CN114533872B - 靶向cd24的胃癌治疗方法 - Google Patents
靶向cd24的胃癌治疗方法 Download PDFInfo
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- CN114533872B CN114533872B CN202011302899.4A CN202011302899A CN114533872B CN 114533872 B CN114533872 B CN 114533872B CN 202011302899 A CN202011302899 A CN 202011302899A CN 114533872 B CN114533872 B CN 114533872B
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Abstract
本发明提供了一种靶向CD24的胃癌治疗方法。具体地,提供了CD24抑制剂的用途,用于制备一药物组合物,所述药物组合物用于预防和/或治疗胃癌。本发明首次发现CD24抑制剂可用于治疗胃癌,从而提供了一种新的胃癌靶向治疗方法。
Description
技术领域
本发明涉及医药领域,具体涉及一种靶向CD24的胃癌治疗方法。
背景技术
胃癌是世界上第五大最常见的癌症类型,也是第三大最常见的癌症相关死亡原因,在中国等的东亚国家发病率和致死率都非常高。胃癌的发生率和死亡率与地区以及环境因素密切相关,如不良饮食、生活习惯和幽门螺杆菌感染。
早期胃癌的治疗方法包括内镜下切除、外科手术(胃切除术)、抗生素治疗根除幽门螺杆菌(Helicobacter pylori)以及辅助治疗。过去20年里,在胃癌的手术治疗、术后护理及多学科治疗方面取得了一些进步,但胃癌的预后仅稍有改善。对于治疗晚期胃癌则非常困难,这是导致胃癌高死亡率的主要原因。目前,晚期胃癌的一线治疗是基于铂类药物和5-氟尿嘧啶(5-Fu)的化学疗法。此外,曲妥珠单抗已被批准用于人类表皮生长因子受体2(HER-2)阳性胃癌患者的一线治疗。以血管内皮生长因子(VEGF)为靶标的药物ramucirumab也已被批准用于一线治疗方案失败的晚期胃癌患者。尽管有许多治疗胃癌的方法,但全世界胃癌的总生存率仅约20%。
近年来,对肿瘤免疫疗法的研究为癌症的治疗带来了新的希望和前景。但由于胃癌免疫微环境的复杂性和肿瘤异质性等原因,免疫疗法在胃癌治疗中研究仍然非常欠缺。
因此,本领域急需提供新的胃癌靶向治疗方法。
发明内容
本发明的目的是提供一种新的胃癌靶向治疗方法。
本发明第一方面,提供了一种CD24抑制剂的用途,用于制备一药物组合物,所述药物组合物用于预防和/或治疗胃癌。
在另一优选例中,所述药物组合物用于上调选自下组的细胞对肿瘤组织的浸润:CD4+T细胞、CD8+T细胞、B细胞、M1型巨噬细胞,或其组合。
在另一优选例中,所述药物组合物用于下调调节T(Treg)细胞和/或M2型巨噬细胞对肿瘤组织的浸润。
在另一优选例中,所述胃癌为对PD-1和/或PD-L1抑制剂不敏感的胃癌或对PD-1和/或PD-L1抑制剂产生抗药性的胃癌。
在另一优选例中,所述胃癌为CD24高表达的胃癌。
在另一优选例中,所述胃癌选自下组:原位胃癌、肠型胃癌、弥散性胃癌、胃腺癌、幽门螺杆菌诱导的胃癌,或其组合。
在另一优选例中,所述胃癌为早期胃癌、中期胃癌或晚期胃癌。
在另一优选例中,所述抑制剂选自下组:靶向CD24和/或其受体蛋白的抗体或小分子抑制剂;靶向CD24和/或其受体基因的靶向核酸分子或基因编辑器;或其组合。
在另一优选例中,所述小分子抑制剂包括小分子抑制剂化合物及其药学上可接受的盐。
在另一优选例中,所述CD24的受体为唾液酸结合的类免疫球蛋白样凝集素10(Siglec-10)。
在另一优选例中,所述抗体选自下组:多克隆抗体、单克隆抗体、嵌合抗体、双特异性抗体、抗体偶联物、小分子抗体、抗体融合蛋白,及其组合。
在另一优选例中,所述小分子抗体选自下组:单链抗体ScFv,Fab抗体,Fv片段,及其组合。
在另一优选例中,所述ScFv抗体包括在治疗细胞中表达(包括过表达)的分泌型单链抗体。
