赢迪行业前沿分享 | 免疫检查点:TIM-3

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赢迪行业前沿分享 | 免疫检查点:TIM-3

日期:2021-01-08 / 人气:

TIM基因家族编码一类跨膜糖蛋白,TIM蛋白都具有共同的结构基序,主要结构有免疫球蛋白样区、黏蛋白样区、跨膜区和有磷酸化位点的胞内区。在人类身上发现Havcr1(Tim-1)、Havcr2(Tim-3)和Timd4(Tim-4),其中TIM-3与自身免疫和癌症中的免疫反应调节有关。针对CTLA-4和PD-1的检查点阻断策略在肿瘤上取得了成功,但仍有很大一部分癌症患者尚未从这种新疗法中受益。在感染性疾病、自身免疫和肿瘤免疫的小鼠模型中, TIM-3已显示出介导的免疫耐受性。因此,靶向TIM-3成为进一步改善当前免疫疗法的一种有前途的方法。

 

TIM-3在CD8+T、Treg、DC、NK等其他淋巴细胞亚群以及肿瘤细胞中均发现表达,已经发现的TIM-3的配体有半乳凝素9(Gal-9),高迁移率族蛋白B1(HMGB1),癌胚抗原细胞粘附分子1(Ceacam-1)和磷脂酰丝氨酸(PtdSer),但目前对于他们之间的亲和力和机制尚未有比较清晰的阐述。Gal-9 多表达于免疫细胞、脏器实质细胞(肝脏、胸腺、小肠、肾脏等)及肿瘤细胞,主要参与调控肿瘤微环境中T细胞的凋亡;HMGB1可抑制TIM-3+DC的抗原提呈功能;CEACAM-1+T细胞可与TIM-3分子胞外功能域结合而引起T细胞耗竭效应;TIM-3与PS的结合则可介导凋亡细胞的清除。在特定的组织环境中,可能是每个配体的分布和表达水平决定了TIM3的信号传递及生物学功能。

 

TIM-3已有多个厂商和临床研究开发,多为单抗,就目前公开的数据披露来看,单药的作用比较差,而在联用组,诺华的MBG453与地西他滨/阿扎胞苷在血液瘤方面取得比较好的疗效,目前已经开展了3期临床试验,我们也期待未来TIM-3在血液瘤的相关适应症取得突破。

 

 

 

 

参考资料:

1. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4 

2. Regulation of T cell trafficking by the T cell immunoglobulin and mucin domain 1 glycoprotein

3. TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

4. TIM3 comes of age as an inhibitory receptor

5. TIM-3 expression in breast cancer 

6. TIM-3 Is a Promising Target to Selectively Kill Acute Myeloid Leukemia Stem Cells 

7. A novel antibody targeting TIM-3 resulting in receptor internalization for cancer immunotherapy

8. Abstract 2753: The molecular basis of blocking the TIM-3 checkpoint with the LY3321367 mAbin cancer immunotherapy

9. Anti-TIM3(LY3321367)单药或联用PDL1抗体:安全性,有效性和PK

10. 2019 ASCO-SITC: Combined Targeting of TIM-3 and PD-L1 Immune Checkpoint Pathways in Advanced Relapsed or Refractory Solid Tumors

11. Abstract CT183: Phase (Ph) I/II study of MBG453±spartalizumab(PDR001) in patients (pts) with advanced malignancies

12. Phase (Ph) II study of MBG453 + spartalizumabin patients (pts) with non-small cell lung cancer (NSCLC) and melanoma pretreated with anti–PD-1/L1 therapy

13. 657 Efficacy and Safety of Sabatolimab(MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients with Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS): Updated Results from a Phase 1b Study

14. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation