CN117122680B - 一种可有效抑制bap1失活突变型葡萄膜黑色素瘤脏器转移的靶向抑制剂 - Google Patents
一种可有效抑制bap1失活突变型葡萄膜黑色素瘤脏器转移的靶向抑制剂 Download PDFInfo
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Abstract
本发明涉及生物医药领域,公开了一种可有效抑制BAP1失活突变型葡萄膜黑色素瘤脏器转移的靶向抑制剂,靶向抑制剂由靶向ITGB2的抑制剂和靶向ICAM1的抑制剂组成。本发明的ITGB2和ICAM1抑制剂可有效地抑制BAP1失活突变型葡萄膜黑色素瘤的肝转移,通过实验检测证明,ITGB2和ICAM1抑制剂可有效抑制BAP1失活突变型葡萄膜黑色素瘤的缺氧微环境和高细胞外基质微环境,从而有效地抑制BAP1失活突变型葡萄膜黑色素瘤的肝转移,可应用于制备抗BAP1失活突变型葡萄膜黑色素瘤的药物。
Description
技术领域
本发明涉及靶向抑制剂领域,尤其涉及一种可有效抑制BAP1失活突变型葡萄膜黑色素瘤脏器转移的靶向抑制剂、应用及药物。
背景技术
葡萄膜黑色素瘤来源于基质中的黑素细胞,是成年人最常见的原发性眼内肿瘤。约90%的葡萄膜黑色素瘤发生在脉络膜,7%发生在睫状体,3%发生在虹膜。高达50%的葡萄膜黑色素瘤病例在平均2.4年内发生转移,其中最常见的转移部位为肝脏(约85%)。一旦发生转移,患者的生存期明显缩短,约90%的患者将在6个月内死亡。葡萄膜黑色素瘤可分为转移风险较低的1类葡萄膜黑色素瘤和具有高转移风险的2类葡萄膜黑色素瘤。2类葡萄膜黑色素瘤通常含有BRCA1相关蛋白1(BAP1)失活突变,该突变与短期存活和葡萄膜黑色素瘤的转移有关。然而BAP1失活突变促进葡萄膜黑色素瘤转移的发生发展机制仍然不清楚。
作为一种当前难以治愈的眼部疾病,葡萄膜黑色素瘤目前主要的治疗方法有下面几种:手术治疗,尽早手术治疗可有效延长生存期;放射治疗,肿瘤较大累及周围器官,或姑息性手术者或无法切除者可行低能X线和电子线混合射线放射治疗;化学治疗,对肿瘤较大累及周围器官者,或姑息性手术者,或无法切除者,或已发现远处转移者,应行放疗与化疗综合治疗。然而,截至目前为止,可用于治疗转移性的葡萄膜黑色素瘤的药物有限,导致患者的预后非常差。因此有必要提供一种新的针对BAP1失活突变导致的葡萄膜黑色素瘤转移的药物。
发明内容
本发明的主要目的在于解决现有技术中治疗转移性的葡萄膜黑色素瘤的药物有限,导致患者的预后非常差的问题。
一种可有效抑制BAP1失活突变型葡萄膜黑色素瘤脏器转移的靶向抑制剂,所述靶向抑制剂由靶向ITGB2的抑制剂和靶向ICAM1的抑制剂组成。
所述靶向抑制剂的给予量为6-10mg/kg动物体重。
所述靶向ITGB2的抑制剂为Anti-ITGB2 mAb。
所述靶向ICAM1的抑制剂为Anti-ICAM-1 mAb。
所述靶向ITGB2的抑制剂的给予量为2-10mg/kg动物体重。
所述靶向ICAM1的抑制剂的给予量为2-10mg/kg动物体重。
本发明还涉及可有效抑制BAP1失活突变型葡萄膜黑色素瘤脏器转移的靶向抑制剂在制备预防和治疗肿瘤药物中的应用。
所述药物的剂型为任何药物治疗学上可接受的剂型。
所述药物的剂量为任何药物治疗学上可接受的剂量。
一种预防或治疗突变型葡萄膜黑色素瘤脏器转移的药物,包含靶向抑制剂以及药学上可接受的载体。
本发明的优异效果是:
本发明的研究人员通过研究发现,ITGB2和ICAM1抑制剂具有抑制BAP1失活突变型葡萄膜黑色素瘤肝转移的功效。该应用给ITGB2和ICAM1抑制剂提供了新用途,为治疗BAP1失活突变型葡萄膜黑色素瘤肝转移提供了一种新的药物。研究发现,ITGB2和ICAM1抑制剂对于治疗BAP1失活突变型葡萄膜黑色素瘤肝转移的药效明显,应用前景广泛,具有较大的推广应用价值。
附图说明
图1为动物实验1各组小鼠的肝转移灶的超声照片,方框指示代表性的肝转移灶;
图2为动物实验1各组小鼠的肝转移灶数量统计图;
图3为动物实验1各组小鼠的肝脏照片;
