CN116920113A - Icam1或其编码基因在制备胆管癌治疗或诊断产品中的用途 - Google Patents
Icam1或其编码基因在制备胆管癌治疗或诊断产品中的用途 Download PDFInfo
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- CN116920113A CN116920113A CN202210334406.8A CN202210334406A CN116920113A CN 116920113 A CN116920113 A CN 116920113A CN 202210334406 A CN202210334406 A CN 202210334406A CN 116920113 A CN116920113 A CN 116920113A
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Abstract
本发明涉及医药领域,特别是涉及ICAM1或其编码基因在制备胆管癌治疗产品或诊断产品中的用途,ICAM1或其编码基因能够作为胆管癌治疗产品或胆管癌诊断产品的分子靶标,具体的,特异性结合ICAM1的物质例如抗体偶联药物或其药学上可接受的盐,或ICAM1抑制剂能够用于制备胆管癌治疗产品中,以及特异性结合ICAM1的MRI分子探针,用于制备ICAM1阳性胆管癌的分子诊断产品中或用于制备预测胆管癌ICAM1相关药物的治疗效果产品中。利用本发明ICAM1或其编码基因制备的抗体偶联药物在对胆管肿瘤细胞杀伤效果显著的情况下,不杀伤正常上皮细胞,克服了传统化疗药物在杀伤肿瘤细胞的同时损伤正常组织、细胞的缺点。
Description
技术领域
本发明涉及医药领域,特别是涉及ICAM1或其编码基因在制备胆管癌治疗或诊断产品中的用途。
背景技术
胆管癌(Cholangiocarcinoma,CCA)是仅次于肝细胞癌(HepatocellularCarcinoma,HCC)的第二大原发性肝脏恶性肿瘤,占原发性肝癌的15%,占所有肿瘤的1%。胆管癌高度侵袭性且无明显临床症状的特点,导致大多数患者在诊断时已经进展至疾病晚期,同时又缺乏有效的治疗药物,严重恶化了其治疗的临床预后,5年临床上总生存率尚不足10%。
目前胆管癌的药物治疗选择有限,手术切除是胆管癌患者唯一可能治愈的治疗方法,但仅有小部分患者能够符合手术根治性切除的条件,且手术切除病变区域后,复发率高达66%。2020年,FGFR2抑制剂培米加替尼(Pemigatinib)被FDA批准成为首个胆管癌靶向治疗药物,但只有不到10%的胆管癌患者携带有可受益于该药物的FGFR2融合或重排突变。2021年,FDA批准靶向药物伊伏西地尼(Ivosidenib)用于治疗晚期或转移性胆管癌,该药物靶向异柠檬酸脱氢酶-1(IDH1)突变,然而仅有13%的胆管癌患者携带有该突变。临床上以二级胆管作为分界点,根据解剖位置的不同将胆管癌分为肝内胆管癌(IntrahepaticCholangiocarcinoma,ICCA)和肝外胆管癌(Extrahepatic Cholangiocarcinoma,ECCA),二者的发病机理、临床表现、治疗方法等有所不同。培米加替尼以及伊伏西地尼这2种已被批准的胆管癌靶向治疗药物分别针对的靶点FGFR2易位以及IDH1/2突变主要发生在肝内胆管癌中。
Kirsten大鼠肉瘤病毒癌基因(Kirsten rat sarcoma viral oncogene,KRAS)是RAS家族中最重要的基因,且KRAS突变是多种肿瘤中最常见的致癌因素之一,KRAS一旦发生突变,就会丧失GTP水解酶活性,进而持续活化,促使细胞持续增殖而癌变。在胆管癌中,KRAS突变普遍存在,ECCA中KRAS突变的频率高达36.7%,而在ICCA中,KRAS突变的频率也能达到24%。在一项关于KRAS突变亚型与手术治疗ICCA患者生存和复发关联的临床研究中发现G12D是肝内胆管癌KRAS突变中最常见的突变亚型,突变频率在KRAS突变ICCA中占43.3%,其次是G12V(19.7%)、G12C(7.1%)和G12D(6.3%),与KRAS非G12突变亚型相比,KRAS G12突变亚型与患者预后水平差存在显著相关性,尤其是KRASG12V突变伴随最差的临床预后。KRAS突变长期以来一直被认为是不可成药的靶点,除了针对KRASG12C突变亚型的抑制剂,如AMG510、MRTX849等成功开发外,直接靶向KRAS突变的药物研究进展仍然有限,临床上也未能研发出适用于靶向在肿瘤中突变频率最高的KRASG12D亚型的小分子抑制剂。
