CN116930494A - Icam1或其编码基因在制备宫颈癌治疗或诊断产品中的用途 - Google Patents
Icam1或其编码基因在制备宫颈癌治疗或诊断产品中的用途 Download PDFInfo
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- CN116930494A CN116930494A CN202210334398.7A CN202210334398A CN116930494A CN 116930494 A CN116930494 A CN 116930494A CN 202210334398 A CN202210334398 A CN 202210334398A CN 116930494 A CN116930494 A CN 116930494A
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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宫颈癌治疗或诊断产品中的用途,ICAM1或其编码基因能够作为宫颈癌治疗产品或宫颈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宫颈癌治疗产品中,以及特异性结合ICAM1的MRI分子探针,用于制备ICAM1阳性宫颈癌的分子诊断产品中或用于制备预测宫颈癌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宫颈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宫颈癌治疗或诊断产品中的用途。
背景技术
宫颈癌在女性肿瘤中仍然是高发病率、高死亡率的恶性肿瘤之一。目前子宫颈癌的治疗方法是手术治疗,放疗,化疗,靶向治疗和免疫治疗。目前临床常用的一线化疗和放疗药物无差别杀伤肿瘤与正常组织,容易产生耐药,以及放化疗相关的并发症。很大比例的宫颈癌患者最终会发展为晚期疾病(IV期或复发性疾病)。由于一线化疗药物存在治疗窗狭窄和不具靶向性等缺陷,晚期宫颈癌患者的5年生存率仅为15%-20%。
近年来,抗体药物偶联物(ADC)作为一种新型的靶向治疗药物,以其高靶向性、高杀伤力及合适的分子大小等特有的优点,成为抗肿瘤研究领域的热点,具有广阔的研究潜力和前景。在不损伤正常器官和组织的情况下选择性地杀死肿瘤细胞,在乳腺癌和胃癌在内的多种实体肿瘤中显示出良好的疗效。虽然ADC类药物的研发在抗肿瘤药物研究领域一直是热点,但迄今为止,现有的ADC药物仍无法满足临床所需,正如宫颈癌一线化疗药物复发的患者,可供选择的二线药物及其缺乏,尤其是ADC类的靶向药物。现阶段临床上的宫颈癌由于其分子分型相对缺失,相关分子标志物研究不够成熟,无法指导临床用药。因此,筛选新的肿瘤特异性靶点或突变抗原,研究开发新的ADC靶向药物,进行精准医学研究,减少对正常组织的杀伤,改善预后,提高宫颈癌患者的五年生存期至关重要。
细胞间黏附分子-1(intercellular cell adhesion molecule-1,ICAM-1),又叫做CD54,属于黏附分子中免疫球蛋白超家族(immunogiobulin superfamily,IGSF)中的成员,是介导黏附反应重要的一个黏附分子。ICAM1是针对宫颈癌的一个全新药物靶点,该靶点是一种细胞表面糖蛋白,在炎症损伤、病毒感染和肿瘤发生期间调节细胞间粘附。ICAM1靶点在多发性骨髓瘤及胰腺癌等的体内外实验研究中已得出令人满意的实验结果,基于该新靶点的ADC在上述实体瘤动物模型中体现出显著且持久的肿瘤消退效果。
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宫颈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宫颈癌诊断或治疗产品中的用途。