在另一优选例中,所述治疗细胞包括间充质干细胞、CAR-T细胞、TCR-T细胞、(CAR-)NK细胞、巨噬细胞、树突细胞。
在另一优选例中,所述抑制剂选自下组:植物提取物抑制剂、小分子化合物抑制剂、核酸类抑制剂、肽类抑制剂、多糖类抑制剂、病毒载体抑制剂、脂质体载体抑制剂、或纳米颗粒载体抑制剂。
在另一优选例中,所述载体包括:细菌质粒、噬菌体、酵母质粒、植物细胞病毒、哺乳动物细胞病毒如腺病毒、逆转录病毒、或其他载体。
在另一优选例中,所述药物组合物还包括第二治疗剂,其中,所述第二治疗剂选自下组:PARP1/2抑制剂、诱导癌细胞DNA损伤的化疗药物、DNA烷基化类疗药物、DNA或RNA合成抑制剂、EGFR、ALK或FGFR酪氨酸受体激酶抑制剂、KRAS、MEK或ERK肿瘤信号通路抑制剂、肿瘤免疫疗法药物(如PD-1抑制剂、PD-L1抑制剂等)。
在另一优选例中,所述药物组合物还包括药学上可接受的载体。
本发明第二方面,提供了一种治疗胃癌的方法,包括步骤:给予向有需要的对象治疗有效量的CD24抑制剂,从而治疗胃癌。
在另一优选例中,所述对象为哺乳动物。
在另一优选例中,所述对象选自下组:人、大鼠或小鼠。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1.(A)在TCGA数据库中分析发现胃腺癌中CD24的mRNA表达水平高于健康对照;(B-C)在螺旋杆菌Helicobacter felis(H.felis)和致癌剂MNU诱导的小鼠模型以及正常对照小鼠中,利用流式细胞法分析胃上皮细胞的CD24表达量,发现H.felis/MNU胃癌模型中胃上皮细胞膜表面CD24的表达高于正常小鼠。**p<0.001,****p<0.0001。
图2.(A)在TCGA数据库中分析发现胃腺癌中CD24的mRNA表达水平显著高于其他两种免疫抑制分子CD47和PD-L1;(B)在螺旋杆菌Helicobacter felis(H.felis)和致癌剂MNU诱导的小鼠模型中,利用流式细胞法分析胃上皮细胞的三种分子的表达量,发现CD24的表达明显高于CD47和PD-L1。**p<0.001,***p<0.001。
图3.在螺旋杆菌Helicobacter felis(H.felis)和致癌剂MNU诱导的小鼠模型中,给已成瘤的小鼠腹腔注射CD24抗体、PD-1抗体或者IgG对照,经过6周的治疗后发现CD24抗体能明显减少胃部肿瘤面积,而PD-1抗体无显著作用。*p<0.01,N.S.=无显著性。
图4.在螺旋杆菌Helicobacter felis(H.felis)和致癌剂MNU诱导的小鼠模型中,给已成瘤的小鼠腹腔注射CD24抗体、PD-1抗体或者IgG对照,经过6周的治疗后对胃组织切片进行HE染色,发现CD24抗体能明显减少胃部肿瘤的大小以及腺体结构的异常表型,而PD-1抗体无显著作用。
图5.在螺旋杆菌Helicobacter felis(H.felis)和致癌剂MNU诱导的小鼠模型中,给已成瘤的小鼠腹腔注射CD24抗体或者IgG对照,经过6周的治疗后对胃组织进行流式细胞法分析,发现CD24抗体能明显增加CD4 T、CD8 T、B细胞和M1型巨噬细胞等具有抗肿瘤功能的免疫细胞的比例,并且能降低促肿瘤的调节T细胞以及M2型巨噬细胞的比例。*p<0.01。
具体实施方式
本发明人经过广泛而深入的研究,通过大量筛选和测试,提供了一种通过靶向CD24的胃癌治疗方法。本发明首次发现,CD24在胃癌细胞中显著高表达,且施用CD24抗体可有效治疗胃癌。进一步地,发现CD24抗体能明显上调CD4T、CD8T、B细胞和M1型巨噬细胞等具有抗肿瘤功能的免疫细胞的比例,并且能上调促肿瘤的调节T细胞以及M2型巨噬细胞的比例,从而抑制胃癌。此外,还发现CD24抑制剂能够抑制对PD-1和/或PD-L1抑制剂不敏感的胃癌。在此基础上完成了本发明。
术语
除非另有定义,否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用,术语“室温”是指温度为4-40℃,较佳地,25±5℃。
如本文所用,术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。