抗体偶联药物(Antibody-drug conjugate,ADC)是一种近年来迅速发展的新型肿瘤靶向治疗药物,利用特定靶点的单克隆抗体靶向肿瘤相关抗原,将通过化学接头连接在单克隆抗体上的高效细胞毒剂传递至肿瘤区域,从而发挥针对肿瘤的选择性杀伤作用,显著减少对正常组织和器官的副作用。高效细胞毒剂通常因本身毒性太大而无法全身给药,而这种靶向药物递送策略将抗体靶向部分的精确性与有效载荷的杀细胞活性相结合,通过这种方式提供了一种通过限制正常组织暴露于有效载荷来减少患者脱靶毒性的方法,与传统的化疗方法相比,显著拓宽了其潜在治疗的局限性。但是,目前ADC药物的研发主要围绕血液系统肿瘤以及少数实体瘤展开,临床上尚无相关的ADC药物获批用于靶向治疗CCA,其背后的关键科学问题是缺乏有效靶向CCA的ADC药物靶点。
现有的胆管癌靶向治疗药物无法满足绝大部分临床患者的治疗需求,研究胆管癌靶向药物的医学需求依然严重未被满足,因此胆管癌治疗领域迫切需要开发一种治疗效果好、副作用少且应用广泛的靶向治疗药物。
细胞间黏附因子-1(intercellular adhesion molecule-1,ICAM1)是免疫球蛋白超家族的一种跨膜糖蛋白,如胰腺癌、黑色素瘤、甲状腺癌和三阴性乳腺癌等多种不同类型的癌症中均表现异常过表达,常与侵袭性的表型及不良预后相关。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供ICAM1或其编码基因在制备胆管癌治疗或诊断产品中的用途,用于解决现有技术中的问题。
为实现上述目的及其他相关目的,本发明提供ICAM1或其编码基因作为分子识别靶标在制备胆管癌诊断或治疗产品中的用途。
本发明还提供特异性结合ICAM1的物质在制备胆管癌治疗或诊断产品中的用途。
优选的,所述特异性结合ICAM1的物质选自抗体偶联药物或其药学上可接受的盐或溶剂化合物。
优选的,所述抗体偶联药物的结构如下所示:Ab-(L-D)n,其中Ab为抗ICAM1抗体,L为连接子,D为细胞毒剂,n为1-40的整数。
优选的,所述抗ICAM1抗体的重链和轻链氨基酸序列分别如SEQ ID NO.1和2所示。
优选的,所述抗体偶联药物选自anti-ICAM1 mAb-MC-VC-PAB-MMAE(简称为ICAM1-MMAE)或anti-ICAM1 mAb-MC-GGFG-Dxd(简称为ICAM1-Dxd)。
如上所述,本发明的ICAM1或其编码基因在制备胆管癌治疗或诊断产品中的用途,具有以下有益效果:将膜蛋白分子ICAM1作为靶向KRAS突变胆管肿瘤的抗体类大分子药物靶点,利用该靶点的特异性抗体能够特异性识别和靶向对应肿瘤细胞表面靶点的能力,将偶联在抗体上的药物毒剂传递至肿瘤细胞内部,发挥药物的杀伤作用,从而实现对KRAS突变胆管肿瘤的杀伤作用,在对肿瘤细胞的杀伤效果显著的情况下,不杀伤正常上皮细胞,克服了传统化疗药物在杀伤肿瘤细胞的同时损伤正常组织、细胞的缺点。本发明为针对KRAS突变型胆管癌的靶向治疗药物的开发提供了新的分子识别靶点以及新的研究思路。
附图说明
图1.不同细胞系膜蛋白ICAM1表达量的检测。(A)KRASG12D突变胆管癌细胞系HuCCT-1膜蛋白ICAM1的流式检测;(B)KRASWT的胆管癌细胞系CCLP-1膜蛋白ICAM1的流式检测;(C)人正常上皮细胞系293T膜蛋白ICAM1的流式检测。
图2.细胞系HuCCT-1膜蛋白ICAM1的免疫荧光染色。(A)ICAM1荧光抗体染色;(B)IgG荧光抗体染色。
图3.细胞系HuCCT-1膜蛋白ICAM1介导的抗体内吞的免疫荧光染色镜检。
图4.细胞系HuCCT-1膜蛋白ICAM1介导的抗体内吞效率的流式定量检测。
图5.ADC药物的化学结构示意图。(A)anti-ICAM1 mAb-MC-VC-PAB-MMAE化学结构示意图;(B)anti-ICAM1 mAb-MC-GGFG-Dxd化学结构示意图。
图6.不同药物对293T细胞以及HuCCT-1细胞的杀伤效果。
具体实施方式
本研究通过流式细胞术首次证实了细胞间黏附因子-1(Intercellular adhesionmolecule-1)ICAM1在KRASG12D突变的CCA细胞系HuCCT-1的表面高度过表达,而在KRAS野生型的细胞系CCLP-1和正常细胞293T表面未检测到表达。进一步研究发现,ICAM1抗体与细胞表面靶蛋白结合后能够出现明显的内吞效应,符合ADC药物靶点研发的要求。基于此,本研究设计了两种基于ICAM1靶点的ADC药物,将靶向ICAM1的抗体分别与微管抑制剂MMAE以及DNA拓扑异构酶Ⅰ抑制剂Dxd通过可裂解连接子进行偶联,用KRASG12D突变的CCA细胞系HuCCT-1进行体外药效检测,结果显示ICAM1-MMAE的抗肿瘤活性高,并且与临床上CCA常用的化疗药物Gemcitabine相比,在有效作用浓度下,ICAM1-MMAE不杀伤人正常上皮细胞系293T。与ICAM1-MMAE相比,ICAM1-Dxd在细胞水平上未产生明显的肿瘤细胞杀伤作用,同时对正常293T细胞也未出现明显的杀伤作用。与临床一线胆管癌化疗药物相比,ICAM1-MMAE的抑癌效果好,对正常细胞的毒性小,具有较高的临床价值。
