CN112870369A - 用于抑制黑素瘤细胞膜表面pd-l1表达的靶向药物及应用 - Google Patents
用于抑制黑素瘤细胞膜表面pd-l1表达的靶向药物及应用 Download PDFInfo
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Abstract
本发明公开了用于抑制黑素瘤细胞膜表面PD‑L1表达的靶向药物及应用,涉及生物技术与医学领域,所述靶向药物用于抑制A20蛋白表达或降低A20蛋白的活性,抑制黑素瘤细胞膜表面PD‑L1的表达,进一步促进细胞毒性T淋巴细胞活化,该药物通过抑制黑素瘤细胞膜表面PD‑L1表达,进一步促进CD8+T细胞瘤团浸润和活化并抑制黑素瘤生长和发展,为抑制PD‑1单抗治疗抵抗、克服耐药性提供有效手段。
Description
技术领域
本发明涉及生物技术与医学领域,尤其涉及用于抑制黑素瘤细胞膜表面PD-L1表达的靶向药物及应用。
背景技术
黑素瘤是黑素细胞来源的恶性肿瘤,其发病率和致死率在近数十年来逐渐增加。在浅肤色人群中,黑色素瘤发病率按照每年3-7%的比例递增,且超过1/5的黑色素瘤患者发生肿瘤转移,与致死相关。和其他实体肿瘤相比,黑色素瘤侵袭转移比例更高,致死的平均年龄更低。因此,黑色素瘤的发病及进展的分子机制研究也受到极大关注。
恶性黑素瘤是由皮肤和其他器官黑素细胞产生的肿瘤,早期黑素瘤患者预后较好,治疗以手术为主;晚期黑素瘤的治疗效果差,死亡率高。其自然病程中出现的与淋巴细胞浸润相关的肿瘤自发回缩或消退现象,以及黑素瘤对各种免疫治疗较好的临床反应均提示了黑素瘤是一种免疫原性肿瘤。且T细胞数量和活性受损是肿瘤免疫逃避的一个重要机制,免疫抑制性分子程序性细胞死亡受体1(PD-1)通路研究在免疫靶向治疗中具有里程碑式的意义,代表药物有nivolumab、pembrolizumab等,2012年美国临床肿瘤学会年会报告的数据显示抗PD-1的免疫治疗对以黑素瘤为主的多种肿瘤有效。
PD-1是第二代免疫检查点临床靶点,它是CD28超家族的一员,是含288个氨基酸的细胞膜蛋白,表达于活化T细胞的抑制性受体,高表达于黑素瘤抗原特异性T细胞,其配体PD-L1表达于抗原呈递细胞及肿瘤细胞。PD-1与配体结合后抑制具有抗肿瘤能力的细胞毒性T细胞的活性,并下调T细胞应答,从而诱导和维持外周免疫耐受,保护组织避免免疫攻击,同时也能减弱感染性免疫和肿瘤免疫。抗PD-1抗体和抗PD-L1抗体通过竞争性地与PD-1及PD-L1结合,从而解除T细胞的免疫抑制状态,进而有效的治疗黑素瘤。虽然PD-1单抗疗法在治疗黑素瘤上有一定的疗效,但是仍存在治疗抵抗,严重限制了该疗法在临床上的使用和患者预后。
大多数细胞中A20都是低表达的,当NF-TNFκB被TNFα等炎性因子活化后,会与A20启动子区的NF-TNFκB受体结合,A20会迅速被活化并且负调控NF-TNFκB、MAPK等通路,从而改变IFNγ、TNFα、IL-12、IL10、IL-15和IL-21在内的多种细胞因子的表达水平。
因此目前急需一种抑制黑素瘤PD-1单抗免疫疗法治疗抵抗的药物,为提高PD-1单抗疗法临床疗效具有重要意义,也为治疗黑素瘤疾病提供新的方向。
发明内容
针对以上问题,本发明提供了用于抑制黑素瘤细胞膜表面PD-L1表达的靶向药物及应用,该药物通过抑制黑素瘤细胞膜表面PD-L1表达,进一步促进CD8+T细胞瘤团浸润和活化并抑制黑素瘤生长和发展,为抑制PD-1单抗治疗抵抗、克服耐药性提供有效手段。
为了实现上述发明目的,本发明提供以下技术方案:
用于抑制黑素瘤细胞膜表面PD-L1表达的靶向药物,所述靶向药物用于抑制A20蛋白表达或降低A20蛋白的活性。
进一步,所述靶向药物抑制黑素瘤细胞膜表面PD-L1的表达,促进细胞毒性T淋巴细胞(CD8+T)活化。
进一步,所述靶向药物为慢病毒携带特异性靶向A20蛋白基因TNFAIP3的shRNA表达产物。
进一步,所述慢病毒的基因组***靶向A20蛋白基因TNFAIP3的干扰RNA(shRNA)序列,通过慢病毒的表达***可以表达出该shRNA,进一步抑制TNFAIP3的表达。
进一步,靶向药物由慢病毒感染特异性靶向A20基因TNFAIP3的shRNA,其中shRNA其序列号包括:TGTAACTCTTTGGGTTATTAC;TTGGAATCAGGTTCCAATTTC。
进一步,所述靶向药物与PD-1单抗药物联合使用。
优选地,所述PD-1单抗药物包括Nivolumab、Atezolizumab、Pembrolizumab中的一种或多种。
优选地,所述靶向药物还包括稳定和/或能够增强所述靶向药物组合物效果的辅料。
优选地,慢病毒携带特异性靶向A20蛋白基因TNFAIP3的shRNA表达产物为溶液剂型。生理盐水溶液等能够为靶向药物提供稳定环境的溶液。
优选地,当所述靶向药物为一种溶液制剂时,可通过静脉注射或者局部注射使用。
进一步,所述靶向药物用治疗黑素瘤。
进一步,所述靶向药物与PD-1单抗药物联合使用用于治疗黑素瘤。
有益效果:
1、慢病毒携带特异性靶向A20蛋白基因TNFAIP3的shRNA表达产物与PD-1单抗药物协同用于抑制A20蛋白表达或降低A20蛋白的活性,进一步抑制黑素瘤细胞膜表面PD-L1表达,促进CD8+T细胞活化,抑制黑素瘤生长和发展。
2、靶向药物与PD-1单抗药物联合使用可以显著提高治疗黑素瘤的效果,提高存活率,减少瘤团体积和降低瘤团重量。
3、本发明对抑制PD-1单抗治疗抵抗、克服耐药性提供有效手段,在医药学领域的应用前景广阔。
附图说明
图1:A20与PD-L1相关性分析及A20调控PD-L1的实验结果图;
图2:单抗治疗与联合治疗的实验结果图;
图3:小鼠瘤团分析图;
图4:免疫组化染色分析和流式细胞术分析图。
具体实施方式
以下将结合具体实施例对本发明进行详细说明:
实施例1:
从图1可以看出,通过对瘤团微阵列分析发现,A20蛋白和PD-L1的表达之间呈现正相关;通过免疫印迹分析黑素瘤患者瘤团组织发现,A20蛋白和PD-L1的表达水平之间呈现正相关。通过免疫印迹和流式细胞术分析发现,沉默A20蛋白可以显著抑制人黑素瘤细胞PD-L1表达水平。
在此基础上,从图2可以看出,沉默A20蛋白可以明显降低人黑素瘤细胞膜表面PD-L1表达水平。同时发现,敲除A20蛋白表达的瘤团中PD-L1的表达明显降低。该结果表明A20蛋白可以正向调控PD-L1的表达水平。
因此,可以说明靶向药物用于抑制A20蛋白表达或降低A20蛋白的活性,进一步抑制黑素瘤细胞膜表面PD-L1的表达,促进细胞毒性T淋巴细胞(CD8+T)活化,能有效的抑制黑素瘤生长和发展,对黑素瘤的治疗具有良好的效果。
实施例2:
通过小鼠荷瘤实验确定联合抑制A20蛋白表达和PD-1单抗治疗黑素瘤的效果:
1、给予C57BL6小鼠皮下注射敲除A20蛋白的5×106个B16F10小鼠黑素瘤细胞;给予C57BL6小鼠皮下注射不敲除A20蛋白的5×106个B16F10小鼠黑素瘤细胞,待瘤团增长到100mm3后,分为A组、B组、C组、D组。
其中A组和B组为不敲除A20蛋白的小鼠,C组和D组为敲除A20蛋白的小鼠,A、B、C、D组小鼠数量均等。
2、A组和C组为不使用PD-1单抗治疗的治疗组;B组为使用PD-1单抗的单治疗组,D组为敲除A20蛋白并联合使用PD-1单抗治疗的联合治疗组,使用的PD-1单抗药物为Pembrolizumab。
单抗组和联合治疗组的PD-1单抗药物均为溶液剂型,溶剂为生理盐水。使用的Pembrolizumab浓度为:1mg/ml。
3、每2天给A组、B组、C组、D组中的所有小鼠注射一次对应药物,2周后观察瘤团体积和重量,并观察治疗后小鼠的存活情况。
得到的结果如图3所示。分析图3结果可知:
(1)治疗100天时,联合治疗组D组小鼠存活率为40%以上,单抗组B组存活率为0%左右,与单用PD-1单抗产品的B组相比,联合使用抑制A20蛋白表达和PD-1单抗产品的B组可显著延长荷瘤小鼠生存期。
(2)治疗14天时,联合治疗组D组瘤团体积约为200mm3,单抗组B组瘤团体积约为900g mm3左右,联合治疗组D组小鼠瘤团体积显著缩小。