如本文所用,术语“上调””指与不施用本发明的活性组分相比,某一指标的量提高至1.2倍,优选地,1.5倍、2.0倍或3.0倍。
如本文所用,术语“下调””指与不施用本发明的活性组分相比,某一指标的量降低至0.8倍,优选地,0.5倍或0.3倍。
CD24
CD24,也称为热稳定抗原,是一高度糖基化的糖基磷脂酰肌醇锚定的细胞表面蛋白。CD24和固有免疫细胞上的Siglec-10分子相互作用,传递免疫抑制性信号,来抑制炎症反应。
CD24抑制剂
本发明的CD24抑制剂包括靶向CD24和/或其受体蛋白的抗体或小分子抑制剂;靶向CD24和/或其受体基因的靶向核酸分子或基因编辑器;或其组合。
特别优选地为CD24单克隆抗体、Siglec-10单克隆抗体,或其组合。
药物组合物及应用
本发明的药物组合物包含上述CD24抑制剂作为活性成分。
实验证明,本发明的药物组合物具有显著的治疗胃癌的效果,可用于治疗胃癌的药物。
特别地,本发明的药物组合物可用于治疗对PD-1和/或PD-L1抑制剂不敏感的胃癌或对PD-1和/或PD-L1抑制剂产生抗药性的患者体内的的胃癌。
本发明的药物组合物包含安全有效量范围内的本发明抑制剂或其药理上可接受的盐及药理上可以接受的赋形剂或载体。
如本文所用,术语“治疗有效剂量”是指药物的任何如下所述的量,当单独使用或与另一种治疗剂组合使用该量的药物时,可促进疾病消退,疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。
本发明药物的“治疗有效剂量”也包括“预防有效剂量”,“预防有效剂量”是药物的任何如下所述的量,当将该量的药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时,可抑制疾病的发生或复发。
通常,药物组合物含有1-2000mg本发明活性成分/剂,更佳地,含有10-500mg本发明活性成分/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明活性成分的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明活性成分可以单独给药,或者与其他药学上可接受的治疗剂联合给药。在另一优选例中,所述药物组合物还包含一种或多种抗癌剂和/或免疫抑制剂,优选地,所述抗癌剂和/或免疫抑制剂选自下组:PARP1/2抑制剂、诱导癌细胞DNA损伤的化疗药物、DNA烷基化类疗药物、DNA或RNA合成抑制剂、EGFR、ALK或FGFR酪氨酸受体激酶抑制剂、KRAS、MEK或ERK肿瘤信号通路抑制剂、肿瘤免疫疗法药物(如PD-1抑制剂、PD-L1抑制剂等)。
在另一优选例中,所述药物组合物还包含有一种或多种抗癌剂和/或免疫抑制剂,优选地,所述抗癌剂和/或免疫抑制剂选自下组:奥拉帕尼、卢卡帕尼、尼拉帕尼、甲氨蝶呤、卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼、赫赛汀、贝伐单抗、利妥昔单抗、曲妥珠单抗、紫杉醇、长春瑞滨、多西他赛、多柔比星、羟基喜树碱、丝裂霉素、表柔比星、吡柔比星、博来霉素、来曲唑、他莫西芬、氟维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、环磷酰胺、卡莫司汀、尼莫司汀、司莫司汀、氮芥、马法兰、瘤可宁、卡铂、顺铂、奥沙利铂、络铂、拓扑特肯、喜树碱、拓扑替康、依维莫司、西罗莫斯、特癌适、6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素或氨鲁米特;如纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、伊匹单抗(ipilimumab)、阿维鲁单抗(avelumab)、度伐单抗(durvalumab)、阿特朱单抗(atezolizumab)或皮地利珠单抗(pidilizumab),或其组合。
在某些实施方式中,向患癌对象联合给予本发明的活性成分和其它传统癌治疗物,例如,放疗或手术。放疗是本领域熟知的并且包括X射线治疗,例如伽马放射,和放射药物治疗。