图4为动物实验1各组小鼠的肝转移灶缺氧相关基因的表达量(RT-PCR)统计图;
图5为动物实验1各组小鼠的肝转移灶细胞外基质相关基因的表达量(RT-PCR)统计图;
图6为动物实验1各组小鼠的肝转移灶缺氧相关蛋白(HIF2A和ENO1)的IHC代表性照片及统计图;
图7为动物实验1各组小鼠的肝转移灶细胞外基质相关蛋白(LOX和VCAN)的IHC代表性照片及统计图。
具体实施方式
本发明的说明书和权利要求书及上述附图中的术语“第一”、“第二”、“第三”、“第四”等(如果存在)是用于区别类似的对象,而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的实施例能够以除了在这里图示或描述的内容以外的顺序实施。此外,术语“包括”或“具有”及其任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
本实施例中,Anti-ITGB2 mAb (BioLegend, USA; 302116)是一种靶向ITGB2的抑制剂,ITGB2:CD18, LAD, LCAMB, LFA-1, MAC-1, MF17, MFI7, integrin subunit beta2。
ITGB2 是一个编码整合素 β2(Integrin Beta 2)蛋白的基因。整合素是一类膜上受体,它们在细胞-细胞和细胞-基质相互作用中发挥重要作用。ITGB2 是整合素家族的成员之一,与免疫细胞的功能密切相关。
抗体是免疫系统产生的蛋白质,能够特异性地结合目标分子(抗原)。单克隆抗体(mAb)是一种由单一细胞克隆产生的抗体,具有高度特异性和一致性。
本实施例中,Anti-ICAM-1 mAb (Bio X Cell, USA; BE0020-2)是一种靶向ICAM1的抑制剂。ICAM1: BB2, CD54, P3.58, intercellular adhesion molecule 1。
ICAM-1 是一种细胞间粘附分子,它在免疫系统和炎症过程中发挥重要作用。ICAM-1 位于细胞膜表面,可以与其他细胞表面上的配体(如白细胞整合素 LFA-1)相互作用,从而介导细胞间的黏附和信号传递。
本发明的研究人员通过研究发现,Anti-ITGB2 mAb和Anti-ICAM-1 mAb具有治疗治疗BAP1失活葡萄膜黑色素瘤肝转移的功效。该应用给Anti-ITGB2 mAb和Anti-ICAM-1mAb提供了新用途,为治疗BAP1失活葡萄膜黑色素瘤提供了一种新的药物。研究发现,Anti-ITGB2 mAb和Anti-ICAM-1 mAb对于治疗BAP1失活葡萄膜黑色素瘤的药效明显,应用前景广泛,具有较大的推广应用价值。
下面结合具体实施例内容以及附图详细介绍本发明的技术研究方案及效果。未注明具体条件的实验方法,通常按照常规实验方案条件,例如教科书、实验指南以及产品说明书中所述条件,或按照制造厂商所建议的条件,为本领域相关技术研究人员掌握或易于获取,以下实施例仅为本发明的优选实施例,并不限制本发明,对于本领域的相关技术研究人员来说,本发明可以有各种条件和方案上的选择与优化,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
以下为动物试验。
脾注射模型具有造模方法简单,转移率高的优点,能较好地模拟葡萄膜黑色素瘤肝转移的临床特征。该动物模型被广泛用于抑制肿瘤肝转移的药物筛选与检测。本试验采用脾注射模型诱发葡萄膜黑色素瘤肝转移。
动物实验1
将12只18周龄大小的雌性huHSC-NCG小鼠,随机分成6组,每组2只。分为BAP1-WT-Control 组(WT组)、BAP1-WT-ITGB2组 (WIT组)、BAP1-WT-ICAM1 (WIC组)、BAP1-MUT-Control (MUT组)、BAP1-MUT- ITGB2 (MIT组) and BAP1-MUT- ICAM1组(MIC组)。
BAP1-WT组(WT组、WIT组和WIC组)第0天进行脾注射,注射BAP1-WT的MUM2B细胞,每只注射3×105个细胞(3×105个细胞悬于50微升PBS中)。