(3)联合治疗组D组瘤团重量小于0.1g,单抗组B组瘤团重量大于0.6g,联合治疗组D组瘤团重量明显减小。
实施例3:
获取图3中所述小鼠瘤团,通过免疫组化染色进行分析,从图4可以看出:在给予PD-1单抗治疗后,与对照组相比,敲除A20可以增加瘤团内淋巴细胞浸润数量。流式细胞术分析显示敲除A20后瘤团内浸润CD8+T细胞的Ki67指数显著增加,颗粒酶B含量也显著增加,表明肿瘤浸润淋巴细胞重新活化,抑制A20对瘤团浸润淋巴细胞的重激活作用,可以增强PD-1单抗治疗时的肿瘤免疫,削弱治疗抵抗。
实施例4:小鼠实验
靶向药物的制备方法为:将慢病毒的基因组***靶向A20蛋白基因TNFAIP3的干扰RNA(shRNA)序列中,通过慢病毒的表达***可以表达出该shRNA,进一步抑制TNFAIP3的表达,抑制A20蛋白。其中,shRNA的基因序列号包括:TGTAACTCTTTGGGTTATTAC;TTGGAATCAGGTTCCAATTTC。PD-1单抗药物为Pembrolizumab。靶向药物使用浓度为:0.01mg,PD-1单抗药物:1mg/ml,每天注射一次药物。
接种有小鼠黑素瘤细胞的C57BL/6小鼠,共计20只,分成I组和II组。I组采用靶向药物+PD-1联合治疗,II组为安慰组。治疗14天时,观察小鼠情况,得到的结果如下:
治疗14天后,I组6只小鼠瘤团体积缩小15-30%,有效率为60%,3只肿瘤稳定不长大,总控制率为90%,II组安慰组小鼠瘤团体积增大100%以上,I组小鼠瘤团重量小于0.1g,II组小鼠瘤团重量大于0.5g。治疗100天后,I组存活率为60%,II组存活率为0。
因此,可以说明本发明的靶向药物,包括慢病毒携带特异性靶向A20基因TNFAIP3的shRNA表达产物和PD-1单抗药物联合使用可以显著提高治疗黑素瘤的效果,提高存活率,减少瘤团体积和降低瘤团重量。
以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。本发明未详细描述的技术、形状、构造部分均为公知技术。
Claims (10)
1.用于抑制黑素瘤细胞膜表面PD-L1表达的靶向药物,其特征在于,所述靶向药物用于抑制A20蛋白表达或降低A20蛋白的活性。
2.如权利要求1所述的靶向药物,其特征在于,所述靶向药物抑制黑素瘤细胞膜表面PD-L1的表达,促进细胞毒性T淋巴细胞活化。
3.如权利要求2所述的靶向药物,其特征在于,所述靶向药物为慢病毒携带特异性靶向A20蛋白基因TNFAIP3的shRNA表达产物。
4.如权利要求3所述的靶向药物,其特征在于,所述shRNA其序列号包括:TGTAACTCTTTGGGTTATTAC;TTGGAATCAGGTTCCAATTTC。
5.如权利要求1-4任一权利要求所述的靶向药物,其特征在于,所述靶向药物与PD-1单抗药物联合使用。
6.如权利要求5所述的靶向药物,其特征在于,所述PD-1单抗药物包括Nivolumab、Atezolizumab、Pembrolizumab中的一种或多种。
7.如权利要求6所述的靶向药物,其特征在于,所述靶向药物还包括稳定和/或能够增强所述靶向药物组合物效果的辅料。
8.如权利要求7所述的靶向药物,所述靶向药物与生理盐水制成溶液制剂。
9.用于抑制黑素瘤细胞膜表面PD-L1表达的靶向药物的应用,其特征在于,所述靶向药物用治疗黑素瘤。
10.如权利要求9所述的靶向药物的应用,其特征在于,所述靶向药物与PD-1单抗药物联合使用用于治疗黑素瘤。
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CN113671196B (zh) * | 2021-07-29 | 2023-09-12 | 中国人民解放军空军军医大学 | Lair-1分子与脂联素的相互作用对于t细胞活化作用影响的研究方法 |
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