异性抗体或其片段的方法。在这种情况下,IGSF1特异性抗体及其片段如上所述。
产生融合蛋白的方法可以包括:i)培养转化细胞;和ii)回收本发明的抗IGSF1抗体或其片段。
如本文所用,术语“培养”是指在适当人工控制的环境条件下使微生物生长的方法。
可以使用本领域熟知的方法进行培养转化细胞的方法。具体而言,培养只要可以通过表达本发明的融合蛋白来生产,就没有特别限制。具体地,培养可以分批进行,也可以分批补料或重复分批补料连续进行。
此外,可以通过本领域已知的方法从培养物中回收融合蛋白二聚体。具体地,回收方法只要能够回收所产生的本发明的融合蛋白,就没有特别限定。优选地,回收方法可以是诸如离心、过滤、萃取、喷雾、干燥、蒸发、沉淀、结晶、电泳、分级溶解(例如硫酸铵沉淀)、色谱法(例如离子交换色谱、亲和色谱、疏水色谱和尺寸排除色谱)的方法。
抗IGSF1抗体的用途
在本发明的另一个方面,提供了一种用于预防或治疗癌症的药物组合物,其包含IGSF1抗体或其片段作为活性成分。
在这种情况下,癌症可以是IGSF1过表达的癌症。此外,癌症可以是选自由以下组成的组中的任何一种癌症:胃癌、肝癌、肺癌、非小细胞肺癌、结直肠癌、膀胱癌、骨癌、血液癌、乳腺癌、黑色素瘤、甲状腺癌、甲状旁腺癌、骨髓癌、直肠癌、咽喉癌、喉癌、食道癌、胰腺癌、舌癌、皮肤癌、脑肿瘤、子宫癌、头颈癌、胆囊癌、口腔癌、肛周癌、结肠癌和中枢神经系统肿瘤。
术语“预防”是指通过施用药物组合物抑制癌症发生或延缓癌症发作的任何作用。术语“治疗”是指通过施用药物组合物改善或有益地改变癌症症状的任何作用。
在本发明的用于预防或治疗癌症的药物组合物中,可以根据用途、制剂、组合目的等以任意量(有效量)包含抗IGSF1抗体或其片段,只要抗IGSF1抗体或其片段可表现出抗癌活性。这里,“有效量”是指能够诱导抗癌作用的活性成分的量。这样的有效量可以在本领域普通技术人员的普通能力范围内通过实验确定。本发明的药物组合物可以包含基于组合物的总重量的约0.1wt%至约90wt%、具体地约0.5wt%至约75wt%、更具体地约1wt%至约50wt%的量的抗体作为活性成分。
本发明的药物组合物可以包含根据常规方法组合成制剂的常规且无毒的药学上可接受的载体。
药学上可接受的载体可以是适合递送给患者的任何无毒材料。蒸馏水、酒精、脂肪、蜡和惰性固体可以作为载体包括在内。此外,药物组合物中可包含药学上可接受的佐剂(缓冲剂、分散剂)。
如本文所用,术语“药学上可接受的载体”是指不刺激生物体并且不抑制所施用化合物的生物活性和性质的载体或稀释剂。用于配制为液体溶液的组合物的药学上可接受的载体是无菌和生物相容的,并且可以使用盐水、无菌水、林格氏溶液、缓冲盐水、白蛋白注射液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇以及这些成分中的一种或多种成分的混合物,并且可以根据需要添加其他常规添加剂,例如增甜剂、增溶剂、润湿剂、乳化剂、等渗剂、吸收剂、抗氧化剂、防腐剂、润滑剂、填充剂、缓冲剂和抑菌剂。
本发明的组合物可以制备成用于肠胃外施用(例如,肌肉内、静脉内或皮下注射)的多种制剂。当本发明的药物组合物制备成肠胃外制剂时,可以根据本领域已知的方法将其与合适的载体一起制成注射剂、透皮制剂、鼻腔吸入剂或栓剂形式的制剂。注射用制剂包括无菌水溶液、非水溶液、悬浮剂、乳剂、冻干制剂和栓剂。非水溶剂和悬浮剂包括丙二醇、聚乙二醇、植物油(如橄榄油)和可注射酯(如油酸乙酯)。作为栓剂的基质,可以使用Witepsol、Macrogol、Tween 61、可可脂、月桂酸甘油酯、甘油明胶等。另一方面,注射剂可包括常规添加剂,例如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂。
药物组合物的配制是本领域已知的,具体可以参考[雷明顿药物科学(第19版,1995年)]等。该文件被认为是本说明书的一部分。
本发明的抗体或组合物可以以治疗有效量或药学有效量施用于患者。
如本文所用,术语“施用”是指通过适当的方法将预定物质引入对象中,并且该组合物可以通过任何一般途径施用,只要该组合物可以到达目标组织即可。施用途径可以包括腹膜内施用、静脉内施用、肌肉内施用、皮下施用、皮内施用、局部施用、鼻内施用和直肠内施用,但不限于此。
本文中,“治疗有效量”或“药学有效量”是指有效预防或治疗目标疾病的抗体或组合物的量,并且意味着该量足以以适用于医疗的合理的收益/风险比来治疗疾病,并且不会造成副作用。有效量水平可以根据以下因素来确定:患者的健康状况、疾病的类型和严重程度、药物的活性、对药物的敏感性、施用方法、施用时间、施用途径和排泄率、治疗持续时间、包括组合的或同时使用的药物在内的因素、以及医学领域众所周知的其他因素。
具体地,本发明的组合物中的抗体的有效量可根据患者的年龄、性别和体重而变化,一般每日或隔日可施用每kg体重约0.1mg至约1000mg,或约5mg至约200mg,或可以分成一天1至3次施用。然而,由于有效量可根据施用途径、疾病的严重程度、性别、体重、年龄等而增加或减少,因此本发明的范围不限于此。
术语“对象”是指可以应用(处方)本发明的组合物的对象,并且可以是包括人在内的哺乳动物,例如大鼠、小鼠或家畜。优选地,对象可以是人,但不限于此。
本发明的抗体或包含其的药物组合物可以作为单独的治疗剂施用或者可以与其他治疗剂一起联合施用,并且可以与常规治疗剂一起依次施用或同时施用,并且可以施用一次或多次。在这种情况下,其他治疗剂可以进一步包括任何已知具有抗癌活性的化合物或天然提取物,并且已经验证了用于改善和增强抗癌活性的安全性。
考虑到所有上述因素,重要的是,施用的量在最小量的副作用或没有副作用的情况下可以获得最大效果,这可由本领域普通技术人员容易地确定。
在本发明的另一个方面,提供了IGSF1特异性抗体或其片段在制备用于预防或治疗癌症的药物中的用途,其中抗IGSF1抗体及其片段、癌症、预防和治疗与上述相同。
在本发明的另一个方面,提供了IGSF1特异性抗体或其片段在预防和治疗癌症中的用途,其中抗IGSF1抗体及其片段、癌症、预防和治疗与上述相同。
在本发明的另一个方面,提供了一种预防和治疗癌症的方法,包括向对象施用IGSF1特异性抗体或其片段,其中抗IGSF1抗体及其片段、癌症、施用、治疗和预防与上述相同。
对象可以是哺乳动物,优选人。此外,对象可以是癌症患者或极可能患有癌症的对象。
IGSF1特异性抗体或其片段的施用途径、剂量和施用频率可以根据患者的状况和是否存在副作用而变化,因此可以按各种方式和量将IGSF1特异性抗体或其片段施用至对象。本领域技术人员可以在适当的范围内选择最佳的施用方法、剂量和施用频率。此外,IGSF1特异性抗体或其片段可以与就癌症而言治疗作用已知的其他药物或生理活性物质组合施用,或者可以与其他药物以组合制剂的形式配制。
具体实施方式
下文将通过以下实施例更为详细地描述本发明。然而,以下实施例仅用于说明本发明,并且本发明的范围不受以下实施例的限制。
实施例1.构建抗IGSF1抗体
实施例1.1.IGSF1抗原的表达与纯化
