大多数HER2阳性胃癌患者对HER2靶向治疗产生耐药性，这其中免疫检查点的上调起到了关键作用。本研究开发了一种重组全人源IgG1双特异性抗体IBI315，同时靶向PD-1和HER2，研究了其抗肿瘤效果及其潜在机制。IBI315通过交联HER2阳性肿瘤细胞和PD-1阳性T细胞之间的物理相互作用，与单一母抗体或它们的组合相比，在体外和体内使用患者来源的异种移植物和器官样体的小鼠肿瘤模型中显著增强了抗肿瘤效果。此外，IBI315治疗还诱导肿瘤内免疫细胞的招募和活化。从机制上看，IBI315在肿瘤细胞中触发了气孔形成素B (GSDMB)介导的火凤凰，导致T细胞的激活和招募。激活的T细胞分泌IFNγ，增强GSDMB的表达，建立了T细胞激活和肿瘤细胞杀伤的正反馈环。值得注意的是，GSDMB在HER2阳性胃癌细胞中表达升高，为IBI315的疗效提供了理论基础。本文支持IBI315作为HER2阳性胃癌双特异性抗体免疫治疗的有望方法，扩展了该患者人群的治疗潜力。© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

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.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.