本发明首先提供ICAM1或其编码基因作为靶标在制备胆管癌治疗或诊断产品中的用途。
所述ICAM1或其编码基因作为靶标在制备胆管癌治疗或诊断产品具体是指:将ICAM1蛋白或其编码基因作为识别对象,能够降低ICAM1水平或杀伤胆管癌细胞的物质。
本发明还提供特异性结合ICAM1的物质在制备胆管癌治疗或诊断产品中的用途。
在一种实施方式中,所述特异性结合ICAM1的物质选自抗体偶联药物或其药学上可接受的盐或溶剂化合物。
在一种实施方式中,所述抗体偶联药物的结构如下所示:Ab-(L-D)n,其中Ab为抗ICAM1抗体,L为连接子,D为细胞毒剂,n为1-40的整数。
本发明中,抗ICAM1抗体选自单克隆抗体(包括具有免疫球蛋白Fc区的全长抗体)、多特异性抗体(例如,双特异性抗体)以及抗体片段(例如,Fab,F(ab’)2,Fv,scFv)。术语“免疫球蛋白”(Ig)和“抗体”可互换使用。
所述抗ICAM1抗体可以选自现有技术中任意能够与ICAM1结合的抗体或其抗原结合片段,例如MabPlex公司的ICAM1抗体。
在一种实施方式中,所述抗ICAM1抗体的重链和轻链氨基酸序列分别如SEQ IDNO.1和2所示。
所述抗ICAM1抗体经连接子偶联至细胞毒剂。连接子分为两类:不可断裂连接子和可断裂连接子。可断裂连接子可以在目标细胞内断裂并释放出药物毒剂。可断裂连接子可分为两个主要的类别:化学不稳定连接子和酶不稳定连接子。化学不稳定连接子可以由于血浆和细胞质性质的不同而选择性的断裂。这样的性质包括pH值、谷胱甘肽浓度等。对pH值敏感的连接子,通常又称为酸断裂连接子,这样的连接子在血液的中性环境下相对稳定(pH7.3-7.5),但是在弱酸性的内涵体(pH5.0-6.5)和溶酶体(pH4.5-5.0)内将会被水解。对于谷胱甘肽敏感的连接子,又称二硫键连接子。酶不稳定连接子,如肽连接子,能够更好地控制药物释放。肽连接子能够被溶酶体内蛋白酶,如组织蛋白酶(Cathepsin B)或纤溶酶(在一些肿瘤组织中此类酶含量增加)有效地切断。这种肽连接在血浆循环中非常稳定,这是因为细胞外不合宜的pH值及血清蛋白酶抑制剂导致蛋白酶通常不具备活性。鉴于较高的血浆稳定性和良好的细胞内断裂选择性和有效性,酶不稳定连接子被广泛用做抗体药物偶联物的可断裂连接子。典型的酶不稳定连接子包括Val-Cit(vc)、Phe-Lys、Gly-Gly-Phe-Gly等。
连接子可以包含一种或多种连接子构件。例示性的连接子构件包括6-马来酰亚胺基己酰基、马来酰亚胺基丙酰基-缬氨酸-瓜氨酸、丙氨酸-苯丙氨酸、对氨基苯甲酰氧基羧基、N-琥珀酰亚胺基4-(2-吡啶基硫代)戊酸酯、N-琥珀酰亚胺基4-(N-马来酰亚胺基甲基)环己烷-1羧酸酯和N-琥珀酰亚胺基(4-碘-乙酰基)氨基苯甲酸酯。其它示例性的连接子构件还可以是包含氨基酸单元以容许蛋白酶切割的连接子,由此便于在暴露于胞内蛋白酶(诸如溶酶体酶)后从抗体偶联药物释放细胞毒剂。示例性的氨基酸单元包括但不限于二肽、三肽、四肽和五肽。示例性的二肽包括:缬氨酸-瓜氨酸;丙氨酸-苯丙氨酸;苯丙氨酸-赖氨酸;或N-甲基-缬氨酸-瓜氨酸。示例性的三肽包括:甘氨酸-缬氨酸-瓜氨酸或甘氨酸-甘氨酸-甘氨酸。示例性的四肽包括:甘氨酸-甘氨酸-苯丙氨酸-甘氨酸。
所述细胞毒剂选自毒素、化疗药物、抗生素、放射性同位素、生长抑制剂。
示例性的细胞毒剂包括:美登素;类美登素;拓扑异构酶Ⅰ抑制剂(如喜树碱衍生物:DX-8951衍生物Dxd);微管蛋白抑制剂(如单甲基耳抑素肽E(MMAE)和单甲基耳抑素肽F(MMAF);卡奇霉素类(如卡奇霉素);阿霉素类(如阿霉素);苯并二吡咯类抗生素(如duocarmycins、CC-1065等)和其它的环丙基吡咯吲哚-4-酮(cyclopropapyrroloind-4-one,CPI)衍生物,如环丙苯并吲哚-4-酮类似物,以及吡咯并苯二氮卓类(PBD)或者PBD二聚体类。
所述抗体偶联药物的结构Ab-(L-D)n中n为药物抗体比值(DAR值),n的范围选自以下任一:1~5、5~10、10~15、15~20、20~25、25~30、30~35、35~40。
在一种实施方式中,所述抗体偶联药物选自anti-ICAM1 mAb-MC-VC-PAB-MMAE(简称为ICAM1-MMAE)或anti-ICAM1 mAb-MC-GGFG-Dxd(简称为ICAM1-Dxd)。
所述ICAM1-MMAE的DAR值为4。
所述ICAM1-DXD的DAR值为8。
所述连接子中的马来酰亚胺基与抗ICAM1抗体中的半胱氨酸共价偶联。
