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该PTPN2/PTPN1抑制剂ABBV-CLS-484释放强大的抗瘤免疫力
Christina K Baumgartner1, Hakimeh Ebrahimi-Nik2,3,4, Arvin Iracheta-Vellve2,3,5
1AbbVie, North Chicago, IL, USA. christina.baumgartner@abbvie.com.
一种新的药物ABBV-CLS-484 (AC484) 针对蛋白质氨酸酸酶PTPN2和PTPN1来增强抗瘤免疫力. 这种口服可用的抑制剂在克服当前癌症免疫疗法的方面表现有前途.
科学领域:
- 免疫学
- 癌症学
- 药理学
背景情况:
- 目前的癌症免疫疗法,如免疫检查点阻塞,只对某些患者有效,因此需要新的治疗策略.
- 蛋白氨酸酸酶PTPN2和PTPN1是炎症的关键调节剂,它们的抑制促进了抗瘤免疫力.
- 由于酸酶是药物标,因此向其活性部位一直是具有挑战性的.
研究的目的:
- 发现和描述ABBV-CLS-484 (AC484),一种新的口服生物可用小分子抑制剂,向PTPN2和PTPN1的活性位点.
- 评估AC484作为单一疗法的疗效,用于对现有免疫疗法有抗性的临床前癌症.
- 阐明AC484增强抗瘤免疫力的机制,重点关注免疫细胞功能和瘤微环境.
主要方法:
- 发现和特征AC484,一个强大的PTPN2和PTPN1活性位点抑制剂.
- 在体外研究评估AC484对干扰素反应和免疫细胞激活的影响.
- 在对抗PD- 1阻断的小鼠癌症模型中对AC484单疗的体内评估.
主要成果:
- 在实验室中,AC484治疗增强了干扰素反应,促进了免疫细胞的激活和功能.
- 在抗PD-1 阻塞的小鼠模型中,AC484 单一治疗显示出强大的抗瘤免疫力.
- 通过JAK- STAT信号传递,AC484可以激发瘤微环境,增强自然杀手和CD8+T细胞功能,并减少T细胞功能障碍.
结论:
- AC484是第一类可口生物利用的PTPN2/PTPN1活性位点抑制剂,具有显著的抗瘤活性.
- 抑制PTPN2和PTPN1代表了癌症免疫治疗的有前途的新策略,有可能克服对当前治疗的耐药性.
- AC484是首个进入癌症免疫治疗临床试验的活性酶抑制剂,表明针对细胞内免疫调节者的新疗法.
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