赢迪行业前沿分享 | 肿瘤治疗的重磅靶点ROR1

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赢迪行业前沿分享 | 肿瘤治疗的重磅靶点ROR1

日期:2020-12-25 / 人气:

ROR1是一种跨膜的受体酪氨酸激酶蛋白,在早期胚胎发育过程中高表达,并且在多种生理过程中发挥重要作用,包括调节细胞分裂、增殖、迁移等,参与神经,骨骼和血管等器官的生成。在随后的胎儿发育过程中,ROR1的表达量逐渐下降,正常的儿童和成人组织细胞表面基本没有ROR1的表达。

 

与ROR1在早期胚胎形成过程中影响干细胞的作用一致,ROR1在侵袭性恶性肿瘤中的表达会启动类似胚胎发育的转录过程。ROR1可与wnt5a结合,参与wnt通路的信号转导,以及与EGFR、Met等信号通路相互作用,促进肿瘤细胞的生长、增殖和转移。ROR1在大部分血液肿瘤中均高表达,例如在CLL患者中ROR+的比例超过90%;在部分实体瘤,如肺癌、胰腺癌、结直肠癌细胞中,ROR1的表达也大幅提高,并且和疾病的进展以及治疗效果密切相关。因此ROR1可作为一种特异性的肿瘤标志物,对病人进行细分,并进行肿瘤治疗药物的开发。

 

目前针对ROR1靶点的药物开发包括小分子抑制剂,单抗,ADC,双抗,CAR-T等,其中单抗和ADC药物进展较快,且取得了较为突出的治疗效果。Oncternal公司的ROR1单抗药物Cirmtuzumab与ROR1胞外的Frizzled结构域结合,阻止ROR1与wnt5a的结合,从而阻断wnt5a途径,抑制癌症的生长和转移。在ASH2020公布的Ib/II期临床结果中,与BTK抑制剂伊布替尼联用,在复发、难治的MCL适应症上ORR达到83.3%,CR58.3%;CLL适应症上ORR91.2%,都是非常亮眼的数据。Velosbio公司开发的ADC药物VLS101也是以ROR1作为靶点,通过可降解的linker连接MMAE毒素靶头,特异性的递送毒素到ROR1+的肿瘤细胞内。在ASH2020上公布的I期临床结果,MCL适应症ORR47%,DLBCL适应症ORR80%,在早期的临床中就体现出较好的治疗前景。

 

近期基石药业1000万美元首付引进韩国LegoChem公司的ROR1 ADC产品 LCB71,默沙东27.5亿美元收购Velosbio,勃林格殷格翰12亿欧元收购NBE-Therapeutics等多笔大额交易,让ROR1靶点成为绝对的热点。目前国内企业对ROR1的布局还较少,仍有快速跟进的机会。

 

 

 

 

参考资料:

1. ROR1, an embryonic protein with an emerging role in cancer biology;
2. Ror1 Is a Pseudokinase That Is Crucial for Met-Driven Tumorigenesis;
3. Receptor tyrosine kinase-like orphan receptor 1: a novel target for cancer immunotherapy;
4. Molecular Mechanisms Associated withROR1-Mediated Drug Resistance: Crosstalk withHippo-YAP/TAZ and BMI-1 Pathways;
5. Orphan receptor tyrosine kinases ROR1 and ROR2 in hematological malignancies;
6. The Onco-Embryonic Antigen ROR1 Is Expressed by a Variety of Human Cancers;
7. ROR1 is a novel prognostic biomarker in patients with lung adenocarcinoma;
8. Review The receptor tyrosine kinase ROR1 – An oncofetal antigen for targeted cancer therapy;
9. First-in-class oral small molecule inhibitor of the tyrosine kinaseROR1 (KAN0439834) induced significant apoptosis of chronic lymphocytic leukemia cells;
10. Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia;
11. Cirmtuzumab, an Anti-ROR1 Antibody, in Combination with Ibrutinib: Clinical Activity in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL) from a Phase 1/2 Study;
12. VLS-101, a ROR1-Targeting Antibody-Drug Conjugate, Demonstrates a Predictable Safety Profile and Clinical Efficacy in Patients with Heavily Pretreated Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma;
13. Wikipedia: Receptor tyrosine kinase; 
14. 获默沙东、基石药业青睐,ROR1为何成为抗癌新兴靶点?
15. Oncternal公司官网;
16. Velosbio公司官网;