CN114931634A - E10a与pd1单抗对肿瘤的联合治疗方法和制药用途 - Google Patents
E10a与pd1单抗对肿瘤的联合治疗方法和制药用途 Download PDFInfo
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Abstract
本发明提供了一种E10A与PD1单抗对肿瘤的联合治疗方法和制药用途,属于生物医药领域。本发明采用重组人内皮抑素腺病毒和PD1抗体联合用药,发现其具有协同增效的作用,能够明显地抑制肿瘤的生长与增殖,且具有较好的抑瘤率,为开发针对肿瘤的新的有效治疗方法提供了参考。
Description
技术领域
本发明属于生物医药领域,具体涉及E10A与PD1单抗对肿瘤的联合治疗方法和制药用途。
背景技术
肿瘤是指机体在各种致瘤因子作用下,局部组织细胞增生所形成的新生物,因为这种新生物多呈占位性块状突起,也称赘生物。根据新生物的细胞特性及对机体的危害性程度,又将肿瘤分为良性肿瘤和恶性肿瘤两大类。恶性肿瘤可分为癌和肉瘤,癌是指来源于上皮组织的恶性肿瘤;肉瘤是指间叶组织,包括纤维结缔组织、脂肪、肌肉、脉管、骨和软骨组织等,发生的恶性肿瘤。
PD-1(程序性死亡受体1)也称为CD279(分化簇279),是一种重要的免疫抑制分子,为免疫球蛋白超家族,是一个288氨基酸残基的膜蛋白。PD-1是免疫检查点,主要通过两种机制防止自身免疫,促进淋巴结中抗原特异性T细胞的凋亡(程序性细胞死亡)以及减少调节性T细胞(抗炎,抑制性T细胞)的细胞凋亡。因此,以PD-1为靶点的免疫调节对抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等均有重要的意义。其配体PD-L1也可作为靶点,相应的抗体也可以起到相同的作用。
PD1的配体PD-L1在几种癌症中高度表达,而PD-1与PD-L1结合,可以传导抑制性的信号,减低淋巴结CD8+T细胞的增生,而且PD-1还可以借由调节Bcl-2基因,控制淋巴结中抗原特异性T细胞的聚积。因此,开发增强免疫系统的靶向PD-1的单克隆抗体用于治疗癌症成为可能,例如Nivolumab、Pidilizumab、Pembrolizumab等单克隆抗体。另有研究发现,使用抗PD1和抗CTLA4抗体的组合在治疗癌症中比单独的任一种抗体更有效。因此,联合治疗已被证明在某些肿瘤的治疗中是一种更有效的治疗方法。此外,专利CN201510492057.2公开了环二核苷酸cGAMP联合PD1的抗体Nivolumab在抗肿瘤联合用药中的用途,其对腺癌、肺癌、乳腺癌、黑色素瘤、结肠癌等细胞均具有显著的抑制作用。专利CN202110200473.6则公开了顺铂纳米药和PD1/PD-L1抑制剂可联合使用用于肿瘤的治疗,其发现顺铂纳米药可诱导肿瘤PD-L1高表达,并具有剂量和时间依赖性;在静脉给药后可持续诱导肿瘤PD-L1高表达,使PD1/PD-L1抑制剂有更多的机会阻断PD1/PD-L1信号通路、活化杀伤性T细胞;在与PD1/PD-L1抑制剂联合用药中,两者可以起到协同增效作用,进一步增强对于肿瘤的抑制。
人内皮抑素(Endostatin)是一种血管生长抑制剂,可应用于“饥饿疗法”原理,广泛适用于肺癌、肝癌、胰腺癌、肠癌及前列腺癌等各种实体瘤的治疗。目前,尚未有研究将人内皮抑素和PD1抗体联合使用治疗肿瘤的相关报道。
发明内容
针对上述不足,本发明提供了一种治疗肿瘤的联合用药物。本发明采用人内皮抑素腺病毒和PD1抗体联合用药,发现其可明显抑制肿瘤的生长和发育,具有较好的抗肿瘤作用,为肿瘤的治疗提供了一种新的思路与方法。
为了实现上述发明目的,本发明的技术方案如下:
一方面,本发明提供了一种人内皮抑素腺病毒和PD1抗体联用在制备抗肿瘤药物中的应用。
具体地,所述的人内皮抑素腺病毒每1次以5-1000×109vp/kg进行给药,优选为1-80×1010vp/kg,进一步优选为2-50×1010vp/kg。
进一步具体地,所述的人内皮抑素腺病毒以每周1-2次给药,优选为每周1次。