通过PCR方法在Jurkat细胞cDNA文库中仅扩增IGSF1的胞外结构域,然后使用N293F运载体(YBiologics Co.,Ltd.))将人Fc(片段可结晶区)和His-tag在羧基端(C端)融合,以构建IGSF1蛋白表达运载体。用构建的IGSF1表达运载体转染HEK293F细胞,然后在添加了1mM丙戊酸(丙戊酸盐)的培养基中培养6天。然后,使用蛋白A琼脂糖对IGSF1胞外结构域进行初步纯化,然后使用Superdex 200凝胶过滤色谱对IGSF1胞外结构域进行二次纯化,然后用于抗体筛选。
实施例1.2.筛选IGSF1人抗体
IGSF1抗原包被和封闭后,使用制备的人抗体文库噬菌体(YBiologics Co.,Ltd.)进行生物淘选(YBiologics Co.,Ltd.),以仅洗脱与抗原特异性结合的噬菌体。用第一轮生物淘选中扩增的噬菌体进行第二轮和第三轮生物淘选。进行ELISA以确认抗原对通过每轮生物淘选获得的阳性噬菌体抗体池的特异性。此外,证实了抗IGSF1抗体在通过第三轮获得的噬菌体池中富集。在各多噬菌体ELISA的第三轮淘选中,选出上百种具有高结合能力的单克隆,使用它们通过ELISA分析确认它们是否与IGSF1特异性结合,从而获得初步的抗体克隆。对选出的初步的抗体克隆进行DNA核苷酸测序,筛选出99个具有不同核苷酸序列的噬菌体。确认选出的99个阳性噬菌体克隆与抗原IGSF1强结合,但不与其他抗原结合。通过上述方法,使用各种其他抗原筛选对IGSF1抗原显示出特异性的抗体,结果总共可以选出95种类型。
实施例1.3.确认对IGSF1抗原的特异性
通过ELISA方法比较和分析所选抗体对其他抗原(包括IGSF1在内)的特异性。确认了噬菌体克隆是否与作为对照抗原的mFc、hRAGE-Fc、CD58-Fc、ITGA6-Fc等各种类型的非特异性抗原结合。将由此获得的抗体从噬菌体转化为IgG完整运载体,证实了转化的95个克隆的重链序列和轻链序列与噬菌体抗体的序列匹配。在获得的抗体中,选出最佳的抗体,并将其命名为“WM-A1-3389”。WM-A1-3389抗体的CDR序列如下表1所示。
[表1]
实施例1.4.产生M-A1-3389抗体
为了产生WM-A1-3389抗体,将编码重链(SEQ ID NO:21)的多核苷酸(SEQ ID NO:23)装载到N293F运载体(YBiologics Co.,Ltd.)(以下简称为“HC DNA”)上。此外,将编码轻链(SEQ ID NO:22)的多核苷酸(SEQ ID NO:24)装载到N293F运载体(YBiologics Co.,Ltd.)(以下称为LC DNA)中。将运载体转化到细胞中,然后得到WM-A1-3389抗体并进行纯化。通过SDS-PAGE鉴定纯化的蛋白质。
[表2]
实施例2.IGSF1表达与肿瘤浸润淋巴细胞的关系分析
实施例2.1.构建IGSF1过表达细胞系
使IGSF1在人肺癌细胞系NCI-H292或人胚肾细胞系HEK293E细胞中过表达以构建IGSF1过表达细胞系(图1)。在这种情况下,空白(MOCK)是不具有IGSF1表达的对照。
具体地,将包含编码IGSF1的多核苷酸的表达运载体(OriGene Technologies,Inc.,目录号RC209621)转染到人肺癌细胞系NCI-H292细胞或人胚胎肾细胞系HEK293F细胞中。之后,通过在含有G418(新霉素)的培养基中培养这些细胞来选择转染细胞。检查所选克隆的IGSF1表达水平,并选择显示最高IGSF1表达的克隆用于实验。空白是指没有装载编码IGSF1的多核苷酸的空运载体。
实施例2.2.肺癌细胞系球体中IGSF1表达与肿瘤浸润淋巴细胞的关系分析
为了在细胞水平上确认肺癌中IGSF1表达与肿瘤浸润淋巴细胞(TIL)之间的相关性,使用IGSF1过表达的肺癌细胞在球体中对肿瘤浸润淋巴细胞进行识别。
首先,为了构建肺癌细胞球体,将NCI-H292 IGSF1 O/E细胞和NCI-H292空白细胞分别接种在U形底96孔板(Nunc,174925)中至2×104个细胞/孔,并在37℃下在二氧化碳培养箱中培养72小时。通过以1200rpm离心10分钟除去上清液并重悬于PBS中来制备外周血单个核细胞(PBMC)。将18μl DMSO添加到CFSE(羧基荧光素琥珀酰亚胺酯,Invitrogen,C34554)中至5mM的浓度并在PBS中稀释至1mM。每1×106个细胞/ml的制备的外周血单个核细胞添加1μl的1mM CFSE溶液,然后在37℃下在二氧化碳培养箱中染色10分钟。然后,将5倍PBS量的含有FBS(胎牛血清)的培养基添加到含有染色的外周血单个核细胞(PBMC)的溶液中。之后,反应在37℃下在二氧化碳培养箱中进行5分钟。通过以1200rpm离心10分钟除去上清液,然后将染色的外周血单个核细胞重悬于培养基中以制备实验用外周血单个核细胞。
然后,将形成的球体转移到超低吸附96孔板(Corning,CLS3474)中的两孔中,然后接种用CFSE染色的外周血单个核细胞至1×105个细胞/孔,在37℃下在二氧化碳培养箱中共培养24小时。在荧光显微镜下观察肿瘤浸润淋巴细胞(TIL)。在这种情况下,NCI-H292空白细胞用作IGSF1过表达细胞的对照。
结果证实,与对照(NCI-H292空白)相比,肿瘤浸润淋巴细胞(TIL)在IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)球体中减少(图2)。
实施例2.3.移植了肺癌细胞系的人源化小鼠的肿瘤组织中IGSF1表达与肿瘤浸润淋巴细胞的关系分析
为了在体内水平上确认肺癌中IGSF1的表达与肿瘤浸润淋巴细胞(TIL)之间的相关性,在移植了IGSF1过表达的肺癌细胞系的人源化小鼠的肿瘤组织中对肿瘤浸润淋巴细胞进行识别。
具体地,将NCI-H292 IGSF1 O/E细胞(IGSF1过表达人肺癌细胞系)或NCI-H292空白细胞(对照)以每只动物5×106个细胞移植到移植了人外周血单个核细胞(PBMC)的NSG小鼠(SID(NSGA)小鼠,F)中,然后在第17天收集小鼠的肿瘤切片。
从各收集的肿瘤中分离人外周血单个核细胞,通过FACS分析,并通过对肿瘤组织进行免疫组织化学染色来证实肿瘤组织中IGSF1的表达水平和肿瘤浸润淋巴细胞。为了识别浸润肿瘤的人外周血单个核细胞,首先将肿瘤组织用胶原酶B(Roche,cat.#11088815001)处理,并在37℃下反应2小时或更长时间以使肿瘤组织解离。当肿瘤组织完全解离成细胞时,通过用1ml移液器进行吹打将该细胞分离成单细胞。
将分离的单细胞转移到50ml管(SPL,cat.#50050)中,然后用20ml PBS洗涤。之后,通过以1200rpm离心3分钟去除上清液。使剩余的细胞与DNase I(Roche,cat.#11284932001)在37℃下反应20分钟。之后,加入20ml PBS,并通过以1200rpm离心3分钟去除上清液。剩余的细胞用0.25%Trysin/EDTA(GIBCO,cat.#15400-054)处理。将细胞充分混合,然后将细胞过滤器(SPL,cat.#93070)置于新的50ml试管上,过滤细胞。将20ml PBS添加到含有过滤后的细胞的试管中并均匀混合。之后,通过以1200rpm离心3分钟除去上清液,然后将1ml染色缓冲液(BD,cat.#554656)添加到剩余的细胞中并洗涤。
