CN116549631A - 靶向il-17a作为抗白血病的治疗用途 - Google Patents
靶向il-17a作为抗白血病的治疗用途 Download PDFInfo
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Abstract
本发明属于药学领域,涉及一种治疗白血病的药物,特别涉及IL‑17A中和性抗体在制备治疗、预防和/或防控白血病的药物中的应用。本发明发现IL‑17A中和性抗体在动物水平能够抑制白血病的疾病进展,为白血病的预防和治疗提供了一种全新的候选药物,具有很强的工业实用性和巨大的商业、社会价值。
Description
技术领域
本发明属于药学领域,涉及一种治疗白血病的药物,特别涉及IL-17A中和性抗体在制备治疗、预防和/或防控白血病的药物中的应用。
背景技术
白血病在发生发展过程中,会将造血微环境改造成有利于自身生长的白血病微环境,抑制正常造血干细胞的功能与数量。微环境中发挥功能的最小生态位称为“Niche”,这种促白血病Niche被认为是白血病进展的协同犯罪者,靶向促白血病Niche被认为是解决白血病耐药、复发的新途径。白血病微环境细胞主要包括基质细胞、免疫细胞、内皮细胞及脂肪细胞等,白血病细胞与微环境细胞通过细胞间黏附,自分泌、旁分泌的细胞因子、趋化因子等进行交互,促进疾病进展。Witkowski等通过单细胞测序手段,发现CD14+CD16+的非经典单核细胞(高表达CSF1R)与B-ALL患者不良预后相关,通过CSF1R中和性抗体,结合TKI药物伊马替尼能够提高白血病模型小鼠对TKI药物的响应。以上研究提示,靶向促白血病Niche组分细胞能够起到协同治疗的作用。
Th17细胞是CD4+T细胞的一个亚群,其特征是分泌IL-17A及表达转录因子RORγt,在炎症因子如TGF-β、IL-6、IL-1β的刺激下可以由naive CD4+T细胞分化而来,且在IL-21、IL-23的作用下可以长时间维持存活状态。Th17细胞在多种白血病,如AML,B-ALL中比例升高。靶向IL-17A的单克隆抗体药物目前主要应用于斑块性银屑病、银屑病关节炎、强直性脊柱炎。目前关于IL-17A的单克隆抗体在预防白血病发生和抗白血病的作用,在国内外没有过任何报道。
发明内容
本发明的目的在于提供IL-17A单克隆抗体在制备治疗和/或预防和/或控制白血病的药物中的应用。
本发明所述的应用为,靶向治疗和/或预防和/或控制与Th17细胞及IL-17A因子相关的疾病。
其中,白血病包括急性淋巴细胞白血病、急性髓系白血病、慢性淋巴细胞白血病、慢性髓系白血病、毛细胞白血病、骨髓增生异常综合征、骨髓增值性疾病等。
本发明所述应用为抑制白血病细胞增殖、预防白血病的发生、或促进白血病细胞死亡中的一种用途或几种用途。
本发明的另一个目的在于提供含有IL-17A单克隆抗体的药物组合物在在制备治疗和/或预防和/或控制白血病的药物中的应用。
本发明的药物组合物中还可以加入其它的具有抗白血病的化合物作为活性成分。
本发明的药物组合物还包括药学上可接受的载体或赋形剂。
本发明的药物组合物可以制备成任何可药用的剂型。
本发明的药物组合物的剂型为注射剂或输注剂。
本发明的另一个目的是提供一种治疗、预防和/或控制白血病的方法。
为实现上述目的,本发明采用以下技术方案:
本发明可以通过单独、或与其它治疗剂联合给予一种或多种抗白血病药物以治疗、预防和/或控制肿瘤。
所述白血病包括急性淋巴细胞白血病、急性髓系白血病、慢性淋巴细胞白血病、慢性髓系白血病、毛细胞白血病、骨髓增生异常综合征、骨髓增值性疾病等。
Th17细胞在多种血液系统肿瘤中比例升高,其分泌的IL-17A因子表达升高,与白血病的不良预后相关,因此,我们推测IL-17A具有促进白血病疾病进展的作用。基于此,本研究分离自发白血病的转基因小鼠的白血病细胞、白血病患者白血病细胞与Th17共培养,通过同种移植方式制备白血病小鼠模型、体外共培养模型,同时基于IL-17A单克隆抗体进行治疗。我们的研究结果显示,与对照组相比,IL-17A单克隆抗体治疗组小鼠的白血病疾病进展减缓,共培养体系中白血病细胞增殖能力减弱。表明IL-17A单克隆抗体具有抑制白血病发生和进展的作用。
一种治疗、预防和/或控制白血病的药物,含有IL-17A单克隆抗体。