具体地,所述的PD1抗体包括但不限于替雷利珠单抗、尼伏单抗、潘利珠单抗、阿替珠单抗、度伐单抗、阿维单抗或特瑞普利单抗等,优选为特瑞普利单抗。
进一步具体地,所述的特瑞普利单抗每1次以1-100mg/kg进行给药,优选为3-20mg/kg,进一步优选为5-10mg/kg。
进一步具体地,所述的特瑞普利单抗以每周1-3次给药,优选为每周2次。
具体地,所述的人内皮抑素腺病毒和PD1抗体分开给药。
具体地,所述的人内皮抑素腺病毒和PD1抗体同时或依次给药。
具体地,所述的人内皮抑素腺病毒和PD1抗体通过瘤内注射、静脉注射或腹腔注射给药。
具体地,所述的肿瘤为实体瘤。
进一步具体地,所述的肿瘤包括但不限于:黑色素瘤、卵巢癌、乳腺癌、宫颈癌、非小细胞肺癌、甲状腺癌、肝癌、食管癌、肺癌、前列腺癌、膀胱癌、成胶质细胞瘤、胃癌、结肠癌、肾癌等。
进一步具体地,所述的肿瘤为结肠癌。
另一方面,本发明提供了一种抗肿瘤药物,所述的药物包括上述人内皮抑素腺病毒和PD1抗体。
具体地,所述的人内皮抑素腺病毒每1次以5-1000×109vp/kg进行给药,优选为1-80×1010vp/kg,进一步优选为2-50×1010vp/kg。
进一步具体地,所述的人内皮抑素腺病毒以每周1-2次给药,优选为每周1次。
具体地,所述的PD1抗体包括但不限于替雷利珠单抗、尼伏单抗、潘利珠单抗、阿替珠单抗、度伐单抗、阿维单抗或特瑞普利单抗等,优选为特瑞普利单抗。
进一步具体地,所述的特瑞普利单抗每1次以1-100mg/kg进行给药,优选为3-20mg/kg,进一步优选为5-10mg/kg。
进一步具体地,所述的特瑞普利单抗以每周1-3次给药,优选为每周2次。
具体地,所述的人内皮抑素腺病毒和PD1抗体分开给药。
具体地,所述的人内皮抑素腺病毒和PD1抗体同时或依次给药。
具体地,所述的人内皮抑素腺病毒和PD1抗体通过瘤内注射、静脉注射或腹腔注射给药。
具体地,所述的肿瘤为实体瘤。
进一步具体地,所述的肿瘤包括但不限于:黑色素瘤、卵巢癌、乳腺癌、宫颈癌、非小细胞肺癌、甲状腺癌、肝癌、食管癌、肺癌、前列腺癌、膀胱癌、成胶质细胞瘤、胃癌、结肠癌、肾癌等。
进一步具体地,所述的肿瘤为结肠癌。
具体地,所述的药物还包括药学上可接受的载体,所述的载体为缓释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、吸附载体、表面活性剂或润滑剂中的任意一种或两种以上的混合物。
又一方面,本发明还提供了一种肿瘤的治疗方法,所述的方法包含:将有效量的人内皮抑素腺病毒和有效量的PD1抗体组合对对象进行给药。
具体地,所述的人内皮抑素腺病毒每1次以5-1000×109vp/kg进行给药,优选为1-80×1010vp/kg,进一步优选为2-50×1010vp/kg。
进一步具体地,所述的人内皮抑素腺病毒以每周1-2次给药,优选为每周1次。
具体地,所述的PD1抗体包括但不限于替雷利珠单抗、尼伏单抗、潘利珠单抗、阿替珠单抗、度伐单抗、阿维单抗或特瑞普利单抗等,优选为特瑞普利单抗。
进一步具体地,所述的特瑞普利单抗每1次以1-100mg/kg进行给药,优选为3-20mg/kg,进一步优选为5-10mg/kg。
进一步具体地,所述的特瑞普利单抗以每周1-3次给药,优选为每周2次。
具体地,所述的人内皮抑素腺病毒和PD1抗体分开给药。
具体地,所述的人内皮抑素腺病毒和PD1抗体同时或依次给药。
具体地,所述的人内皮抑素腺病毒和PD1抗体通过瘤内注射、静脉注射或腹腔注射给药。
具体地,所述的肿瘤为实体瘤。
进一步具体地,所述的肿瘤包括但不限于:黑色素瘤、卵巢癌、乳腺癌、宫颈癌、非小细胞肺癌、甲状腺癌、肝癌、食管癌、肺癌、前列腺癌、膀胱癌、成胶质细胞瘤、胃癌、结肠癌、肾癌等。
进一步具体地,所述的肿瘤为结肠癌。
与现有技术相比,本发明的积极和有益效果在于:
本发明采用人内皮抑素腺病毒联合PD1抗体作为联合用药物,发现其具有协同增效的作用,能够明显地抑制肿瘤的生长与增殖,且具有较好的抑瘤率,为开发针对肿瘤的新的有效治疗方法提供了参考。