在一种实施方式中,所述抗体偶联药物的制备方法包括如下步骤:
1)将二硫键还原剂与抗ICAM1抗体混合,使抗ICAM1抗体半胱氨酸中的二硫键至少部分被还原成巯基;
2)将连接子、细胞毒剂与步骤1)的产物混合,使抗ICAM1抗体与连接子偶联得到所述抗体偶联药物。
步骤1)中所述二硫键还原剂选自DTT、三(2-羧乙基)膦或他们的盐。在一种实施方式中,所述二硫键还原剂选自三(2-羧乙基)膦盐酸盐。
在本发明的某些实施方式中,步骤1)和2)的反应在溶剂中进行。本领域技术人员可以选择合适的溶剂种类和用量,以使反应物可以在反应体系中充分分散。所述溶剂可以是缓冲液。更具体的,所述溶剂可以选自硼酸盐缓冲液、磷酸盐缓冲液中的任一种或多种。
在本发明的某些实施方式中,步骤1)或步骤2)的反应温度为0-37℃。在本发明的某些实施方式中,所述反应温度为10-35℃。较佳的,所述反应温度为15-30℃。
步骤1)中,二硫键还原剂的量相对于抗ICAM1抗体按照摩尔量计通常是等量或过量的。在本发明的某些实施方式中,二硫键还原剂与抗ICAM1抗体的摩尔比为1-50:1。在一较佳的实施方式中,二硫键还原剂与抗ICAM1抗体的摩尔比为1-30:1。在一更佳的实施方式中,二硫键还原剂与抗ICAM1抗体的摩尔比为5-20:1。
连接子与细胞毒剂可以是市购的已经连接成功的一种试剂,即为连接子-细胞毒剂;连接子与细胞毒剂也可以自制。
在本发明的某些实施方式中,连接子与细胞毒剂已经连接成功为连接子-细胞毒剂,步骤2)中不同连接子-细胞毒剂的使用量可能不同,但连接子-细胞毒剂的量相对于步骤1)产物按照摩尔量计通常是等量或过量的。在本发明的某些实施方式中,连接子-细胞毒剂与步骤1)产物的摩尔比为1-50:1。在一较佳的实施方式中,连接子-细胞毒剂与步骤1)产物的摩尔比为1-40:1。在一更佳的实施方式中,连接子-细胞毒剂与步骤1)产物的摩尔比为5-25:1。在本发明的某些实施方式中,步骤2)中还包括去除未反应的连接子与细胞毒剂。
在另一种实施方式中,所述特异性结合ICAM1的物质选自ICAM1抑制剂。
ICAM1抑制剂指对于ICAM1具有抑制效果的分子。对于ICAM1具有抑制效果包括但不限于:抑制ICAM1的水平或活性。
抑制ICAM1活性是指使ICAM1活力下降。优选地,相比抑制前,ICAM1活力下降至少10%,较佳的降低至少30%,再佳的降低至少50%,更佳的降低至少70%,最佳的降低至少90%。
抑制ICAM1水平可以是通过抑制ICAM1基因的转录或翻译,具体的,可以是指:使ICAM1基因不转录,或降低ICAM1基因的转录活性,或者使ICAM1基因不翻译,或降低ICAM1基因的翻译水平。
本领域技术人员可以使用常规方法对ICAM1基因表达进行调节,如基因敲除、同源重组,干扰RNA等。
优选地,与野生型相比,ICAM1基因表达降低至少10%,较佳的降低至少30%,再佳的降低至少50%,更佳的降低至少70%,又佳的降低至少90%,最佳地ICAM1基因完全没有表达。
所述ICAM1抑制剂包括但不限于:核酸分子、碳水化合物、脂类、小分子化学药、抗体药、多肽、蛋白、干扰慢病毒或腺相关病毒。所述核酸包括但不限于:反义寡核苷酸、双链RNA(dsRNA)、核酶、核糖核酸内切酶I II制备的小干扰RNA或者短发夹RNA(shRNA)。
所述胆管癌治疗或诊断产品必然包括特异性结合ICAM1的物质,并以特异性结合ICAM1的物质作为有效成分。
所述胆管癌治疗或诊断产品可以为单成分物质,亦可为多成分物质。
所述胆管癌治疗或诊断产品的形式无特殊限制,可以为固体、液体、凝胶、半流质、气雾等各种物质形式。
所述胆管癌治疗或诊断产品主要针对的对象为哺乳动物。所述哺乳动物优选为啮齿目动物、偶蹄目动物、奇蹄目动物、兔形目动物、灵长目动物等。所述灵长目动物优选为猴、猿或人。
所述胆管癌治疗或诊断产品包括但不限于药物、保健品、食品等。
所述胆管癌治疗产品选自:靶向的ICAM1抗体或抗原结合片段,外泌体,脂质体,SLP纳米颗粒,CAR-T细胞,溶瘤病毒,ADC,小分子偶联药物,双特异性抗体,核酸分子、小分子化学药、多肽、蛋白、干扰慢病毒或腺相关病毒等等;所述胆管癌诊断产品选自:外泌体,CTC,CT DNA,血液/尿液蛋白或MRI/PET/超声等影像探针等。
所述胆管癌选自肝内胆管癌或肝外胆管癌。所述胆管癌选自KRAS突变的胆管癌。
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前,应理解,本发明的保护范围不局限于下述特定的具体实施方案;还应当理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围;在本发明说明书和权利要求书中,除非文中另外明确指出,单数形式“一个”、“一”和“这个”包括复数形式。