本发明还提供特异性结合ICAM1的物质在制备宫颈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或其编码基因作为分子识别靶标在制备宫颈癌诊断或治疗产品中的用途,具有以下有益效果:确定ICAM1是治疗宫颈癌的一个全新的靶点,且该靶点可以作为ADC的靶点。并测定了2个ADC候选药物的体外抗肿瘤活性和生物安全性,确定了一个靶向ICAM1靶蛋白的最佳抗体偶联药物IC1-MMAE,为宫颈癌的靶向治疗提供了一种有潜力的靶向治疗候选药物。
附图说明
图1显示为宫颈癌组织和癌旁组织的IHC染色图像(a)及肿瘤标本中ICAM1+和ICAM1-的染色强度(b)和存活曲线(c)。
图2显示为宫颈癌细胞SiHa(a)、CaSki(b)和正常宫颈细胞HcerEpic(c)的ICAM1表达图。
图3显示为宫颈癌细胞SiHa(a)和CaSki(b)的IF图像。
图4显示为宫颈癌细胞SiHa(a、c)和CaSki(b、d)的内化图像和效率曲线。
图5显示为抗ICAM1抗体(a)和两组连接子-细胞毒剂的化学结构(b、c)。
图6显示为ADC药物和化药对宫颈癌细胞株和正常宫颈细胞的体外抑制活性IC50。
具体实施方式
本发明首先提供ICAM1或其编码基因作为靶标在制备宫颈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宫颈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水平或杀伤宫颈癌细胞的物质。
本发明还提供特异性结合ICAM1的物质在制备宫颈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、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、腺相关病毒、纳米颗粒、脂质体、细胞外囊泡或细胞。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)。
所述宫颈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。
所述宫颈癌治疗或诊断产品可以为单成分物质,亦可为多成分物质。
所述宫颈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。
所述宫颈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。
所述宫颈癌治疗或诊断产品包括但不限于药物、保健品、食品等。
所述宫颈癌治疗产品选自: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;所述宫颈癌诊断产品选自:外泌体,CTC,CT DNA,血液/尿液蛋白或MRI/PET/超声等影像探针等。
所述宫颈癌选自鳞癌、腺癌或腺鳞癌。
鳞癌按照组织学分化分为Ⅲ级,Ⅰ级为高分化鳞癌,Ⅱ级为中分化鳞癌(非角化性大细胞型),Ⅲ级为低分化鳞癌(小细胞型),多为未分化小细胞。
腺癌占宫颈癌15%~20%,主要组织学类型有2种:
①黏液腺癌:最常见,来源于宫颈管柱状黏液细胞,镜下见腺体结构,腺上皮细胞增生呈多层,异型性增生明显,见核分裂象,癌细胞呈乳突状突入腺腔。可分为高、中、低分化腺癌。
②恶性腺瘤:又称微偏腺癌,属高分化宫颈管黏膜腺癌。癌性腺体多,大小不一,形态多变,呈点状突起伸入人宫颈间质深层,腺上皮细胞无异型性,常有淋巴结转移。
腺鳞癌占宫颈癌的3%~5%,是由储备细胞同时向腺细胞和鳞状细胞分化发展而形成,癌组织中含有腺癌和鳞癌两种成分。
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。