为了阻断分离的细胞的非特异性抗体反应,添加2μg人Fc阻断剂(BD,目录号#564219)并在室温下反应10分钟。反应后,添加抗人CD45(BD,cat.#564357)抗体并在4℃下遮光反应30分钟。反应后,添加1ml染色缓冲液并洗涤。之后,通过1,200rpm离心3分钟除去上清液,并收集细胞,然后添加200μl染色缓冲液添加并通过BD LSRFortessaTM流式细胞仪进行分析(图3)。
此外,通过免疫组织化学染色法确定了肿瘤中表达的肿瘤淋巴细胞的分布和IGSF1的表达。具体地,将NCI-H292 IGSF1 O/E细胞(人肺癌细胞系)或NCI-H292空白细胞以每只动物5×106个细胞移植到移植了人外周血单个核细胞(PBMC)的NSG小鼠(SID(NSGA)小鼠,F)中。之后,在第17天,将从小鼠收集的肿瘤组织切片脱蜡并再水化。
然后,将其浸泡在目标修复缓冲液中并在微波炉中加热15分钟进行热诱导表位修复。之后,将其置于目标修复缓冲液中30分钟,然后用Tris缓冲盐水-0.05%Tween 20(TBS-T)洗涤3次,并用封闭液封闭60分钟。一抗为抗IGSF1抗体(Santacruz,sc-393786),按1:100稀释,使其在4℃下结合过夜。第二天,用TBS-T洗涤3次,并与内源性过氧化物酶封闭试剂(Cell Marque,925B)在室温下反应5分钟,然后使二抗(Vector,PK-6101PK-6102)在室温下结合60分钟。用TBS-T洗涤3次,然后与亲和素-生物素反应60分钟。进行最终的DAB染色(Vector,SK-4100),然后通过脱水过程完成组织染色,并在显微镜下观察染色的组织切片。
结果证实,与对照(NCI-H292空白)相比,人免疫细胞hCD45+细胞在移植了IGSF1过表达人肺癌细胞(NCI-H292 IGSF1 O/E)的人源化小鼠的肿瘤组织中减少(图4)。
实施例3.抗IGSF1抗体的结合亲和力分析
实施例3.1.抗IGSF1抗体体外结合亲和力分析
使用ELISA分析在体外证实WM-A1-3389抗体与IGSF1抗原的结合亲和力。
具体地,用100ng IGSF1处理以包被96孔板,然后添加200μl 4%脱脂牛奶(PBST)并在室温下封闭1小时。将WM-A1-3389抗体在4%脱脂牛奶(PBST)中每次以1/3连续稀释12个浓度,处理,然后在室温下反应2小时。反应完成后,用PBST洗涤孔,用人IgGFc-HRP抗体处理,并在室温下反应1小时。之后,用PBST洗涤孔,然后添加TMB过氧化物酶底物以确认显色程度,然后在450nm处测量吸光度,并对结果进行比较和分析。
结果,WM-A1-3389抗体的Kd值约为2.2×10-11,表明WM-A1-3389抗体对IGSF1抗原具有高结合亲和力(图5)。
实施例3.2.细胞中抗IGSF1抗体与IGSF1的结合亲和力分析
为了在细胞水平上确认WM-A1-3389抗体与IGSF1抗原的结合亲和力,使用IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)和对照(NCI-H292空白)来证实WM-A1-3389抗体与IGSF1的结合能力。
具体地,去除NCI-H292 IGSF1 O/E细胞和NCI-H292空白细胞的培养基,用PBS洗涤一次,然后用2ml 0.25%胰蛋白酶-EDTA处理,并分离细胞。分离的细胞用8ml含有2%FBS和0.05%叠氮化钠的PBS(以下称为FACS缓冲液)稀释,然后以1200rpm离心1分钟以除去上清液。然后,将细胞重悬于FACS缓冲液中至1×105个细胞/ml。之后,将各1ml细胞分配到FACS管中,并通过以1200rpm离心1分钟除去上清液。
通过涡旋释放剩余在FACS管中的沉淀,并将WM-A1-3389抗体以1/4稀释至每200μlFACS缓冲液中20μM至0μM,加入共12个浓度,然后在4℃下反应30分钟。反应完成后,每管中加入1ml FACS缓冲液,以1200rpm离心1分钟以除去上清液。这个过程总共进行了两次。通过涡旋释放剩余在FACS管中的沉淀,每200μl FACS缓冲液中添加5μg/ml FITC标记的山羊抗人IgG抗体(Invitrogen,62-8411),并在4℃下遮光反应30分钟。反应完成后,每管中加入1ml FACS缓冲液,以1200rpm离心1分钟以除去上清液。这个过程总共进行了两次。
最后,去除上清液,然后将剩余的沉淀重悬于200μl FACS缓冲液中并通过FACS进行分析。对于FACS分析,使用BD LSRFortessaTM流式细胞仪测量各细胞中标记的FITC荧光值,然后使用FlowJo软件对结果进行分析,并使用sigma绘图程序计算EC50值。在这种情况下,使用NCI-H292空白细胞作为IGSF1过表达细胞的对照。
结果,在对照(NCI-H292空白)中证实,无论WA-A1-3389抗体的浓度如何,都不存在结合。另一方面,在IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)中,WM-A1-3389抗体的EC50值确认为约69nM(图6)。
实施例4.细胞中抗IGSF1抗体对IGSF1抗原的抗原特异性分析
为了在细胞水平上分析WM-A1-3389抗体对IGSF1抗原的抗原特异性结合能力(目标选择性),使用IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)确认WM-A1-3389抗体与细胞中表达的IGSF1的结合。
具体地,去除了IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)及其对照(NCI-H292空白)的培养基,用PBS洗涤一次,然后用2ml 0.25%胰蛋白酶-EDTA处理,并分离细胞。分离的细胞用8ml含有2%FBS和0.05%叠氮化钠的PBS(以下称为FACS缓冲液)稀释,然后以1200rpm离心1分钟以除去上清液。然后,将细胞重悬于FACS缓冲液中至1×105个细胞/ml。之后,将各1ml细胞分配到FACS管中,并通过以1200rpm离心1分钟除去上清液。
通过涡旋释放剩余在FACS管中的沉淀,每200μl FACS缓冲液中加入0.4μg人IgG同种型抗体(Bio X细胞,BE0297)或WM-A1-3389抗体,然后在4℃下反应30分钟。反应完成后,每管中加入1ml FACS缓冲液,以1200rpm离心1分钟以除去上清液。这个过程总共进行了两次。通过涡旋释放剩余在FACS管中的细胞沉淀,每200μl FACS缓冲液中添加0.4μg/ml FITC标记的山羊抗人IgG抗体(Invitrogen,62-8411),并在4℃下遮光反应30分钟。
反应完成后,每管中加入1ml FACS缓冲液,以1200rpm离心1分钟以除去上清液。这个过程总共进行了两次。最后,去除上清液,然后将剩余的沉淀重悬于200μl FACS缓冲液中并通过FACS进行分析。对于FACS分析,使用BD LSRFortessaTM流式细胞仪测量各细胞中标记的FITC荧光值,并使用FlowJo软件对结果进行分析。在这种情况下,使用NCI-H292空白细胞作为IGSF1过表达细胞的对照,并使用人IgG同种型作为WM-A1-3389抗体的对照。
