<br>抗 PD-1/Her2 双特异性抗体 IBI315 通过 Gasdermin B 裂解诱导的细胞焦亡增强 Her2 阳性胃癌的治疗效果,Advanced Science

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抗 PD-1/Her2 双特异性抗体 IBI315 通过 Gasdermin B 裂解诱导的细胞焦亡增强 Her2 阳性胃癌的治疗效果
Advanced Science ( IF 14.3 ) Pub Date : 2023-08-16 , DOI: 10.1002/advs.202303908
Wu Lin _{1,

2,

3,

4} , Yingzi Zhang ₁ , Yan Yang ₁ , Ben Lin ₅ , Mengjia Zhu ₆ , Jinling Xu ₆ , YiRan Chen ₁ , Weiwei Wu ₆ , Bingliang Chen ₆ , Xiangliu Chen ₁ , Jin Liu ₁ , Haohao Wang ₁ , Fei Teng ₁ , Xiongfei Yu ₁ , Haiyong Wang ₁ , Jun Lu ₁ , Quan Zhou ₇ , Lisong Teng _{1,

3,

4}

Affiliation

大多数人表皮生长因子受体 2 （Her2）阳性胃癌患者对 Her2 靶向治疗难治，其中免疫检查点的上调起着至关重要的作用。在此，开发了一种靶向 PD-1 和 Her2 的重组全人 IgG1 双特异性抗体 IBI315，并研究了其抗肿瘤功效以及潜在机制。IBI315 交联 Her2 阳性肿瘤细胞和 PD-1 阳性 T 细胞之间的物理相互作用，与使用患者来源的异种移植物和类器官用人类免疫细胞重构的体外和体内小鼠肿瘤模型相比，IBI315 的抗肿瘤作用显著增强。此外，IBI315 治疗还诱导肿瘤中免疫细胞的募集和激活。从机制上讲，IBI315 触发肿瘤细胞中 gasdermin B （GSDMB）介导的细胞焦亡，导致 T 细胞的活化和复发。活化的 T 细胞分泌 IFNγ，增强 GSDMB 表达并建立 T 细胞活化和肿瘤细胞杀伤的正反馈回路。值得注意的是，发现 GSDMB 在 Her2 阳性胃癌细胞中升高，为 IBI315 的疗效提供了基本原理。IBI315 在临床前研究中作为一种有前途的基于双抗体的免疫治疗方法得到支持，用于治疗 Her2 阳性胃癌，拓宽了该患者群体的治疗前景。

"点击查看英文标题和摘要"

Anti-PD-1/Her2 Bispecific Antibody IBI315 Enhances the Treatment Effect of Her2-Positive Gastric Cancer through Gasdermin B-Cleavage Induced Pyroptosis

The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation of immune checkpoints plays an essential role. Herein, a recombinant fully human IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed and its antitumor efficacy as well as the underlying mechanism is investigated. IBI315 crosslinks the physical interaction between Her2-positive tumor cells and PD-1-positive T cells, resulting in significantly enhanced antitumor effects compared to each parent antibody or their combination, both in vitro and in vivo mouse tumor models reconstituted with human immune cells using patient-derived xenografts and organoids. Moreover, IBI315 treatment also induces the recruitment and activation of immune cells in tumors. Mechanistically, IBI315 triggers gasdermin B (GSDMB)-mediated pyroptosis in tumor cells, leading to the activation and recruiments of T cells. The activated T cells secret IFNγ, enhancing GSDMB expression and establishing a positive feedback loop of T cell activation and tumor cell killing. Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.

更新日期：2023-08-16

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