在某些实施方式中,本发明的活性成分在相同或分开的制剂中与作为联合治疗方案的部分的其它试剂同时使用,或与所述其它试剂依次使用。
本发明的活性成分的组合物的治疗有效剂量的一般范围将是:约1-2000mg/天、约10-约1000mg/天、约10-约500mg/天、约10-约250mg/天、约10-约100mg/天,或约10-约50mg/天。治疗有效剂量将以一个或多个剂量给予。然而,应理解,对于任何特定患者的本发明化合物的特定剂量将取决于多种因素,例如,待治疗的患者的年龄、性别、体重、一般健康状况、饮食、个体响应,给予时间、待治疗的疾病的严重性、施用的具体化合物的活性、剂型、应用模式和伴用药物。给定情况的治疗有效量能用常规实验测定,并在临床医生或医师能力和判断范围内。在任何情况中,所述化合物或组合物将基于患者的个体情况以多个剂量给予并以允许递送治疗有效量的方式给予。
本发明的主要优点包括:
1.本发明首次发现CD24抑制剂可有效治疗胃癌,提供了通过靶向抑制CD24从而治疗胃癌治疗方法,特别地,本发明的方法可用于治疗中、晚期胃癌。
2.本发明还发现CD24抑制剂可以治疗对PD-1抑制剂不敏感的胃癌,从而为此类患者提供了新的治疗方法。
下面结合具体实施,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
通用方法
流式分析:小鼠胃组织使用组织匀浆器gentleMACS Octo dissociator(MiltenyiBiotec)和1mg/mL胶原酶VI(Thermo Fisher Scientific)and 50mg/mL DNA酶I(Sigma-Aldrich)处理,分散成单细胞悬液,随后使用红细胞裂解液(BioLegend)处理。在FACS AriaII细胞仪(BD Biosciences)上采集荧光数据,并使用FlowJo软件进行数据分析。
流式抗体详细信息如下:
CD3e(145-2C11),CD11c(N418),CD11b(M1/70),CD279(PD-1;29F.1A12),F4/80(BM8),CD24(M1/69)and MHC-II(I-A/I-E;M5/114.15.2)购自BioLegend;CD4(GK1.5)和CD8a(53-6.7)购自BD Biosciences;CD45(30-F11)和Ly-6G/Ly-6C(Gr1;RB6-8C5)购自eBioscience.
免疫组化:取新鲜胃癌小鼠胃组织用4%多聚甲醛固定2小时,随后酒精梯度脱水,二甲苯透明,石蜡包埋后切片。将组织切片脱蜡并重新水化,使用苏木素和伊红(碧云天)处理组织切片,并在显微镜(Zeiss LSM 710)下观察拍照。
实施例1
幽门螺杆菌(H.felis)和N-甲基-N-的小鼠模型亚硝基脲(MNU)诱发的胃癌小鼠模型:野生型C57BL/6小鼠是通过灌胃感染螺旋杆菌Helicobacter felis(H.felis)(ATCC49179)。H.felis感染后两周,隔周给小鼠喝含240ppm MNU的饮用水,总共12周(总共暴露6周),MNU开始处理后36周获得胃癌(中晚期)小鼠模型。
对TCGA数据库中胃腺癌核酸测序数据进行分析,如图1A所示,发现CD24的mRNA表达在胃癌样品中比正常胃组织中有明显的上调。
在螺旋杆菌Helicobacter felis(H.felis)和致癌剂MNU诱导的小鼠模型以及正常对照小鼠中,利用流式细胞法分析胃上皮细胞的CD24表达量,如图1B-C所示,发现发生胃癌的小鼠胃上皮比正常对照中CD24的蛋白表达明显上升。这些结果说明胃癌发生过程中,CD24的表达有显著的上调。
此外,如图2A所示,在TCGA数据库中分析发现胃癌组织中的CD24mRNA表达水平比另外两中免疫抑制分子CD47和PD-L1的表达更高。在H.felis和MNU诱导的小鼠胃癌模型中(MNU处理开始36周后),利用流式细胞分析同样发现E-Cadherin阳性的上皮细胞中CD24的表达比CD47和PD-L1的更高,这提示CD24在胃癌中可能是比CD47和PD-L1更理想的治疗靶点。
实施例2