结果,与IgG同种型处理组相比,WM-A1-3389抗体处理组在对照(NCI-H292空白)中显示出约2.6%的结合能力,在IGSF1过表达细胞(NCI-H292 IGSF1 O/E)中显示出约78.9%的结合能力(图7)。
之后,用与mRNA编码IGSF1的mRNA特异性结合的shRNA(以下简称shIGSF1)转染IGSF1过表达的NCI-H292 IGSF1 O/E细胞和HEK293E IGSF1 O/E细胞,以减少IGSF1的表达(以下简称IGSF1 K/D细胞),然后测定WM-A1-3389抗体与细胞中IGSF1抗原的结合能力。在这种情况下,使用不具有shIGSF1的乱序RNA(以下简称sc细胞)作为转染对照(IGSF1 K/D),而人IgG同种型用作WM-A1-3389抗体的对照。基于sc细胞中的结合能力,相对于在IGSF1 K/D细胞中的结合能力,比较WM-A1-3389抗体的抗原特异性。此外,NCI-H292空白细胞和HEK293E空白细胞分别用作IGSF1过表达细胞的对照。
具体地,去除NCI-H292(IGSF1 O/E和空白)和HEK293E(IGSF1 O/E和空白)细胞系的培养基并用PBS洗涤一次,然后分别用2ml 0.25%胰蛋白酶-EDTA处理NCI-H292细胞,用2ml 0.05%胰蛋白酶-EDTA处理HEK293E细胞,并分离细胞。分离的细胞用8ml培养基稀释,然后以800rpm离心3分钟以去除上清液。将剩余的细胞分别重悬至浓度为1×105个细胞/ml(NCI-H292)和0.5×105个细胞/ml(HEK293E),然后将3ml细胞添加到60mm培养板中,在37℃下在培养细胞培养箱中培养一天。第二天,进行shIGSF1转染。添加200μl jet PRIME缓冲液和10nM shIGSF1并在1.5ml管中混合,然后添加4μl jet PRIME试剂,混合,并在室温下反应10分钟。之后,更换前一天制备的细胞培养基,然后向每个细胞中添加200μl转染混合物,并在细胞培养箱中反应24小时。24小时后,更换新鲜培养基并继续培养24小时。
对于转染的细胞,去除培养基,并以与上述相同的方式进行FACS分析。
结果,与人IgG同种型处理组相比,在sc细胞系中证实了WM-A1-3389抗体的结合。此外,当根据结合能力减少IGSF1表达时(IGSF1 K/D细胞),证实了WM-A1-3389抗体的结合能力一起减少(图8)。
实施例5.抗IGSF1抗体在肺癌细胞球体中的免疫抗癌功效分析
为了在细胞水平上分析WM-A1-3389抗体的免疫抗癌功效,将肺癌细胞球体和外周血单个核细胞(PBMC)共培养以确认肿瘤浸润淋巴细胞(TIL)和免疫原性细胞的死亡。
以与实施例2.2中相同的方式进行肺癌细胞球体和外周血单个核细胞的共培养。
将共培养的细胞和上清液收集在试管中,以1200rpm离心2分钟除去上清液。通过用500μl 0.25%胰蛋白酶-EDTA进行处理使细胞沉淀成为单细胞,然后用2ml含2%FBS和0.05%NaN3的PBS(以下简称FACS缓冲液)稀释,然后以1200rpm离心3分钟以除去上清液。将剩余的细胞沉淀重悬于200μl FACS缓冲液中,然后添加抗HMGB1抗体(Biolegend,651408)和抗Hsp90抗体(Enzo Life Science,ADI-SPA-830PE-D),在4℃下染色30分钟。
每管中添加1ml FACS缓冲液,以1200rpm离心2分钟以除去上清液。这个过程总共重复了两次。之后,使用BD LSRFortessaTM流式细胞仪进行分析。使用FlowJo软件对FACS分析的结果进行分析。此外,在荧光显微镜下观察肿瘤浸润淋巴细胞(TIL)。在这种情况下,人IgG同种型用作WM-A1-3389抗体的对照。
结果证实,在IGSF1过表达的肺癌细胞(NCI-H292 IGSF1 O/E)球体中,与对照相比,WM-A1-3389抗体处理组中的肿瘤浸润淋巴细胞(TIL)增加(图9)。此外,已证实,在IGSF1过表达的肺癌细胞球体中,与对照相比,WM-A1-3389抗体处理组中的免疫原性细胞死亡(ICD)也增加了(图10)。
实施例6.抗IGSF1抗体在同种异体移植小鼠模型中的肿瘤生长抑制功效分析
为了在动物水平上证实WM-A1-3389抗体的抗癌功效,用IGSF1过表达的人肺癌细胞(NCI-H292 IGSF1 O/E)对外周血单个核细胞人源化模型(PBMC人源化模型)小鼠进行移植,然后对WM-A1-3389抗体的肿瘤生长抑制功效进行了评估。
具体地,购买6周龄雌性外周血单个核细胞人源化小鼠(Gem biosciences),使小鼠适应1周,然后将IGSF1过表达的人肺癌细胞NCI-H292 IGSF1 O/E(5×106个细胞/每只)在PBS和基质胶(Matrigel)中稀释,并在小鼠右背侧皮下注射(200μl)。当肿瘤大小达到约120mm3,分别以10mg/kg的剂量腹膜内注射IgG同型(对照)或WM-A1-3389抗体。每3天进行一次施用,持续4周,并且每周测量两次小鼠的肿瘤大小和体重。施用第22天时,获得来自附加组(Satellite group)小鼠的血液和肿瘤,并进行FACS分析。施用完成后,对实验动物实施安乐死,提取肿瘤,并测量重量。使用人IgG同种型作为WM-A1-3389抗体的对照。
结果,与对照相比,WM-A1-3389抗体施用组表现出高肿瘤生长抑制功效,表现出的肿瘤抑制率(TGI)约为64.5%(图11)。此外,还确认了甚至个别对象的肿瘤生长受到抑制(图12)。
实施例7.高加索人种肺癌患者组织中IGSF1表达的分析
免疫组织化学染色法证实高加索人种肺癌患者组织中IGSF1的表达。
具体地,将人非小细胞肺癌患者的组织切片脱蜡并再水化,然后浸泡在目标修复缓冲液中,然后在微波炉中加热15分钟进行热诱导表位修复。之后,在目标修复缓冲液中再反应30分钟。之后,将其用含有0.05%Tween 20的Tris缓冲盐水(TBS-T)洗涤3次,然后用封闭液封闭60分钟。一抗为抗IGSF1抗体(Santacruz,sc-393786),按1:100稀释,使其在4℃下结合过夜。次日,用TBS-T洗涤组织切片3次,然后与内源性过氧化物酶封闭试剂(CellMarque,925B)反应5分钟。然后,使二抗(Vector,PK-6101PK-6102)在室温下结合60分钟。然后用TBS-T洗涤3次,用亲和素-生物素处理,并反应60分钟,然后进行DAB染色(Vector,SK-4100)。在显微镜下观察染色的组织切片(图13)。
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Glu Thr Asn Phe Pro Leu Ala Pro Trp Lys Asn Leu Thr Leu Trp Cys
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His Ser Trp Glu Glu Met Ala Val Ser Glu Pro Ser Glu Ala Leu Glu
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Thr Ile Arg Gly Gln Glu Leu Gln Leu Arg Cys Lys Gly Trp Leu Ala
