Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer

作者：Shiru Chen, Yuchong Zhao, Mengdie Cao, Peng Wang, Hai Huang, Yilei Yang, Jingwen Liang, Wei Chen, Shuya Bai, Qiaodan Zhou, Jiamei Jiang, Yilin Gu, Ronghua Wang, Bin Cheng · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-012144 · 被引用次数：6 · 研究领域：Connective Tissue Growth Factor Research、Fibroblast Growth Factor Research、Bone and Dental Protein Studies

Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic and immunosuppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint inhibitors such as anti-programmed cell death 1 (PD-1). Methods This study aimed to evaluate the therapeutic potential of Y126S, a recombinant IgG1/IgG2 hybrid bispecific antibody (BsAb), in reshaping the immunotherapy-resistant TME in PDAC. Orthotopic PDAC and KPC (Kras LSL-G12D/+ ; Trp53 LSL-R172H/+ ; Pdx1-Cre) mouse models were established and treated with Y126S, α-connective tissue growth factor (CTGF), α-PD-1, or a combination of α-CTGF and α-PD-1. TME remodeling, antibody distribution, and therapeutic efficacy were assessed using flow cytometry, immunohistochemical/Masson staining, atomic force microscopy, positron emission tomography (PET) imaging, distribution analysis, and other experimental techniques. Results Here, Y126S was characterized in vitro and its antitumor efficacy was evaluated and validated in orthotopic PDAC mice and KPC mouse models. Notably, Y126S significantly remodeled the TME and demonstrated superior tumor-specific accumulation compared with single α-PD-1 treatment, leading to markedly enhanced antitumor efficacy relative to its parental antibodies or their combination. Mechanistically, Y126S suppressed cancer-associated fibroblasts (CAFs) activation, reduced collagen deposition, and downregulated programmed cell death ligand 1 (PD-L1) expression on CAFs by targeting CT...