当实施例给出数值范围时,应理解,除非本发明另有说明,每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义,本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外,根据本技术领域的技术人员对现有技术的掌握及本发明的记载,还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
本发明中通过流式细胞术和免疫荧光共聚焦实验证实ICAM1在KRASG12D突变的CCA细胞系HuCCT-1表面过表达,同时该靶点的相应抗体能够被细胞识别并内吞,表明ICAM1具有成为KRAS突变胆管癌药物靶点的潜力。同时,在ICAM1单克隆抗体上分别连接微管抑制剂MMAE以及DNA拓扑异构酶抑制剂Dxd,设计并制备了这2种ADC药物,通过CCK-8方法在体外对ADC药物的药效进行了测定,实验结果表明ICAM1-MMAE对KRAS突变CCA细胞系有明显的抑制生长的效果,同时该药物对正常细胞杀伤性弱,生物安全性高,有望成为治疗或诊断KRAS突变胆管肿瘤的候选药物。
实施例中主要实验材料如下:
人胆管癌细胞系(HuCCT-1、CCLP-1)和人胚胎肾上皮细胞系293T购于中国科学院细胞库;DMEM高糖培养基、RPMI 1640培养基、0.25%胰蛋白酶、青霉素-链霉素溶液购于Gibco;南美胎牛血清购于Biological Industries;CCK-8试剂盒购于Biosharp;PBS缓冲液、4%多聚甲醛购于Solarbio;DAPI染色液购于碧云天;牛血清白蛋白(BSA)购于Sigma-Aldrich;PE anti-human CD54(Mouse IgG1)、PE mouse IgG1、Purified anti-human CD54(Mouse IgG1)、PE anti-mouse IgG1(Rat IgG)购于BioLegend;抗体偶联药物Anti-ICAM1mAb-MC-VC-PAB-MMAE、Anti-ICAM1 mAb-MC-GGFG-Dxd和Anti-ICAM1 mAb由申请人自制,其中Anti-ICAM1 mAb委托第三方公司合成,Anti-ICAM1 mAb重链和轻链氨基酸序列分别如SEQ ID NO.1和2所示,MC-VC-PAB-MMAE、MC-GGFG-Dxd购于陶术生物。
实施例中细胞培养方法如下:
人胆管癌细胞系HuCCT-1培养于含有10%胎牛血清和1%青霉素-链霉素的RPMI1640培养基中;人胆管癌细胞系CCLP-1和人胚胎肾上皮细胞系293T均培养于含有10%胎牛血清和1%青霉素-链霉素的DMEM培养基中;细胞培养箱设置温度为37℃,CO2浓度为5%。
实施例1膜蛋白ICAM1在CCA细胞系表面的表达量及膜定位分析
1.流式细胞术定量检测KRAS突变及KRAS野生型CCA细胞系ICAM1膜蛋白的表达
胰酶消化收集2.0×106个细胞,用PBS悬浮冲洗一次,1000rpm离心3min,去除上清液。冰浴条件下,用2mL含1%BSA的PBS封闭细胞30min。于1000rpm离心3min,弃去上清液,细胞沉淀中加入500μL含1%BSA的PBS,用移液枪混匀。取2个流式管,每管加入200μL细胞混悬液。第一组(阴性对照组)加入2μL PE mouse IgG1(Mouse IgG1);第二组(实验组)加入2μLPE anti-human CD54(Mouse IgG1)。37℃摇床100rpm震荡避光孵育45min。1000rpm离心5min,去除上清,用1mL PBS重悬清洗细胞1次,细胞最后重悬于500μL PBS中,用流式细胞分析仪检测每组荧光值。
通过流式细胞术对2个已建立的人CCA细胞系(KRASG12D突变CCA细胞系HuCCT-1和KRAS野生型CCA细胞系CCLP-1)表面膜蛋白ICAM1的表达量进行了检测(图1A和图1B),同时以人胚胎肾上皮细胞系293T作为正常细胞对照(图1C)。实验结果表明ICAM1在KRASG12D突变的CCA细胞系HuCCT-1表面高度过表达,而在KRASWTCCA细胞系CCLP-1以及正常上皮细胞系293T表面未检测到表达(图1)。结合已发表的文献研究,在胰腺腺泡细胞中引入KRAS G12D突变会上调细胞表面ICAM1的表达量,表明ICAM1能够成为KRAS突变肿瘤潜在的药物设计靶点。
2.免疫荧光共聚焦实验鉴定膜蛋白ICAM1在KRASG12D突变细胞系HuCCT-1表面的膜定位