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Gly Met Gly Phe Ala Leu Tyr Lys Glu Gly Glu Gln Glu Pro Val Gln
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Gln Leu Gly Ala Val Gly Arg Glu Ala Phe Phe Thr Ile Gln Arg Met
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Glu Asp Lys Asp Glu Gly Asn Tyr Ser Cys Arg Thr His Thr Glu Lys
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Arg Pro Phe Lys Trp Ser Glu Pro Ser Glu Pro Leu Glu Leu Val Ile
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His Met Ser Phe Ile Leu Tyr Lys Asp Gly Ser Glu Ile Ala Ser Ser
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Asp Arg Ser Trp Ala Ser Pro Gly Ala Ser Ala Ala His Phe Leu Ile
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Ile Ser Val Gly Ile Gly Asp Gly Gly Asn Tyr Ser Cys Arg Tyr Tyr
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Asp Phe Ser Ile Trp Ser Glu Pro Ser Asp Pro Val Glu Leu Val Val
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Thr Glu Phe Tyr Pro Lys Pro Thr Leu Leu Ala Gln Pro Gly Pro Val
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Val Phe Pro Gly Lys Ser Val Ile Leu Arg Cys Gln Gly Thr Phe Gln
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Phe Arg Ser Val Ser Gly Asn Ser Ala Asp Phe Leu Leu His Thr Val
340 345 350
Gly Ala Glu Asp Ser Gly Asn Tyr Ser Cys Ile Tyr Tyr Glu Thr Thr
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Met Ser Asn Arg Gly Ser Tyr Leu Ser Met Pro Leu Met Ile Trp Val
370 375 380
Thr Asp Thr Phe Pro Lys Pro Trp Leu Phe Ala Glu Pro Ser Ser Val
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Val Pro Met Gly Gln Asn Val Thr Leu Trp Cys Arg Gly Pro Val His
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Leu Trp Gly Ser Thr Ser Asn Asp Gly Ala Phe Pro Ile Thr Asn Ile
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Ser Gly Thr Ser Met Gly Arg Tyr Ser Cys Cys Tyr His Pro Asp Trp
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Thr Ser Ser Ile Lys Ile Gln Pro Ser Asn Thr Leu Glu Leu Leu Val
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Val Ala Pro Gly Glu Asn Met Thr Leu Gln Cys Gln Gly Glu Leu Pro
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Asp Ser Thr Phe Val Leu Leu Lys Glu Gly Ala Gln Glu Pro Leu Glu
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Gln Gln Arg Pro Ser Gly Tyr Arg Ala Asp Phe Trp Met Pro Ala Val
530 535 540
Arg Gly Glu Asp Ser Gly Ile Tyr Ser Cys Val Tyr Tyr Leu Asp Ser
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Thr Pro Phe Ala Ala Ser Asn His Ser Asp Ser Leu Glu Ile Trp Val
565 570 575
Thr Asp Lys Pro Pro Lys Pro Ser Leu Ser Ala Trp Pro Ser Thr Met
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Phe Lys Leu Gly Lys Asp Ile Thr Leu Gln Cys Arg Gly Pro Leu Pro
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Gly Val Glu Phe Val Leu Glu His Asp Gly Glu Glu Ala Pro Gln Gln
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Phe Ser Glu Asp Gly Asp Phe Val Ile Asn Asn Val Glu Gly Lys Gly
