A novel anti-PD-L1/IL-8 bispecific antibody BP2402 enhances antitumor immunity and modulates inflammatory signaling in triple-negative breast cancer mice model

作者：Liying Song, Sumin Tang, Xuelei Pi, Yuanyuan Yan, Chenxi Hu, Liang Liu, Hongna Chen, Yating Zhang, Shishi Liu, Dongsheng Yu, Chengkai Yin, Tianyan Liu, Li Xu, Deshan Li, Zhenzhong Wang, Wei‐Guo Zhu, Kaiyuan Hui, Zhihang Liu, Xiaodong Jiang · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07105-x · 被引用次数：5 · 研究领域：Cancer Immunotherapy and Biomarkers、Chemokine receptors and signaling、Immunotherapy and Immune Responses

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options. Immune checkpoint inhibitors targeting the programmed death-ligand 1 (PD-L1) pathway show restricted efficacy in TNBC, with response rates of only 5-10% as monotherapy. Interleukin-8 (IL-8/CXCL8) signaling promotes immunosuppression and mediates resistance to anti-PD-L1 therapy, necessitating combination approaches to overcome these limitations. However, the underlying mechanisms of enhanced efficacy from dual pathway targeting require further investigation. METHODS: We generated humanized mouse models by reconstituting immunodeficient mice with human PBMCs from five donors (n = 5 mice/group). MDA-MB-231 TNBC cells were implanted subcutaneously, and mice were treated with vehicle control, atezolizumab (anti-PD-L1), HuMax-IL8 (anti-IL-8), combination therapy, or a novel bispecific antibody BP2402 targeting both PD-L1 and IL-8. Antitumor activity was assessed alongside single-cell RNA sequencing of tumors and mechanistic analyses including immunofluorescence and Western blot. RESULTS: Combination therapy demonstrated significantly enhanced tumor growth inhibition compared to atezolizumab monotherapy in responsive donor models (51.28% vs. 39.13% for donor 3, p < 0.01; 44.01% vs. 6.57% for donor 4, p < 0.01). Single-cell RNA sequencing showed higher intratumoral T-cell fractions with combination therapy (donor 3: 80.5% vs. 26.7%; donor 4: 63.6% vs. 13.0% compared to cont...