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波纳替尼通过降低MAPK38表达来避免αCD40抗体中介毒性,并在小鼠瘤模型中表现出免疫效应

Vidit Gaur^1,2, Anjali Barnwal^1,2, Khushboo Singh^1,2

¹Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.

ACS pharmacology & translational science

|August 14, 2025

概括

结合ponatinib与激动性CD40抗体 (αCD40) 疗法,有效地延缓瘤生长,改善小鼠的存活率. 这种组合还减少了αCD40诱导的毒性,为癌症治疗提供了一个有希望的策略.

科学领域:

免疫治疗是一种免疫疗法.
在瘤学瘤学.
药理学药理学是指药理学的学科.

背景情况:

激素CD40抗体 (αCD40) 治疗具有前景,但受到细胞因子释放综合征 (CRS),肝毒性和诱导PD-L1表达的限制.
纳替尼 (ponatinib) 是一种氨酸激酶抑制剂,此前已被证明可以抑制编程死亡配体1 (PD-L1) 的表达.

研究的目的:

在临床前癌症模型中评估将αCD40与ponatinib结合的疗效和安全性.
为了研究这种组合治疗的免疫学和毒理学影响.

主要方法:

携带B16-F10黑色素瘤和4T1正型瘤的小鼠接受了αCD40和ponatinib联合治疗.
评估了瘤生长,整体存活率,免疫细胞种群 (CD45+CD8+T细胞),免疫标记物表达 (CD86,PD-L1,FOXP3,阿尔金纳-1),以及毒性标记物 (ALT,AST,IL-6,IL-10,IL-1β).
分析了MAPK38和ERK1/2的表达水平.

主要成果:

组合治疗显著延迟了瘤生长,并改善了小鼠的整体存活率.
在瘤中观察到CD45+CD8+T细胞透和CD86表达的增加.
在瘤和脏中注意到PD-L1,FOXP3和阿基纳-1的表达减少.
波纳替尼通过降低ALT,AST,IL-6,IL-10和IL-1β水平来减轻αCD40诱导的肝毒性和全身炎症,与MAPK38和ERK1/2.2.的下调相关.

结论:

在临床前模型中,αCD40和ponatinib的组合显示出增强的抗瘤疗效和降低的毒性.
这种组合策略有可能通过克服αCD40的局限性来改善癌症免疫治疗的临床结果.

关键词:

波纳提尼布 (ponatinib) 是一种编程死亡连接剂-1 编程死亡连接剂-1 毒性的毒性毒性的毒性瘤微环境是一个微环境.瘤调节的方法 αCD4040 的时间.

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