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Ile Gly Asn Tyr Ser Cys Ser Tyr Arg Leu Gln Ala Tyr Pro Asp Ile
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Trp Ser Glu Pro Ser Asp Pro Leu Glu Leu Val Gly Ala Ala Gly Pro
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Val Ala Gln Glu Cys Thr Val Gly Asn Ile Val Arg Ser Ser Leu Ile
675 680 685
Val Val Val Val Val Ala Leu Gly Val Val Leu Ala Ile Glu Trp Lys
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Gln Thr Ile Ala Leu Glu Glu Cys Asn Gln Glu Gly Glu Pro Gly Thr
725 730 735
Pro Ala Asn Ser Pro Ser Ser Thr Ser Gln Arg Ile Ser Val Glu Leu
740 745 750
Pro Val Pro Ile
755
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Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Ala Asp
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Val His Ser Gln His His His His His His His His Glu Glu Thr Glu
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Ile Val Met Pro Thr Pro Lys Pro Glu Leu Trp Ala Glu Thr Asn Phe
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Pro Leu Ala Pro Trp Lys Asn Leu Thr Leu Trp Cys Arg Ser Pro Ser
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Gly Ser Thr Lys Glu Phe Val Leu Leu Lys Asp Gly Thr Gly Trp Ile
65 70 75 80
Ala Thr Arg Pro Ala Ser Glu Gln Val Arg Ala Ala Phe Pro Leu Gly
85 90 95
Ala Leu Thr Gln Ser His Thr Gly Ser Tyr His Cys His Ser Trp Glu
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Glu Met Ala Val Ser Glu Pro Ser Glu Ala Leu Glu Leu Val Gly Thr
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Gln Glu Leu Gln Leu Arg Cys Lys Gly Trp Leu Ala Gly Met Gly Phe
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Ala Leu Tyr Lys Glu Gly Glu Gln Glu Pro Val Gln Gln Leu Gly Ala
165 170 175
Val Gly Arg Glu Ala Phe Phe Thr Ile Gln Arg Met Glu Asp Lys Asp
180 185 190
Glu Gly Asn Tyr Ser Cys Arg Thr His Thr Glu Lys Arg Pro Phe Lys
195 200 205
Trp Ser Glu Pro Ser Glu Pro Leu Glu Leu Val Ile Lys Glu Met Tyr
210 215 220
Pro Lys Pro Phe Phe Lys Thr Trp Ala Ser Pro Val Val Thr Pro Gly
225 230 235 240
Ala Arg Val Thr Phe Asn Cys Ser Thr Pro His Gln His Met Ser Phe
245 250 255
Ile Leu Tyr Lys Asp Gly Ser Glu Ile Ala Ser Ser Asp Arg Ser Trp
260 265 270
Ala Ser Pro Gly Ala Ser Ala Ala His Phe Leu Ile Ile Ser Val Gly
275 280 285
Ile Gly Asp Gly Gly Asn Tyr Ser Cys Arg Tyr Tyr Asp Phe Ser Ile
290 295 300
Trp Ser Glu Pro Ser Asp Pro Val Glu Leu Val Val Thr Glu Phe Tyr
305 310 315 320
Pro Lys Pro Thr Leu Leu Ala Gln Pro Gly Pro Val Val Phe Pro Gly
325 330 335
Lys Ser Val Ile Leu Arg Cys Gln Gly Thr Phe Gln Gly Met Arg Phe
340 345 350
Ala Leu Leu Gln Glu Gly Ala His Val Pro Leu Gln Phe Arg Ser Val
355 360 365
Ser Gly Asn Ser Ala Asp Phe Leu Leu His Thr Val Gly Ala Glu Asp
370 375 380
Ser Gly Asn Tyr Ser Cys Ile Tyr Tyr Glu Thr Thr Met Ser Asn Arg
385 390 395 400
Gly Ser Tyr Leu Ser Met Pro Leu Met Ile Trp Val Thr Asp Thr Phe
405 410 415
Pro Lys Pro Trp Leu Phe Ala Glu Pro Ser Ser Val Val Pro Met Gly
420 425 430
Gln Asn Val Thr Leu Trp Cys Arg Gly Pro Val His Gly Val Gly Tyr
435 440 445
Ile Leu His Lys Glu Gly Glu Ala Thr Ser Met Gln Leu Trp Gly Ser
450 455 460