BAP1-MUT组(MUT组、MIT组和MIC组)第0天进行脾注射,注射BAP1-KO(BAP1敲除)的MUM2B细胞,每只注射3×105个细胞(3×105个细胞悬于50微升PBS中)。
WT组和MUT组在第16天,第19天和第22天的同一时间,腹腔注射IgG2a (Bio XCell, USA; BE0085) 200微克。
WIT组和MIT组在第19天,第19天和第22天的同一时间,腹腔注射anti-ITGB2 mAb(BioLegend, USA; 302116) 120微克。
MIC组和MIC组在第22天,第19天和第22天的同一时间,腹腔注射anti-ICAM-1 mAb(Bio X Cell, USA; BE0020-2) 200微克。
在第23天对小鼠的肝脏进行超声探查并统计肝转移灶数量。肝转移灶数量计算方法:每只小鼠取三个肝截面计算转移灶数量,每组两只小鼠,共统计每一组六个肝截面的转移灶数量。使用two-way ANOVA (*代表p < 0.05, **代表p < 0.01, ***代表p < 0.001,and ****代表p < 0.0001)评估统计学差异。
在第23天超声探查结束后处死小鼠,取小鼠肝转移灶提取RNA行RT-PCR和包埋切片行免疫组化。
从图1和图3可知,WT组小鼠的肝转移灶明显少于MUT组小鼠的肝转移灶;WIT与WIC组的肝转移灶与WT组无明显差异。而MIT与MIC组的肝转移灶较MUT组明显减少。
将六组小鼠的肝转移灶数量制成柱状图,并进行统计学分析,如图2所示,WT组小鼠的肝转移灶明显少于MUT组小鼠的肝转移灶(p < 0.0001);WIT与WIC组的肝转移灶数量与WT组无统计学差异。而MIT与MIC组的肝转移灶数量较MUT组明显减少(p< 0.0001和p <0.05)。
从图4和图5的RT-PCR结果可知,MUT组小鼠的肝转移灶的缺氧相关基因和细胞外基质相关基因的表达量明显高于WT组,经过ITGB2和ICAM1抑制剂的治疗后,MIT组和MIC组小鼠的肝转移灶的缺氧相关基因和细胞外基质相关基因的表达量明显低于MUT组。由此可知,ITGB2和ICAM1抑制剂可通过缓解缺氧微环境和细胞外基质抑制BAP1失活葡萄膜黑色素瘤的肝转移。
从图6和图7的IHC结果可知,MUT组小鼠的肝转移灶的缺氧相关蛋白(HIF2A和ENO1)和细胞外基质相关蛋白(LOX和VCAN)表达量明显高于WT组,经过ITGB2和ICAM1抑制剂的治疗后,MIT组和MIC组小鼠的肝转移灶的缺氧相关基因和细胞外基质相关蛋白的表达量明显低于MUT组。
本发明的ITGB2和ICAM1抑制剂可有效地抑制BAP1失活突变型葡萄膜黑色素瘤的肝转移,通过实验检测证明,ITGB2和ICAM1抑制剂可有效抑制BAP1失活突变型葡萄膜黑色素瘤的缺氧微环境和高细胞外基质微环境,从而有效地抑制BAP1失活突变型葡萄膜黑色素瘤的肝转移,可应用于制备抗BAP1失活突变型葡萄膜黑色素瘤的药物。
以上所述,以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (5)
1.一种靶向抑制剂在制备预防和治疗BAP1失活突变型葡萄膜黑色素瘤肝转移药物中的应用,其特征在于,所述靶向抑制剂由靶向ITGB2的抑制剂和靶向ICAM1的抑制剂组成,所述靶向ITGB2的抑制剂为Anti-ITGB2 mAb,所述靶向ICAM1的抑制剂为Anti-ICAM-1 mAb。
2.如权利要求1所述的应用,其特征在于,所述靶向抑制剂的给予量为6-10mg/kg动物体重。
3.如权利要求1所述的应用,其特征在于,所述靶向ITGB2的抑制剂的给予量为2-10mg/kg动物体重。
4.如权利要求1所述的应用,其特征在于,所述靶向ICAM1的抑制剂的给予量为2-10mg/kg动物体重。
5.如权利要求1所述的应用,其特征在于,所述药物的剂型为任何药物治疗学上可接受的剂型。
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