以下实施例首先通过免疫组织化学(IHC)法检测新靶点蛋白ICAM1在宫颈癌和癌旁组织中表达水平的差异。其次,应用免疫荧光(IF)染色、流式细胞术和单光子共聚焦显微镜,确定新靶点ICAM1在2种人宫颈癌细胞(Si-Ha和Ca-Ski)和1种正常宫颈细胞(HcerEpic)上的位置。随后,通过共聚焦成像观察宫颈癌细胞对抗ICAM1抗体的内吞能力,并用流式细胞仪分析其内吞效率。最后通过CCK8实验评估2个具有不同连接子和细胞毒剂的ADC候选药物IC1-MMAE(ICAM1-MC-VC-PAB-MMAE)、IC1-Dxd(ICAM1-Maleimide GGFG peptide-Dxd)在宫颈癌细胞和正常宫颈细胞上的体外抑制活性。临床标本IHC显示新靶点ICAM1在宫颈癌组织中的表达水平明显高于癌旁组织,宫颈癌组织中靶蛋白ICAM1表达阳性率为24.32%(27/111),癌旁组织阳性率为0%(0/25)。2株宫颈癌细胞过表达ICAM1靶蛋白,宫颈癌细胞SiHa和CaSki的ICAM1表达分别比正常宫颈细胞HcerEpic高80倍和106倍;确定了ICAM1靶蛋白在细胞膜位置;高表达ICAM1的宫颈癌细胞对抗ICAM1抗体显示显著的内吞活性,内化效率在1小时内达到30%以上。IC1-MMAE在SiHa和CaSki肿瘤细胞中IC50分别为0.1198ug/ml和1.149ug/ml,显示出良好的抗肿瘤活性。综上,实施例确定了ICAM1是治疗宫颈癌的一个全新的ADC靶点。测定了2个ADC候选药物的体外抗肿瘤活性和生物安全性,确定了一个靶向ICAM1靶蛋白的最佳抗体偶联药物IC1-MMAE,为宫颈癌的靶向治疗提供了一种有潜力的靶向治疗候选药物。
实施例中主要实验材料如下:
生存期子宫颈癌组织芯片(阵列编号:HUteS136Su01,批号:XT17-039),购自上海芯超生物科技公司。人宫颈癌细胞株(Si-Ha和Ca-Ski),留存自浙江省肿瘤医院和上海肿瘤医院细胞库;正常宫颈细胞(HcerEpic),购自通派(上海)生物科技有限公司。培养基MEM、RPMI-1640,和胎牛血清购自美国Gibco公司。CCK8试剂盒(货号:BS350B),购自Bioshrp公司;PE anti-mouse IgG1(货号:406608)和Purified anti-human CD54(货号:322702),均购自美国Biolegend公司。抗体偶联药物Anti-ICAM1 mAb-MC-VC-PAB-MMAE、Anti-ICAM1mAb-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:
MGWSCIILFLVATATGVHSQVQLQQSGPELVRPGVSVKISCKGSGYTFIDYAIHWVKESHAKSLEWIGVISAYSGDTNYNQKFKGKATMTVDKSSNTAYLELARLTSEDSAIYYCARGGWLLLSFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:1)MGWSCIILFLVATATGVHSDVVMTQSPLSLPVSLGDQASISCRSSQSLVHSNGNNYLHWYLQKSGQAPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:2)
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:
宫颈癌细胞和人宫颈上皮细胞采用含10%胎牛血清、青霉素100U/ml和链霉素100μg/ml的MEM培养液置37℃、5%CO2培养箱常规培养。2-3天换一次培养液,对细胞生长密度到达90%左右、处于对数生长期的细胞,用胰酶消化,进行传代和后续实验。
实施例中统计学方法如下:
应用GraphPad Prism 8.0和FlowJo V10对实验数据进行统计分析,计量数据以均数±方差(SD)表示,两组间的差异性比较用t检验进行分析,P<0.05被认为有统计学差异。对于生存分析,使用GraphPad Prism 8.0中Mantel-Cox测试显著性水平分为*p<0.05、**p<0.01、***p<0.001和****p<0.0001。应用GraphPad Prism 8.0对实验数据进行相关图片的绘制。
实施例1临床标本的免疫组化染色IHC实验
采用免疫组织化学(IHC)法检测了25组人宫颈癌组织和癌旁组织以及86例宫颈癌组织中ICAM1靶蛋白表达水平的差异。用TMA半定量分析组织芯片阵列中ICAM1的表达。由于未查到宫颈癌中ICAM1相关评分标准,故参考国科大肿瘤医院朱秀老师的建议,将染色强度(1+、2+、3+)与阳性肿瘤细胞百分率相乘,如将(2+,50%)量化1.0,将>0的判定为有表达(ICAM1+,positive),将=0的判断为不表达(ICAM1-,negative)。