附图说明
图1为小鼠体重变化检测结果图。
图2为结肠癌CT26移植瘤肿瘤生长曲线图。
图3为肿瘤重量检测结果图。
具体实施方式
下面结合具体实施例,对本发明作进一步详细的阐述,下述实施例不用于限制本发明,仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明,实施例中未注明具体条件的实验方法,通常按照常规条件,下述实施例中所使用的材料、试剂等,如无特殊说明,均可从商业途径得到。
1.人内皮抑素腺病毒
本发明所述的人内皮抑素腺病毒携带重组构建的人内皮抑素基因,转染肿瘤细胞后可表达人内皮抑素,抑制血管内皮细胞增殖,一直肿瘤血管的生成,阻断肿瘤组织血液供应,从而特异性地抑制肿瘤生长、诱导肿瘤细胞的凋亡。
在以下实施例中,本发明所述的人内皮抑素腺病毒购自广州达博生物制品有限公司,批号为A20210501,样品代号为E10A。
本发明所述的人内皮抑素腺病毒理化性质及生物特性如下:性状:融化至室温后为无色澄明液体;含量(浓度):1×1012vp/mL;规格:1mL/瓶;纯度:>95%;溶剂及溶解性:水溶液。
本发明所述的人内皮抑素腺病毒每1次以5-1000×109vp/kg进行给药,优选为1-80×1010vp/kg,进一步优选为2-50×1010vp/kg。
本发明所述的人内皮抑素腺病毒以每周1-2次给药,优选为每周1次。
2.PD1抗体
PD1主要在激活的T细胞和B细胞中表达,功能是抑制细胞的激活,这是免疫系统的一种正常的自稳机制,过度的T/B细胞激活会引起自身免疫病。但是,肿瘤微环境会诱导浸润的T细胞高表达PD1分子,肿瘤细胞会高表达PD1的配体PD-L1和PD-L2,导致肿瘤微环境中PD1通路持续激活,T细胞功能被抑制,无法杀伤肿瘤细胞。PD1的抗体可以阻断这一通路,部分恢复T细胞的功能,使这些细胞能够继续杀伤肿瘤细胞。
本发明中使用的PD1抗体是指可直接或间接地中和、阻断、抑制、降低或者妨碍PD1活性的物质。PD1抗体通过与一个或多个PD1结合,可以中和、阻断、抑制、降低或者妨碍PD1的活性。PD1抗体包含:抗PD1抗体及其抗原结合片段、受体分子和与PD1特异性地结合以隔绝其与一个或多个受体结合的衍生物等。本发明所述PD1抗体包括但不限于替雷利珠单抗、尼伏单抗、潘利珠单抗、阿替珠单抗、度伐单抗、阿维单抗或特瑞普利单抗等,优选为特瑞普利单抗。
在以下实施例中,本发明所述的PD1抗体(特瑞普利单抗)购自苏州众合生物医药科技有限公司,批号为202103015,样品代号为PD1单抗。
本发明所述的特瑞普利单抗理化性质及生物特性如下:性状:无色澄明液体;规格:80mg(2mL),1瓶/盒;纯度:>95%;溶剂及溶解性:水溶液。
进一步具体地,所述的特瑞普利单抗每1次以1-100mg/kg进行给药,优选为3-20mg/kg,进一步优选为5-10mg/kg。
进一步具体地,所述的特瑞普利单抗以每周1-3次给药,优选为每周2次。
3.对照品
本发明所述的对照品为生理盐水(0.9%氯化钠注射液)的来源不进行限定,市售或者本领域技术人员熟知的方法制备即可。
在以下实施例中,本发明所述的生理盐水(0.9%氯化钠注射液)购自广东怡翔制药有限公司,批号为200816501。
本发明所述的生理盐水(0.9%氯化钠注射液)理化性质及生物特性如下:性状:无色的澄明液体;组分:氯化钠、稀盐酸、注射用水;规格:500mL:4.5g。
4.药物和治疗方法
本发明的一个方案为:将人内皮抑素腺病毒和PD1抗体组合形成的、用于治疗或预防癌症的药物。
上述方案中的“将人内皮抑素腺病毒和PD1抗体组合形成的、用于治疗或预防癌症的药物”是指,在癌症的治疗或预防中为了将人内皮抑素腺病毒和PD1抗体同时、分开或者依次进行给药而组合的药物。本发明的药物还可以以同时含有人内皮抑素腺病毒和PD1抗体的配方剂的形式提供。另外,分别提供含有人内皮抑素腺病毒的制剂和含有PD1抗体的制剂,这些制剂可以同时或依次使用。