胃癌小鼠治疗方案:为了进行抗体治疗,从开始用MNU饮用水处理小鼠后37周开始,每周两次腹腔注射50μg CD24单克隆抗体/只/针(R&D Systems),100μg PD-1单克隆抗体/只/针(Bio X Cell)或对照IgG。连续治疗6周。治疗结束后处死小鼠,并对胃组织进行检测。
如图3所示,在胃癌小鼠模型中,给已成瘤的小鼠腹腔注射CD24抗体、PD-1抗体或者IgG对照,经过6周的治疗后发现CD24抗体能明显减少胃部肿瘤面积,而PD-1抗体无显著作用。这提示,CD24抗体可以用于治疗中晚期胃癌,尤其是对PD-1不敏感和/或产生抗药性的胃癌。
免疫染色结果如图4所示,对胃组织切片进行HE染色,发现CD24抗体能明显减少胃部肿瘤的大小以及腺体结构的异常表型,而PD-1抗体无显著作用。
流式细胞法分析结果如图5所示,结果表明CD24抗体能明显增加CD4 T、CD8 T、B细胞和M1型巨噬细胞等具有抗肿瘤功能的免疫细胞的比例,并且能降低促肿瘤的调节T细胞以及M2型巨噬细胞的比例。
综上所述,CD24在胃癌小鼠的胃上皮细胞中表达显著高于对照样本,并且相较于PD-L1和CD47也显著高表达,该现象在人类肿瘤TCGA数据库中也得到了一致的结论。
通过对螺旋杆菌Helicobacter felis(H.felis)和致癌剂MNU诱导的胃癌小鼠模型进行CD24抗体治疗,发现有非常好的治疗效果。流式细胞术分析后,发现CD24发挥效果的机制是通过增加效应T细胞(尤其是CD4+和CD8+T细胞)的浸润以及减少调节T细胞的浸润来实现,另外,治疗的结果发现治疗亦促进了肿瘤相关巨噬细胞M2型向M1型转化,这提示通过CD24抗体治疗,小鼠体内激起了免疫效应来对抗免疫抑制的肿瘤微环境,抑制肿瘤进展,从而取得良好的治疗效果。
讨论
热稳定抗原CD24在组织和肿瘤干细胞中是重要的肿瘤干细胞标志物,并与肿瘤转移、侵袭密切相关。此外,还广泛用作分化造血细胞和神经元细胞的标志物。在许多不同肿瘤类型中,均发现了CD24的高水平表达,在一项新的研究中,研究人员也发现CD24是一种新的“不要吃我”的信号('don't eat me'signal),这提示CD24是癌症免疫疗法的潜在靶标。
虽然CD24通常在肿瘤细胞中广泛表达,但并不代表抑制CD24一定可以对癌症产生治疗效果,如白血病等癌症对CD24抑制剂不敏感,所以通过抑制CD24治疗癌症的方法仍需进一步研究。
而本发明首次通过实验证明了CD24抑制剂对胃癌(尤其是中晚期胃癌)的显著疗效,从而提供了一种新的胃癌治疗方法。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (8)
1.一种CD24抑制剂的用途,其特征在于,用于制备一药物组合物,所述药物组合物用于预防和/或治疗胃癌;
所述胃癌为对PD-1和/或PD-L1抑制剂不敏感的胃癌或对PD-1和/或PD-L1抑制剂产生抗药性的胃癌;且
所述CD24抑制剂为靶向CD24的抗体。
2.如权利要求1所述的用途,其特征在于,所述药物组合物用于上调选自下组的细胞对肿瘤组织的浸润:CD4+T细胞、CD8+T细胞、B细胞、M1型巨噬细胞,或其组合。
3.如权利要求1所述的用途,其特征在于,所述胃癌为对PD-1和/或PD-L1抑制剂产生抗药性的胃癌。
4.如权利要求1所述的用途,其特征在于,所述胃癌选自下组:原位胃癌、肠型胃癌、弥散性胃癌、胃腺癌、幽门螺杆菌诱导的胃癌,或其组合。
5.如权利要求1或3所述的用途,其特征在于,所述胃癌为早期胃癌、中期胃癌或晚期胃癌。
6.如权利要求1所述的用途,其特征在于,所述抗体选自下组:多克隆抗体、单克隆抗体、嵌合抗体、双特异性抗体、抗体偶联物、小分子抗体、抗体融合蛋白,及其组合。
7.如权利要求1所述的用途,其特征在于,所述药物组合物还包括第二治疗剂,其中,所述第二治疗剂选自下组:PARP1/2抑制剂、诱导癌细胞DNA损伤的化疗药物、DNA烷基化类疗药物、DNA或RNA合成抑制剂、EGFR、ALK或FGFR酪氨酸受体激酶抑制剂、KRAS、MEK或ERK肿瘤信号通路抑制剂。
8.如权利要求1所述的用途,其特征在于,所述药物组合物还包括药学上可接受的载体。
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