生物芯片中共111例生存期宫颈肿瘤,其中107例为鳞状细胞癌,4例为腺癌。新靶点ICAM1在宫颈癌组织阳性率为24.32%(27/111)。其中高级别为:26.87%(18/67);低级别:21.05%(8/38);腺癌:17.67%(1/6)。癌旁组织阳性率为0(0/25)。对IHC染色结果量化为ICAM1+表达强度,肿瘤样本中ICAM1+的染色强度与ICAM1-比较,有统计学差异,P<0.0001。
而由此可知,在人宫颈肿瘤组织中的ICAM1表达水平明显高于癌旁组织,癌旁组织不表达ICAM1靶蛋白。ICAM1靶蛋白在宫颈癌组织中特异性表达,有作为ADC药物靶点的潜力。免疫组化IHC典型图像如图1a和图1b所示。
通过对生物芯片中111例患者的生存数据进行Kaplan-Meier法统计分析,ICAM1高表达的宫颈癌患者预后更差,差异有统计学意义,P<0.05。因此,研究开发一种针对ICAM1阳性的宫颈癌患者的ADC药物,对改善临床宫颈癌不良预后的有重要的意义。
实施例2流式细胞术(FACS)检测细胞株ICAM1表达强度
用流式细胞术分别检测体外培养的2株人宫颈癌细胞株SiHa和CaSki和1株正常宫颈细胞HcerEpic中ICAM1的表达水平。收集1×106细胞,用PBS冲洗两次。获得的细胞在冰浴中用PBS中的1%牛血清白蛋白(Bovine Serum Albumin,BSA)封闭30分钟。BSA阻断后,细胞在室温下分别与藻红蛋白(Phycoerythrin,PE)结合的ICAM1抗体孵育1小时。PE结合的IgG作为对照。用1%BSA在PBS中冲洗细胞三次,在PBS中再悬浮,并使用流式细胞仪进行评估各细胞株中ICAM1的表达强度。
由流式结果可知,2株宫颈癌细胞SiHa和CaSk过表达ICAM1靶蛋白,ICAM1峰(橙色)和非特异性lgG峰(蓝色)显著分离,而正常宫颈细胞HcerEpic的ICAM1峰和lgG峰基本重合。SiHa和CaSki的ICAM1靶蛋白表达水平分别比HcerEpic高80倍和106倍。流式结果表明,ICAM1在人类宫颈癌细胞SiHa和CaSki中的高度表达,在正常宫颈细胞中低表达。这验证了ICAM1靶点的高度特异性,为成功研究开发一种靶向ICAM1靶蛋白的ADC药物提供了可能性。流式结果如图2。
实施例3免疫荧光染色(IF)验证ICAM1靶蛋白在细胞膜上
在单光子共聚焦显微镜下观察两株宫颈癌细胞SiHa和CaSki中靶蛋白的亚细胞位置。取1×106细胞接种在共聚焦皿中,共3皿,各加1mL培养基,37℃过夜培养。去除培养基,PBS浸润洗涤1次。冰浴条件下,取1ml含1%BSA的PBS封闭细胞15-30min。封闭后,吸去液体,在37℃分三组孵育抗体:第①组取1ml的PBS孵育细胞1h;第②组取2μl的lgG-PE+1ml的PBS孵育细胞1h;第③组取2μl的ICAM1-PE+1ml的PBS孵育细胞1h;加1ml的PBS洗1次;加1ml的Hoechst细胞核染液,37℃静置染色20-30min;取1ml的PBS洗涤1-2次,单光子共聚焦显微镜下观察。
用免疫荧光IF法对两株宫颈癌细胞SiHa和CaSki进行处理后,在单光子共聚焦显微镜下观察ICAM1靶蛋白在细胞上的位置。红色荧光圈为带PE的ICAM1抗体,蓝色荧光团为被hoechst染液染过的细胞核。可以看到,两株高表达ICAM1的宫颈癌细胞SiHa和CaSki细胞膜位置显示一圈红色荧光,验证了ICAM1靶蛋白定位在细胞膜上。免疫荧光染色结果如图3。
实施例4成像流式细胞术定量ICAM1抗体的细胞内化效率
用成像流式细胞术确定ICAM1 ADCs是否能选择性进入宫颈癌细胞并被快速转运至细胞内溶酶体。将1×106个细胞接种在共聚焦皿,种5皿,各加1ml培养基,37℃过夜;去除培养基,冰浴条件下,加2μl ICAM1-PE+1ml的PBS;置冰上染色30min后,用冷的PBS洗一遍;加1ml PBS,37℃中使其内吞0、30、60、120、240min。各组时间一到,即用PBS洗1-2次,随后用4%多聚甲醛固定10min,PBS洗1-2次。吸出PBS,加1ml的hoechst染液,37℃染色20-30min,吸去染液,PBS洗1-2次;最后在共聚焦仪器下拍照,分析,保存。