所述含有IL-17A单克隆抗体的药物可以和药学上可接受的载体制备治疗、预防和/或控制白血病。其中所述的药学上可接受的载体可根据药物剂型进行常规选择,如稀释剂、填充剂等。在该药物中,所述IL-17A单克隆抗体可以作为单一活性成分或者与其它具有治疗、预防和/或控制白血病活性的化合物联合作为活性成分。
本发明所述的治疗、预防和/或控制白血病的药物剂型没有特别限制,为本领域常规剂型,如固体、半固体、液体,水溶液、非水溶液或者混悬液,较佳为注射剂或输注剂。所述的药物给药途径为本领域常规给药途径,较佳为注射给药。其中注射给药包括:静脉注射、肌肉注射、腹腔注射、皮内注射或者皮下静脉注射途径。
所述药物还含有生物体可接受的辅料或载体。其中,“治疗、预防和/或控制有效量”是指在给予所需对象足以有效预防或治疗本文所述的疾病或病症的化合物的量。虽然构成“治疗、预防和/或控制有效量”的化合物的量将根据化合物、病症及其严重度、以及欲治疗所需对象的年龄而变化,但可由本领域技术人员以常规方式确定。
一种治疗、预防和/或控制白血病的方法,该方法包括给予哺乳动物治疗有效量的IL-17A中和性抗体。
本发明所述的药物在治疗时的使用剂量较佳地为1-2000μg/kg,更佳为5~1000μg/kg,优选为25μg/kg,给药次数较佳为一天一次或者数次。
本发明所述“预防“是指在可能的白血病因素的存在下,使用后放置或者降低白血病疾病的产生。本发明所述”治疗“是指减白血病疾病情况或者使之正常化,或者是延缓疾病进程。
“所需对象“是指在任何可能的促进白血病因素的存在下,可能患有本文所述疾病或者病症的温血动物,或者患有本文所述疾病和病症的温血动物,如哺乳动物,本发明优选人类或小鼠。
在符合本领域尝试的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明提供了一种含有IL-17A中和性抗体在制备预防或治疗白血病药物中的用途,该药物能够有效改善白血病患者的疾病进程,疗效显著,同时该药物还具备毒副作用少、使用安全的优点。
本发明的优点是:本发明发现IL-17A单克隆抗体对于白血病疾病进展的抑制作用,为白血病的预防和治疗提供了一种全新的候选药物。动物实验显示IL-17A单克隆抗体的抑制白血病效果优于伊马替尼,因此具备很强的临床应用性和社会价值。
下面结合附图和具体实施方式对本发明做进一步详细说明,并不视为对本发明的限制,凡依照本发明公开内容所进行的本领域等同替换,均属于本发明的保护范围。
附图说明
图1、各组别实验小鼠脾脏肿瘤及重量统计图
A脾脏肿瘤,B重量统计
图2、实施例7各组别实验小鼠外周血及脾脏吉姆萨染色图
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例中所述的PBS,指浓度为0.1M,pH值为7.2的磷酸盐缓冲液。
实施例中所述的室温为本领域常规的室温,较佳地为20~30℃。
实验结果用均值±标准误表示。
实施例1、含有IL-17A中和性抗体的药物
一.实验材料
1.活性成分:小鼠IL-17A中和性抗体(anti-mouse IL-17A,BE0173)、人IL-17A中和性抗体(anti-human IL-17A,SIM0013),购于美国BioX cell公司;
2.药物溶剂:PBS
二.制法
使用PBS稀释IL-17A中和性抗体,其中活性成分IL-17A中和性抗体的浓度为0.5μg/μL,即得本发明药物。
实施例2、B淋巴细胞急性白(B-ALL)血病防治细胞实验
1.分离诱导Th17细胞:采用流式分选分离健康人外周血中的Th17细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
2.分离B-ALL白血病患者的白血病细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
3.取步骤1,2所制得的细胞悬液,按细胞比例为1:1接种至12孔板进行共培养,接种细胞分别为2万个,所用培养基为DMEM培养基,购自Thermo公司;培养温度为37℃,培养体积为1mL。
4.治疗孔加入1μg/mL实例1所制得的中和性抗体anti-IL-17A。24小时后,使用流式细胞术检测白血病细胞的增殖比例。实验结果见表1.