Thr Ser Asn Asp Gly Ala Phe Pro Ile Thr Asn Ile Ser Gly Thr Ser
465 470 475 480
Met Gly Arg Tyr Ser Cys Cys Tyr His Pro Asp Trp Thr Ser Ser Ile
485 490 495
Lys Ile Gln Pro Ser Asn Thr Leu Glu Leu Leu Val Thr Gly Leu Leu
500 505 510
Pro Lys Pro Ser Leu Leu Ala Gln Pro Gly Pro Met Val Ala Pro Gly
515 520 525
Glu Asn Met Thr Leu Gln Cys Gln Gly Glu Leu Pro Asp Ser Thr Phe
530 535 540
Val Leu Leu Lys Glu Gly Ala Gln Glu Pro Leu Glu Gln Gln Arg Pro
545 550 555 560
Ser Gly Tyr Arg Ala Asp Phe Trp Met Pro Ala Val Arg Gly Glu Asp
565 570 575
Ser Gly Ile Tyr Ser Cys Val Tyr Tyr Leu Asp Ser Thr Pro Phe Ala
580 585 590
Ala Ser Asn His Ser Asp Ser Leu Glu Ile Trp Val Thr Asp Lys Pro
595 600 605
Pro Lys Pro Ser Leu Ser Ala Trp Pro Ser Thr Met Phe Lys Leu Gly
610 615 620
Lys Asp Ile Thr Leu Gln Cys Arg Gly Pro Leu Pro Gly Val Glu Phe
625 630 635 640
Val Leu Glu His Asp Gly Glu Glu Ala Pro Gln Gln Phe Ser Glu Asp
645 650 655
Gly Asp Phe Val Ile Asn Asn Val Glu Gly Lys Gly Ile Gly Asn Tyr
660 665 670
Ser Cys Ser Tyr Arg Leu Gln Ala Tyr Pro Asp Ile Trp Ser Glu Pro
675 680 685
Ser Asp Pro Leu Glu Leu Val Gly Ala Ala Gly Pro Val Ala Gln Glu
690 695 700
Cys Thr Val Gly Asn Ile Val Arg Ser Ser Leu Ile Val Val Val Val
705 710 715 720
Val Ala Leu Gly Val Val Leu Ala Ile Glu Trp Lys Lys Trp Pro Arg
725 730 735
Leu Arg Thr Arg Gly Ser Glu Thr Asp Gly Arg Asp Gln Thr Ile Ala
740 745 750
Leu Glu Glu Cys Asn Gln Glu Gly Glu Pro Gly Thr Pro Ala Asn Ser
755 760 765
Pro Ser Ser Thr Ser Gln Arg Ile Ser Val Glu Leu Pro Val Pro Ile
770 775 780
<210> 21
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> WM-A1-3389的重链
<400> 21
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Phe Val Gly Thr Val Asp Tyr Ala Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Gly Gly Arg Ser Tyr Phe Asp Ser Trp Gly Pro Gly Ile
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 22
<211> 217
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> WM-A1-3389的轻链
<400> 22
Gln Phe Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Asp Val Ile Ile Ser Cys Ser Gly Asn Thr Ser Asn Ile Gly Ser Asn
20 25 30
Leu Val Ser Trp Phe Gln Gln Phe Pro Glu Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn His Lys Arg Pro Ser Gly Ile Ser Asp Arg Phe Ser
50 55 60
Gly Thr Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Val Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 23
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码WM-A1-3389的重链的多核苷酸
<400> 23
caagttcagc tggttcagtc tggcgccgaa gtgaaaagac ctggcagcag cgtgaaggtg 60
tcctgcaaag cttctggcgg caccttcagc acctacgcca tctcttgggt tcgacaggcc 120
cctggacaag gcctggaatg gatgggcaga atcatcccct ttgtgggcac cgtggactac 180
gcccagaaat tccaggacag agtgaccatc accgccgaca agagcaccaa caccgcctac 240
atggaactga gcagcctgag aagcgaggac accgccgtgt actactgcgt ccgagatggc 300
ggcagaagct acttcgattc ttggggccct ggcatcctgg tcacagtgtc tagcgcctct 360
acaaagggcc ccagcgtttt cccactggct cctagcagca agagcacaag cggaggaaca 420
gccgctctgg gctgtctggt caaggactac tttcccgagc ctgtgaccgt gtcttggaac 480
tctggcgctc tgacaagcgg cgtgcacaca tttccagccg tgctgcaaag cagcggcctg 540