结合ADC的靶向作用原理,抗ICAM1抗体能否被细胞膜上的抗原靶点介导内吞,是影响ADC疗效的另一个重要因素。因此,本发明试图用成像流式细胞术确定ICAM1 ADCs是否能选择性进入宫颈癌细胞并快速转运至细胞内溶酶体。使用成像流式细胞术定量了两株宫颈癌细胞SiHa、CaSki和正常细胞株HcerEpic中ICAM1抗体的细胞内化率。ICAM1靶蛋白在SiHa和CaSki中高度过度表达。2株靶蛋白高表达的肿瘤细胞SiHa和CaSki,对抗ICAM1抗体结合物有明显的内化趋势,并随时间变化,靶蛋白抗体结合物向肿瘤细胞内移动,如图4a和图4b。观察的2株宫颈癌细胞在1h内均能达到30%的内化率,如图4c和图4d。
这些结果说明了该靶点ICAM1作为宫颈癌的ADC靶点具有突出的潜在效用,可以进行ICAM1抗体偶联物的设计、制备和表征,并测定其ADC药物的体外、体内抗宫颈癌活性。共聚焦荧光图像和内吞效率曲线,如图4所示。
实施例5ADC药物的设计、制备和表征
ADC药物的结构组成决定了其高靶向性,高肿瘤细胞杀伤力的特性。药物是否能被肿瘤细胞吞噬,并在细胞内有效释放是研究ADC是否有效的重要因素。因此确定ADC药物能被表面抗原介导内化后,还需确定药物在细胞内被转运至溶酶体,在溶酶体内连接子被降解,药物受控释放进而杀伤肿瘤细胞。因此,在确定了靶蛋白ICAM1的基础上,选择合适的抗体、连接子和细胞毒剂,确定药物/抗体比值(DAR),设计几种ICAM1-ADC候选药物,并对其进行制备和表征。
通过将单克隆抗ICAM1嵌合抗体分别与两种不同的连接子(MC-VC-PAB,MaleimideGGFG peptide)和不同的药物毒剂(MMAE,Dxd)结合,设计并构建了一组ICAMI ADC,包括ICAMI-MC-VC-PAB-MMAE(IC1-MMAE),ICAMI-Maleimide GGFG peptide-Dxd(IC1-Dxd)。具体化学结构如图5。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。
通过疏水相互作用色谱法(HIC)测定两种ICAM1 ADCs的DAR值,得到IC1-MMAE的DAR为4,IC1-Dxd的DAR为8。
实施例6体外细胞毒实验-CCK8实验
CCK8实验测定2种人宫颈癌细胞系Si-Ha、Ca-Ski和1种正常宫颈细胞HcerEpic的IC50值。细胞以每孔5000个细胞的密度接种在96孔培养皿中,培养过夜,贴壁后加入两种不同的ICAM1 ADC(IC1-MMAE、IC1-Dxd)药物作用,药物浓度为0-10μg/mL,10倍连续稀释,共8个浓度,3个平行孔。细胞和药物培养72小时后,弃去原培养基,用新鲜细胞培养基将CCK8检测试剂10倍稀释,100PL/孔加入到96孔板中,37℃孵育,最后用酶标仪在450nm的吸收波长下读取吸光值(OD)。通过比较药物孵育的细胞与不加药物孵育的对照细胞的吸光度来确定细胞活力。
比较两种ADC候选药物在两株宫颈癌肿瘤细胞Si-Ha和Ca-Ski和正常宫颈细胞HcerEpic的体外抑制活性IC50,可以看出,IC1-MMAE和IC1-Dxd在肿瘤细胞Si-Ha和Ca-Ski中的杀伤效果比在正常宫颈细胞HcerEpic更显著,IC1-Dxd对正常宫颈细胞基本没有杀伤效果。而在Si-Ha和Ca-Ski中,IC1-MMAE杀伤效果更好,IC50分别为0.1198μg/ml和1.149μg/ml;IC1-Dxd的杀伤效果稍差,IC50基本在10μg/ml以上,IC50是IC1-MMAE的10-100倍。
和临床上治疗宫颈癌的一线标准化疗药物顺铂(Cisplatin,Cis)和紫杉醇(Paclitaxel,Pac)进行对比,可知Pac的对细胞系的杀伤效果比Cis更显著,IC50相差1000-10000倍。Cis在肿瘤细胞和正常宫颈细胞中杀伤效果无显著差别,IC50均在100μg/ml以上;Pac在Si-Ha的IC50为0.1254μg/ml,Ca-Ski的IC50为0.0036μg/ml,而Pac对正常宫颈细胞的杀伤力更强,IC50为0.0016μg/ml,杀伤效果要强2-100倍,可能会导致更多的不良反应。