表1说明,IL-17A中和性抗体能够抑制Th17细胞对B-ALL白血病细胞的促增殖作用。
组别 | 增殖细胞比例(%) |
B-ALL(对照组) | 23.88±2.54 |
Th17+B-ALL | 47.67±3.31 |
Th17+B-ALL+anti-IL-17A | 21.63±1.53 |
实施例3、T淋巴细胞急性白血病(T-ALL)防治细胞实验
1.分离诱导Th17细胞:采用流式分选分离健康人外周血中的Th17细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
2.分离T-ALL白血病患者的白血病细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
3.取步骤1,2所制得的细胞悬液,按细胞比例为1:1接种至12孔板进行共培养,接种细胞分别为2万个,所用培养基为DMEM培养基,购自Thermo公司;培养温度为37℃,培养体积为1mL。
4.治疗孔加入1μg/mL实例1所制得的中和性抗体anti-IL-17A。24小时后,使用流式细胞术检测白血病细胞的增殖比例。实验结果见表2.
表2说明,IL-17A中和性抗体能够抑制Th17细胞对T-ALL白血病细胞的促增殖作用。
组别 | 增殖细胞比例(%) |
T-ALL(对照组) | 32.48±4.23 |
Th17+T-ALL | 58.13±5.23 |
Th17+T-ALL+anti-IL-17A | 22.46±2.14 |
实施例4、急性髓系白血病(AML)防治细胞实验
1.分离诱导Th17细胞:采用流式分选分离健康人外周血中的Th17细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
2.分离AML白血病患者的白血病细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
3.取步骤1,2所制得的细胞悬液,按细胞比例为1:1接种至12孔板进行共培养,接种细胞分别为2万个,所用培养基为DMEM培养基,购自Thermo公司;培养温度为37℃,培养体积为1mL。
4.治疗孔加入1μg/mL实例1所制得的中和性抗体anti-IL-17A。24小时后,使用流式细胞术检测白血病细胞的增殖比例。实验结果见表3.
表3说明,IL-17A中和性抗体能够抑制Th17细胞对AML白血病细胞的促增殖作用。
组别 | 增殖细胞比例(%) |
AML(对照组) | 26.37±5.16 |
Th17+AML | 33.48±2.49 |
Th17+AML+anti-IL-17A | 19.25±1.95 |
实施例5、慢性淋巴细胞白血病(CLL)防治细胞实验
1.分离诱导Th17细胞:采用流式分选分离健康人外周血中的Th17细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
2.分离CLL白血病患者的白血病细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
3.取步骤1,2所制得的细胞悬液,按细胞比例为1:1接种至12孔板进行共培养,接种细胞分别为2万个,所用培养基为DMEM培养基,购自Thermo公司;培养温度为37℃,培养体积为1mL。
4.治疗孔加入1μg/mL实例1所制得的中和性抗体anti-IL-17A。24小时后,使用流式细胞术检测白血病细胞的增殖比例。实验结果见表4。
表4说明,IL-17A中和性抗体能够抑制Th17细胞对CLL白血病细胞的促增殖作用。
实施例6、多发性骨髓瘤(MM)防治细胞实验
1.分离诱导Th17细胞:采用流式分选分离健康人外周血中的Th17细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
2.分离MM多发性骨髓瘤患者的白血病细胞,调整细胞浓度,制成浓度为15万个/mL的细胞悬液。
3.取步骤1,2所制得的细胞悬液,按细胞比例为1:1接种至12孔板进行共培养,接种细胞分别为2万个,所用培养基为DMEM培养基,购自Thermo公司;培养温度为37℃,培养体积为1mL。
4.治疗孔加入1μg/mL实例1所制得的中和性抗体anti-IL-17A。24小时后,使用流式细胞术检测浆细胞的增殖比例。实验结果见表5.