胰酶消化收集2.0×106个细胞,用2mL完全培养基重悬细胞,将其均分为2份加入共聚焦皿中,将共聚焦皿转移至37℃细胞培养箱(5%CO2)中过夜培养。次日去除培养基上清,1mL PBS清洗细胞表面2次。每皿加入1mL 1%BSA(PBS),冰浴条件下封闭30min。封闭完成后,第一组(阴性对照组)加入2μL PE mouse IgG1(Mouse IgG1),第二组(实验组)加入2μL PE anti-human CD54(Mouse IgG1)。37℃静置孵育1h。1mL PBS清洗细胞表面2次,每皿加入1mL DAPI染色液,室温孵育20min。1mL PBS清洗细胞2次,每皿加入1mL 4%多聚甲醛室温固定20min。固定完成后用1mL PBS清洗细胞1次,每组加入0.5mL PBS,于共聚焦显微镜下观察实验结果。
通过免疫荧光染色对KRASG12D突变CCA细胞系HuCCT-1表面ICAM1的表达进行可视化定位(图2)。实验结果显示,Phycoerythrin(PE)标记的ICAM1荧光抗体结合于HuCCT-1细胞的膜表面(图2A),而对照组PE标记的无靶点IgG未与任何靶蛋白结合(图2B),表明ICAM1表达于HuCCT-1细胞的膜上,符合ADC药物的靶点需定位于细胞膜上的要求。
实施例2 KRAS突变细胞系HuCCT-1表面膜蛋白ICAM1介导的抗体内吞效率分析
1.免疫荧光共聚焦观察细胞系HuCCT-1表面膜蛋白ICAM1介导的抗体内吞
胰酶消化收集5.0×106个细胞,用5mL完全培养基混匀后平均分到5个共聚焦皿中。将共聚焦皿转移至37℃细胞培养箱(5%CO2)中过夜培养。次日,弃去旧培养基,用1mLPBS清洗一次。每皿加入1mL含有1%BSA的PBS缓冲液,冰上静置封闭30min。取5mL预冷的1%BSA(PBS),加入10μL PE anti-human CD54(Mouse IgG1),涡旋混匀后,先弃去皿中的封闭液,接着每个共聚焦皿加入1mL抗体稀释液,冰浴30min。从此步骤起开始避光操作。抗体孵育完成后,每皿细胞用1mL PBS清洗2次,再加入1mL 1%BSA(PBS)。第一组(0min)不加入1mL1%BSA(PBS),直接加入1mL 4%多聚甲醛冰浴固定30min,固定完成后用1mL预冷PBS清洗1次;第二组(30min)37℃恒温摇床静置孵育30min后,去除1%BSA,直接加入1mL 4%多聚甲醛冰浴固定30min,固定完成后用1mL预冷PBS清洗1次;第三组(60min)37℃恒温摇床静置孵育60min后,去除1%BSA,直接加入1mL 4%多聚甲醛冰浴固定30min,固定完成后用1mL预冷PBS清洗1次;第四组(240min)37℃恒温摇床静置孵育240min后,去除1%BSA,直接加入1mL4%多聚甲醛冰浴固定30min,固定完成后用1mL预冷PBS清洗1次。各实验组固定步骤完成后,每皿加入1mL DAPI染色液,冰浴20min。1mL PBS清洗细胞2次,每组加入1mL 1%BSA(PBS),4℃保存,次日共聚焦显微镜下观察实验结果。
通过免疫荧光共聚焦显微镜观察PE荧光标记的ICAM1抗体通过膜蛋白ICAM1介导的内吞效应(图3)。实验结果显示,靶向ICAM1的荧光标记抗体在0min时结合于细胞系HuCCT-1的表面,随着时间的推移,荧光抗体逐渐被细胞内吞进入胞浆,该现象在抗体结合240min时最为显著。以上实验结果表明KRAS突变CCA细胞系HuCCT-1表面膜蛋白ICAM1能够有效介导抗体内吞,是ADC药物设计的理想靶点。
2.流式细胞术量化细胞系HuCCT-1表面膜蛋白ICAM1介导的抗体内吞效率
胰酶消化收集5.0×106个细胞,用PBS重悬清洗细胞1次,离心,吸去上清液。冰浴条件下,用4mL预冷的1%BSA(PBS)重悬细胞,冰浴静置封闭30min。加入10μL Purifiedanti-human CD54(Mouse IgG1)抗体,混匀后冰浴静置30min。细胞混合液于1000rpm离心3min,用4mL预冷的PBS清洗细胞2次,最后用1.2mL 1%BSA(PBS)重悬细胞。取5个流式细胞管,每管加入200μL细胞混悬液,从此步骤开始避光。第一组(0min)加入2μL PE anti-mouseIgG1(Rat IgG),混匀后冰浴30min;第二组(30min)37℃恒温摇床静置孵育30min后,加入2μL PE anti-mouse IgG1(Rat IgG),混匀后冰浴30min;第三组(60min)37℃恒温摇床静置孵育60min后,加入2μL PE anti-mouse IgG1(Rat IgG),混匀后冰浴30min;第四组(120min)37℃恒温摇床静置孵育120min后,加入2μL PE anti-mouse IgG1(Rat IgG),混匀后冰浴30min;第五组(240min)37℃恒温摇床静置孵育240min后,加入2μL PE anti-mouse IgG1(Rat IgG),混匀后冰浴30min。以上每组细胞在PE二抗(即PE anti-mouse IgG1)孵育完成后,均用1mL预冷PBS清洗细胞2次。最后每组加入500μL 4%多聚甲醛室温固定20min。固定完成后用1mL预冷PBS清洗细胞1次,最后用400μL PBS重悬细胞。流式细胞仪上样检测各组荧光值,检测结果用FlowJo软件计算每组平均荧光强度(Mean fluorescence intensity,MFI),测定每个时间点MFI相对于0min,即第一组实验组的MFI下降百分比确定细胞的内吞效率。