因此,综合考虑IC1-MMAE为最优化的ICAM1 ADC药物。本实验测定了2种ADC药物IC1-MMAE、IC1-Dxd和2种临床用一线化疗药物Cis、Pac在2种人宫颈癌细胞系(Si-Ha和Ca-Ski)和1种正常宫颈细胞(HcerEpic)的IC50值。结果如图6。
本发明中确定了ICAM1是治疗宫颈癌的一个新的ADC靶点,且设计、制备并表征了2个ADC候选药物,确定了其良好的体外抗肿瘤活性和生物安全性,为宫颈癌研发一类新的ADC药物的提供了新的方向。
基于ADC药物的组成特点,本发明验证了ICAM1靶蛋白在宫颈癌组织和细胞系表面的过表达水平,及在癌旁组织和正常宫颈细胞的低表达或不表达。结合ADC的靶向作用原理,抗ICAM1抗体能否被细胞膜上的抗原靶点介导内吞,是影响ADC疗效的另一个重要因素。内化、转运或再循环有关的干扰、抗原的脱落以及ADC的溶酶体降解缺陷都会导致药物释放的减少,从而影响ADCs的疗效,因此还测定了ICAM1 ADC在ICAM1+的宫颈癌细胞介导的内吞作用下,令人满意的内化效率,即1h内均能达到30%。
在设计ADC候选药物IC1-MMAE和IC1-Dxd上,通过对比抗体常用单克隆抗体,拟定用的是lgG1亚型的抗体,抗ICAM1抗体。连接子选用可裂解连接子,包括连接子MC-Val-Cit-PAB(MC-VC-PAB),是一种蛋白酶裂解的连接子;选择了在体内循环更稳定的马来酰亚胺-GGFG接头(Maleimide GGFG peptide),它在细胞内酶(如蛋白酶)的裂解作用下,能更好地控制释放药物。选用的细胞毒剂MMAE、Dxd是临床上使用的ADC毒剂,包括作用于细胞增殖分化过程,抗细胞有丝分裂的微管抑制剂一甲基奥瑞斯他汀E(monomethyl auristatin E,MMAE),和拓扑异构酶I抑制剂,一种具有独特六环结构的喜树碱的水溶性结构类似物exatecan的高效衍生物deruxtecan(DXd)。抗体/药物比值DAR为4和8,在临床上现有的ADC合适范围内,能平衡有效性和毒性。研究中可发现这两种ADC候选药物IC1-MMAE和IC1-Dxd都有其优越之处,在特异性杀伤肿瘤细胞上比Cis和Pac更佳。与IC1-MMAE相比,IC1-Dxd对正常宫颈细胞基本无杀伤作用,靶向特异性好;IC1-MMAE对肿瘤细胞的综合杀伤效果更好,IC50值比IC1-Dxd高10倍。
综上所述,本研究探索ICAM1新靶点在宫颈癌中开发新型ADC的可能性,确定了一种ICAM1靶向ADC的最佳药物IC1-MMAE,为宫颈癌的靶向治疗提供了一种有前途的靶向治疗候选药物。
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宫颈癌治疗或诊断产品中的用途
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
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Ile Asp Tyr Ala Ile His Trp Val Lys Glu Ser His Ala Lys Ser Leu
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Glu Trp Ile Gly Val Ile Ser Ala Tyr Ser Gly Asp Thr Asn Tyr Asn
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Claims (12)
1.ICAM1或其编码基因作为靶标在制备宫颈癌治疗或诊断产品中的用途。
2.特异性结合ICAM1的物质在制备宫颈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、腺相关病毒、纳米颗粒、脂质体、细胞外囊泡或细胞。
12.根据权利要求2所述的用途,其特征在于,所述宫颈癌选自鳞癌、腺癌或腺鳞癌。
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