表5说明,IL-17A中和性抗体能够抑制Th17细胞对多发性骨髓瘤细胞的促增殖作用。
组别 | 增殖细胞比例(%) |
MM(对照组) | 25.34±3.21 |
Th17+MM | 45.38±5.27 |
Th17+MM+anti-IL-17A | 18.23±4.66 |
实施例7、白血病防治动物实验
A.白血病小鼠模型构建
1.取已发病的B淋巴细胞白血病自发小鼠(BCR-ABLtTA)骨髓细胞,制备单细胞悬液,使用PBS调整细胞浓度为8000个/mL。
2.通过尾静脉注射方式注射白血病细胞,800个白血病细胞/只小鼠。
B.中和性抗体治疗
操作步骤如下:
1.实验动物分组:将6-8周龄已造模小鼠随机分为4组,每组10只,分别为模型对照组,中和性抗体治疗组,伊马替尼组、联合给药组。
2.造模完成3天后,开始进行治疗,给药方式为尾静脉给药,每只给药剂量为25μg。
3.给药15天后,取材对脾脏、骨髓、外周的肿瘤负荷进行测定,结果见图1-2,表6-8。结果表明:IL-17A中和性抗体能够显著降低白血病小鼠各脏器肿瘤负荷,结果见表6-8。
表6.IL-17A中和性抗体降低白血病小鼠骨髓肿瘤负荷
组别 | B220细胞比例(%) |
对照组 | 82.73±6.52 |
伊马替尼组 | 51.36±8.31 |
中和性抗体治疗组 | 27.17±5.21 |
联合给药组 | 15.49±3.47 |
表7.IL-17A中和性抗体降低白血病小鼠脾脏肿瘤负荷
组别 | B220细胞比例(%) |
对照组 | 92.13±9.51 |
伊马替尼组 | 49.18±4.28 |
中和性抗体治疗组 | 32.91±1.81 |
联合给药组 | 24.19±2.83 |
表8.IL-17A中和性抗体降低白血病小鼠外周血肿瘤负荷
组别 | B220细胞比例(%) |
对照组 | 45.62±6.21 |
伊马替尼组 | 31.62±5.78 |
中和性抗体治疗组 | 21.58±5.34 |
联合给药组 | 12.94±2.61 |
。
Claims (10)
1.单克隆抗体IL-17A在制备治疗和/或预防和/或控制白血病的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,靶向治疗和/或预防和/或控制与Th17细胞及IL-17A因子相关的疾病的药物中的应用。
3.根据权利要求1所述的应用,其特征在于,白血病包括急性淋巴细胞白血病、急性髓系白血病、慢性淋巴细胞白血病、慢性髓系白血病、毛细胞白血病、骨髓增生异常综合征、骨髓增值性疾病等。
4.根据权利要求1所述的应用,其特征在于,所述应用为抑制白血病细胞增殖、预防白血病的发生、或促进白血病细胞死亡中的一种用途或几种用途。
5.根据权利要求1所述的应用,其特征在于,该药物为含有IL-17A单克隆抗体的药物组合物。
6.根据权利要求5所述的应用,其特征在于,药物组合物还含有其它的具有抗白血病的化合物作为活性成分。
7.根据权利要求5所述的应用,其特征在于,药物组合物还包括药学上可接受的载体或赋形剂。
8.根据权利要求5的药物组合物,其特征在于,药物组合物的剂型为任何可药用的剂型。
9.根据权利要求5的药物组合物,其特征在于,药物组合物的剂型为注射剂或输注剂。
10.根据权利要求9的药物组合物,其特征在于,注射给药包括:静脉注射、肌肉注射、腹腔注射、皮内注射或者皮下静脉注射途径。
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