通过流式细胞术进一步量化细胞系HuCCT-1表面膜蛋白ICAM1介导的抗体内吞效率,通过结合于细胞表面ICAM1抗体上的抗鼠荧光二抗荧光强度的下降水平得出相对于0min时,不同时间点细胞表面ICAM1抗体的结合量,换算出不同时刻下ICAM1抗体进入细胞胞浆的内吞效率(图4)。实验结果显示,随着时间的推移,结合于细胞系HuCCT-1表面膜蛋白ICAM1上的抗体被内吞的数量逐渐增加,内吞效率在240min时接近60%,进一步表明ICAM1能够有效介导抗体内吞,能够成为传递高效细胞毒剂的ADC药物设计靶点。
实施例3抗体偶联药物的制备
将ICAM1单克隆抗体与通过马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苯甲酰氧基羧基(MC-VC-PAB)连接子与微管抑制剂Monomethyl auristatin E(MMAE)偶联制备获得anti-ICAM1 mAb-MC-VC-PAB-MMAE(ICAM1-MMAE)药物;将ICAM1单克隆抗体与通过马来酰亚胺-GGFG四肽(MC-GGFG)连接子与拓扑异构酶Ⅰ抑制剂喜树碱衍生物(DX-8951衍生物Dxd)偶联制备获得anti-ICAM1 mAb-MC-GGFG-Dxd(ICAM1-Dxd)药物。具体制备过程如下:
将ICAM1抗体在硼酸盐缓冲液中与三(2-羧乙基)膦盐酸盐反应在25℃反应2h,把半胱氨酸中的二硫键部分还原成巯基。再加入过量的MC-VC-PAB-MMAE(摩尔比值10:1)或MC-GGFG-DXD(摩尔比值20:1),在pH=6.5的PBS缓冲液中通过巯基反应将ICAM1单克隆抗体上的巯基与MC-VC-PAB-MMAE或MC-GGFG-DXD连接子在25℃进行反应2h,生成最终产物ICAM1-MMAE或ICAM1-DXD,并通过超滤方法去除未反应的MC-VC-PAB-MMAE或MC-GGFG-DXD。通过控制投料比方法将ICAM1-MMAE的药物抗体比值(DAR值)控制为4;ICAM1-DXD的DAR值控制为8。
两种ADC药物的反应原理是首先用还原剂将ICAM1抗体半胱氨酸中的二硫键还原为巯基,再将巯基与连接子中的马来酰亚胺基进行共价偶联反应,形成ADC复合结构,制备完成的ADC药物以1mg/mL的浓度溶解于PBS中,分装后冻存于-80℃。
ICAM1单克隆抗体与MC-VC-PAB-MMAE或MC-GGFG-Dxd偶联制备的两种ADC药物的化学结构如图5所示。
实施例4 ADC药物和CCA常见化疗药物Gemcitabine的体外药效测定
细胞用胰酶消化下来并离心,去除上清后用适量完全培养基重悬细胞并计数。用完全培养基将细胞密度调整为5×104个细胞/mL。在96孔板中设置一列阴性对照组(无药物组)以及8列实验组(梯度稀释药物组),每组设置3个复孔。将细胞稀释液加入96孔板中,每孔100μL,其余孔用PBS补全等量体积。细胞培养箱培养三天后,细胞融合度达到40%-50%,此时准备加入药物。药物用完全培养基稀释为10μg/mL,之后依次进行10倍梯度稀释,共设置8个稀释度。去除96孔板中的旧培养基,补入等量的药物稀释液,于37℃细胞培养箱继续培养72h。药物作用结束后,每孔加入10μL CCK-8试剂,轻震混匀后于37℃静置孵育,每半小时用酶标仪检测波长450nm下每孔的吸光值。当阴性对照组OD450值达到1.0时,停止检测。
通过CCK-8方法检测2种ADC药物和1种CCA常用化疗药物Gemcitabine对KRAS突变CCA细胞系HuCCT-1以及人正常胚胎肾上皮细胞系293T的杀伤效果(图6)。检测结果显示,ICAM1-MMAE可以显著杀伤CCA细胞系HuCCT-1,其半数抑制浓度(IC50)为0.4714μg/mL,对正常细胞293T的生长未产生抑制效果;ICAM1-Dxd对HuCCT-1细胞以及293T细胞均无抑制作用;化药Gemcitabine则对2种细胞系都有明显的杀伤效果,对HuCCT-1细胞的IC50值为0.1224μg/mL,对293T细胞的IC50值为0.2554μg/mL。体外药效测定结果表明,ICAM1-MMAE能够对KRAS突变CCA细胞系产生接近临床常用化药Gemcitabine的杀伤效果,但在生物安全性上对正常细胞的毒性远低于化疗药物,证明该药物具有临床转化价值。