tactctctga gcagcgtcgt gacagtgcca agcagctctc tgggcaccca gacctacatc 600
tgcaatgtga accacaagcc tagcaacacc aaggtggaca agaaggtgga acccaagtcc 660
tgcgacaaga cccacacctg tcctccatgt cctgctccag aactgctcgg cggaccttcc 720
gtgttcctgt ttcctccaaa gcctaaggac accctgatga tcagcagaac ccctgaagtg 780
acctgcgtgg tggtggatgt gtcccacgag gacccagaag tgaagttcaa ttggtacgtg 840
gacggcgtgg aagtgcacaa cgccaagacc aagcctagag aggaacagta caactccacc 900
tacagagtgg tgtccgtgct gacagtgctg caccaggatt ggctgaacgg caaagagtac 960
aagtgcaagg tgtccaacaa ggccctgcct gctcctatcg agaaaaccat cagcaaggcc 1020
aagggccagc ctagggaacc ccaggtttac acactgcctc caagccggga agagatgaca 1080
aagaaccagg tgtccctgac ctgcctcgtg aagggcttct acccttccga tatcgccgtg 1140
gaatgggaga gcaatggcca gccagagaac aactacaaga caacccctcc tgtgctggac 1200
agcgacggct cattcttcct gtacagcaag ctgaccgtgg acaagtccag atggcagcag 1260
ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacacagaag 1320
tccctgtctc tgagccccgg caaa 1344
<210> 24
<211> 651
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码WM-A1-3389的轻链的多核苷酸
<400> 24
cagtttgttc tgacacagcc tccaagcgtg tccgccgctc ctggacagga tgtgatcatc 60
agctgcagcg gcaacaccag caacatcggc agcaatctgg tgtcctggtt ccagcagttc 120
cccgagacag cccctaagct gctgatctac gacaaccaca agcggcccag cggcatcagc 180
gatagattca gcggcacaaa gagcggcacc agcgcttctc tggccatctc tggactgcag 240
agcgaggacg aggccgacta ctattgtgtg gcctgggacg acagcctgaa cggctatgtg 300
tttggcaccg gcaccaaagt gaccgtgctg agaacagtgg ccgctcctag cgtgttcatc 360
ttcccacctt ccgacgagca gctgaagtct ggcacagcca gcgttgtgtg cctgctgaac 420
aacttctacc ctcgggaagc caaggtgcag tggaaggtgg acaatgccct gcagtccggc 480
aacagccaag agagcgtgac agagcaggac agcaaggact ccacctacag cctgagcagc 540
accctgacac tgagcaaggc cgattacgag aagcacaagg tgtacgcctg cgaagtgaca 600
caccagggcc tgtctagccc tgtgaccaag agcttcaaca gaggcgagtg c 651
Claims (12)
1.一种抗癌剂,包含与IGSF1的C端特异性结合的抗IGSF1抗体作为有效成分。
2.一种IGSF1特异性抗体或其片段,包括:
重链可变区,所述重链可变区包含SEQ ID NO:1的H-CDR1、SEQ ID NO:2的H-CDR2和SEQID NO:3的H-CDR3;和
轻链可变区,所述轻链可变区包含SEQ ID NO:4的L-CDR1、SEQ ID NO:5的L-CDR2和SEQID NO:6的L-CDR3。
3.根据权利要求2所述的IGSF1特异性抗体或其片段,其中,
所述重链可变区具有SEQ ID NO:7的氨基酸序列;以及
所述轻链可变区具有SEQ ID NO:8的氨基酸序列。
4.一种多核苷酸,所述多核苷酸编码包含SEQ ID NO:1的H-CDR1、SEQ ID NO:2的H-CDR2和SEQ ID NO:3的H-CDR3的重链可变区。
5.一种多核苷酸,所述多核苷酸编码包含SEQ ID NO:4的L-CDR1、SEQ ID NO:5的L-CDR2和SEQ ID NO:6的L-CDR3的轻链可变区。
6.一种表达运载体,包含根据权利要求4或5所述的多核苷酸。
7.一种转化细胞,导入了根据权利要求6所述的运载体。
8.一种产生IGSF1特异性抗体或其片段的方法,包括:
i)培养根据权利要求7所述的转化细胞;和
ii)回收IGSF1特异性抗体或其片段。
9.一种用于预防或治疗癌症的药物组合物,包含根据权利要求2或3所述的IGSF1特异性抗体或其片段作为活性成分。
10.根据权利要求9所述的用于预防或治疗癌症的药物组合物,其中,所述癌症是IGSF1过表达的癌症。
11.根据权利要求10所述的用于预防或治疗癌症的药物组合物,其中,所述癌症为选自由以下组成的组中的任何一种癌症:胃癌、肝癌、肺癌、非小细胞肺癌、结直肠癌、膀胱癌、骨癌、血液癌、乳腺癌、黑色素瘤、甲状腺癌、甲状旁腺癌、骨髓癌、直肠癌、咽喉癌、喉癌、食道癌、胰腺癌、舌癌、皮肤癌、脑肿瘤、子宫癌、头颈癌、胆囊癌、口腔癌、肛周癌、结肠癌和中枢神经系统肿瘤。
12.一种预防或治疗癌症的方法,包括向对象施用根据权利要求2或3所述的IGSF1特异性抗体或其片段。
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EP3800270B1 (en) | 2014-07-29 | 2021-10-27 | Wellmarker Bio Co., Ltd. | Inhibitors of met and igsf1 for treating gastric and lung cancer |
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BR112022021592A2 (pt) | 2023-03-14 |
US20240262906A1 (en) | 2024-08-08 |
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