在本发明中,同时给药是指在同一时期给予人内皮抑素腺病毒和PD1抗体进行联合用药,可以以配方剂的形式进行给药,也可以以在给药时进行用时调制的混合物的形式给药,还可以在同一时期给予其他形态的制剂。在同时给药进行使用时,可以从各自的路径进行给药,也可以从相同路径进行给药,给药剂型可以相同也可以各自不同。
在本发明中,在将人内皮抑素腺病毒和PD1抗体分开给药时,人内皮抑素腺病毒和PD1抗体的给药顺序可以是在给予人内皮抑素腺病毒后给予PD1抗体,也可以同时给予人内皮抑素腺病毒和PD1抗体,还可以在给予PD1抗体后给予人内皮抑素腺病毒。
本发明的人内皮抑素腺病毒和PD1抗体依次给药是指在给予一种药剂后再给予另一种药剂,对人内皮抑素腺病毒和PD1抗体的给药间隔没有特别限定,可以考虑给药途径或剂型等因素来设定。另外,除给药途径及剂型等因素外,还可参考本发明的人内皮抑素腺病毒和PD1抗体各自在对象中的残留浓度。即,在给予人内皮抑素腺病毒前给予PD1抗体的情况下,可以在获得人内皮抑素腺病毒的所期望的效果的、检测到对象中的该PD1抗体的残留浓度的时间点给予人内皮抑素腺病毒。通过各种使用了色谱法等的分离装置的本领域技术人员所公知的分析方法分析由对象采集的样品,根据结果即可确定该浓度。反之亦然。
在上述药物中,在将人内皮抑素腺病毒和PD1抗体包含在各自的制剂中进行提供时,这些制剂的剂型可以是相同剂型,也可以是不同剂型。例如,双方可以是口服制剂、非口服制剂、注射剂、点滴剂、静脉内点滴剂中的一种且彼此不同的剂型,双方也可以是口服制剂、非口服制剂、注射剂、点滴剂、静脉内点滴剂中的一种且相同的剂型。另外,在上述药物中还可以组合一种以上的不同的制剂。
在本发明中,“对象”没有限定,是指作为本发明药物的给药对象的人或者非人哺乳动物,例如包含牛、马、狗、绵羊或猫在内的哺乳动物。优选对象为人。对象包含患者(包含人和非人哺乳动物)。
实施例1
1.实验材料
(1)实验动物:hPD1-BALB/c小鼠,雌性/雄性,4-6周龄,体重18-24克,由江苏集萃药康生物科技股份有限公司提供。
(2)细胞系:小鼠结肠癌CT26细胞株,购自武汉普诺赛生命科技有限公司,货号:CL-0071。
(3)RPMI-1640:Gibco。
(4)FBS:YOSHI。
2.实验方法
(1)造模:D0天,将含结肠癌CT26细胞株1×106细胞的悬液200μL注射至hPD1-BALB/c小鼠背部皮下,一周后(D7),肿瘤长到直径120-150mm3时,随机分组如下表1所示。
表1
(2)给药方式和给药频率
E10A为瘤内注射,每周1次,其给药时间点为D7、D14、D21;PD1单抗为腹腔注射,每周2次,其给药时间点为D7、D10、D14、D17、D21、D24。
(3)体重测定:D7、D14、D21、D28用电子天平称量小鼠的体重。
(4)肿瘤生长速率检测:D7、D10、D14、D17、D21、D24、D28用数显游标卡尺测量肿瘤的长和宽,计算肿瘤的体积。
肿瘤体积V(mm3)=宽2×长×0.5
(5)抑瘤率检测:D28处死小鼠,取肿瘤称重。
(6)统计学处理:统计方法:Student t test,P值<0.05为有显著性差异(双侧)。
3.结果
(1)体重
D7、D14、D21、D28用电子天平称量小鼠的体重,实验组和对照比较无明显的体重变化,表明无明显的全身毒性,详见下表2、图1。其中,A组在D28天有2只死亡,可能与肿瘤进程有关。
表2.体重表(X±SD,g)
(2)肿瘤生长速率
B组(E10A组)和C组(PD1单抗组)在D14、D17、D21、D24、D28的肿瘤体积比A组(生理盐水组)小但无统计学意义(P>0.05)。D组(E10A+PD1单抗组)在D14的肿瘤体积比A组(生理盐水组)小但无统计学意义(P>0.05),在D17与A组(生理盐水组)比较有显著性差异(P<0.05),在D21、D24、D28与A组(生理盐水组)比较有极显著性差异(P<0.01),见下表3、图2。
表3.结肠癌CT26移植瘤肿瘤生长曲线(mm3)
注:与A组比较,*,P<0.05,**,P<0.01。
(3)抑瘤率