本发明通过流式细胞术和免疫荧光共聚焦实验确认了靶蛋白ICAM1在KRAS突变CCA细胞系上高度过表达,而在正常上皮细胞系上不表达,符合理想ADC药物靶点的表达分布。同时进一步检测了细胞的抗体内吞效率,确认了细胞膜蛋白ICAM1能够高效介导抗体内吞,有利于ADC药物结合靶蛋白后将细胞毒剂递送至细胞内部,发挥细胞毒作用。在细胞毒剂的选择上,本研究尝试设计了两种细胞毒剂,其中一种细胞毒剂为MMAE,作为合成的巴胺素10衍生物,具有极强的抗有丝分裂的作用,能够通过阻断微管蛋白的聚合来抑制细胞分裂,从而达到抗肿瘤的目的;另一种细胞毒剂为Dxd,是一种喜树碱衍生物,能够作用于DNA拓扑异构酶Ⅰ,通过抑制DNA的转录和复制发挥杀伤肿瘤细胞的作用。两种ADC药物通过体外药效测定进行比较,检测结果显示ICAM1-MMAE的体外肿瘤细胞杀伤效果明显优于ICAM1-Dxd,同时与CCA临床常见化疗药物Gemcitabine相比,在保留有效杀伤肿瘤细胞的前提下,对正常上皮细胞不产生杀伤效果,具有显著的生物安全性。
本研究设计的ADC药物的相关临床前研究数据证明了ICAM1-MMAE能够有效杀伤ICAM1过表达的KRASG12D突变的CCA细胞系。该药物对肿瘤细胞的杀伤效果显著,在有效作用浓度下不杀伤正常上皮细胞,克服了传统化疗药物不仅杀伤肿瘤细胞,还会损伤正常组织、细胞的缺点。本研究为KRAS突变型CCA的靶向治疗提供一种具有临床转化潜力的精准治疗ADC药物。
以上的实施例是为了说明本发明公开的实施方案,并不能理解为对本发明的限制。此外,本文所列出的各种修改以及发明中方法的变化,在不脱离本发明的范围和精神的前提下对本领域内的技术人员来说是显而易见的。虽然已结合本发明的多种具体优选实施例对本发明进行了具体的描述,但应当理解,本发明不应仅限于这些具体实施例。事实上,各种如上所述的对本领域内的技术人员来说显而易见的修改来获取发明都应包括在本发明的范围内。
序列表
<110> 浙江省肿瘤医院
中国科学院基础医学与肿瘤研究所(筹)
<120> ICAM1或其编码基因在制备胆管癌治疗产品中的用途
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 468
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Claims (11)
1.ICAM1或其编码基因作为靶标在制备胆管癌治疗或诊断产品中的用途。
2.特异性结合ICAM1的物质在制备胆管癌治疗或诊断产品中的用途。
3.根据权利要求2所述的用途,其特征在于,所述特异性结合ICAM1的物质选自抗体偶联药物或其药学上可接受的盐。
4.根据权利要求2所述的用途,其特征在于,所述抗体偶联药物的结构如下所示:Ab-(L-D)n,其中Ab为抗ICAM1抗体,L为连接子,D为细胞毒剂,n为1-40的整数。
5.根据权利要求4所述的用途,其特征在于,抗ICAM1抗体选自全长抗体或抗体片段;优选的,所述抗体片段选自Fab,F(ab’)2,Fv或scFv。
6.根据权利要求4所述的用途,其特征在于,所述抗ICAM1抗体的重链和轻链氨基酸序列分别如SEQ ID NO.1和2所示。
7.根据权利要求4所述的用途,其特征在于,所述连接子选自不可断裂连接子或可断裂连接子;优选的,所述可断裂连接子选自化学不稳定连接子或酶不稳定连接子。
8.根据权利要求4所述的用途,其特征在于,所述连接子包含一种或多种连接子构件,所述连接子构件选自马来酰亚胺基丙酰基、马来酰亚胺基己酰基、对氨基苯甲酰氧基羧基、缬氨酸-瓜氨酸、丙氨酸-苯丙氨酸、甘氨酸-甘氨酸-甘氨酸、甘氨酸-缬氨酸-瓜氨酸、甘氨酸-甘氨酸-苯丙氨酸-甘氨酸中的任一个或多个;优选的,所述连接子选自马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苯甲酰氧基羧基或马来酰亚胺-GGFG四肽。
9.根据权利要求4所述的用途,其特征在于,所述细胞毒剂选自毒素、化疗药物、抗生素、放射性同位素或生长抑制剂。
10.根据权利要求4所述的用途,其特征在于,所述细胞毒剂选自以下中的任一个或多个:美登素、类美登素、拓扑异构酶Ⅰ抑制剂、微管蛋白抑制剂、卡奇霉素及其衍生物、阿霉素及其衍生物;优选的,所述细胞毒剂选自DX-8951衍生物Dxd、MMAE或MMAF。
11.根据权利要求2所述的用途,其特征在于,所述特异性结合ICAM1的物质为ICAM1抑制剂;优选的,所述ICAM1抑制剂选自核酸、小分子化学药、多肽、蛋白、干扰慢病毒或腺相关病毒。
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