B组(E10A组)瘤重为2.08(n=10),C组(PD1单抗组)瘤重为1.88(n=10),D组(E10A+PD1单抗组)瘤重为0.69(n=10),A组(生理盐水组)瘤重为3.72(n=8);
肿瘤生长抑制率:B组(E10A组)对A组(生理盐水组)=43.99%(P=0.168);C组(PD1单抗组)对A组(生理盐水组)=49.43%(P=0.111);D组(E10A+PD1单抗组)与A组(生理盐水组)=81.41%(P=0.0005),说明E10A+PD1单抗组联用显著抑制结肠癌CT26移植瘤的生长。见下表4、图3。
表4.E10A和PD1单抗对结肠癌CT26的抑瘤作用
组别 | n | 瘤重平均值(g) | 抑瘤率(%) |
A组(生理盐水组) | 8 | 3.72 | - |
B组(E10A组) | 10 | 2.08 | 43.99 |
C组(PD1单抗组) | 10 | 1.88 | 49.43 |
D组(E10A+PD1单抗组) | 10 | 0.69 | 81.41** |
注:与A组比较,*,P<0.05,**,P<0.01。
(4)两药相互作用指数(CDI)计算
表5.各组瘤重与对照组比值
组别 | n | 瘤重平均值(g) | 与对照组比值 |
A组(生理盐水组) | 8 | 3.72 | - |
B组(E10A组) | 10 | 2.08 | 0.56 |
C组(PD1单抗组) | 10 | 1.88 | 0.51 |
D组(E10A+PD1单抗组) | 10 | 0.69 | 0.19 |
用两药相互作用系数(CDI)来评价两药相互作用性质,CDI按下列公式计算:CDI=AB/(A×B),其中AB是两药联合组与对照组瘤重的比值,A或B是各单药组与对照组瘤重的比值。CDI<1,表明两药作用性质为协同;CDI=1,则两药作用性质为相加;CDI>1,则两药作用性质为拮抗。
根据表5,CDI=0.19/(0.56×0.51)=0.67<<1。因此,E10A与PD1单抗协同作用非常显著。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (11)
1.一种人内皮抑素腺病毒和PD1抗体联用在制备抗肿瘤药物中的应用。
2.根据权利要求1所述的应用,其特征在于:所述的人内皮抑素腺病毒每1次以5-1000×109vp/kg进行给药,优选为1-80×1010vp/kg,进一步优选为2-50×1010vp/kg。
3.根据权利要求1所述的应用,其特征在于:所述的PD1抗体为替雷利珠单抗、尼伏单抗、潘利珠单抗、阿替珠单抗、度伐单抗、阿维单抗或特瑞普利单抗,优选为特瑞普利单抗。
4.根据权利要求3所述的应用,其特征在于:所述的特瑞普利单抗每1次以1-100mg/kg进行给药,优选为3-20mg/kg,进一步优选为5-10mg/kg。
5.根据权利要求1所述的应用,其特征在于:所述的人内皮抑素腺病毒和PD1抗体分开给药、同时或依次给药。
6.根据权利要求1所述的应用,其特征在于:所述的人内皮抑素腺病毒和PD1抗体通过瘤内注射、静脉注射或腹腔注射给药。
7.根据权利要求1所述的应用,其特征在于:所述的肿瘤为实体瘤。
8.根据权利要求7所述的应用,其特征在于:所述的肿瘤为黑色素瘤、卵巢癌、乳腺癌、宫颈癌、非小细胞肺癌、甲状腺癌、肝癌、食管癌、肺癌、前列腺癌、膀胱癌、成胶质细胞瘤、胃癌、结肠癌和/或肾癌;所述的肿瘤为结肠癌。
9.一种抗肿瘤药物,其特征在于:所述的药物包括人内皮抑素腺病毒和PD1抗体。
10.根据权利要求9所述的药物,其特征在于:所述的药物还包括药学上可接受的载体,所述的载体为缓释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、吸附载体、表面活性剂或润滑剂中的任意一种或两种以上的混合物。
11.一种肿瘤的治疗方法,其特征在于:所述的方法包含:将有效量的人内皮抑素腺病毒和有效量的PD1抗体组合对对象进行给药。
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