Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer
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 o...
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BMJ Publishing Group
2025-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/6/e012144.full |
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| author | Wei Chen Hai Huang Wang Peng Jingwen Liang Shiru Chen Yuchong Zhao Mengdie Cao Yilei Yang Shuya Bai Qiaodan Zhou Jiamei Jiang Yilin Gu Ronghua Wang Bin Cheng |
| author_facet | Wei Chen Hai Huang Wang Peng Jingwen Liang Shiru Chen Yuchong Zhao Mengdie Cao Yilei Yang Shuya Bai Qiaodan Zhou Jiamei Jiang Yilin Gu Ronghua Wang Bin Cheng |
| author_sort | Wei Chen |
| collection | DOAJ |
| description | 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 (KrasLSL-G12D/+; Trp53LSL-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 CTGF and enhanced the anti-PD-1-mediated reinvigoration of cytotoxic CD8+ T cells, thereby establishing a less desmoplastic and potent tumor-killing microenvironment.Conclusions Our findings highlight the potential of Y126S as a promising BsAb-based immunotherapy strategy for PDAC by remodeling the desmoplastic and immunosuppressive TME. |
| format | Article |
| id | doaj-art-ef124ba82947454fb659032d280da564 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ef124ba82947454fb659032d280da5642025-08-20T02:39:58ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-06-0113610.1136/jitc-2025-012144Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancerWei Chen0Hai Huang1Wang Peng2Jingwen Liang3Shiru Chen4Yuchong Zhao5Mengdie Cao6Yilei Yang7Shuya Bai8Qiaodan Zhou9Jiamei Jiang10Yilin Gu11Ronghua Wang12Bin Cheng134 School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China2 Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China5 Department of Internal Medicine, University of Pittsburgh Medical Center Mercy Hospital, Pittsburgh, Pennsylvania, USA1 Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, ChinaBackground 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 (KrasLSL-G12D/+; Trp53LSL-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 CTGF and enhanced the anti-PD-1-mediated reinvigoration of cytotoxic CD8+ T cells, thereby establishing a less desmoplastic and potent tumor-killing microenvironment.Conclusions Our findings highlight the potential of Y126S as a promising BsAb-based immunotherapy strategy for PDAC by remodeling the desmoplastic and immunosuppressive TME.https://jitc.bmj.com/content/13/6/e012144.full |
| spellingShingle | Wei Chen Hai Huang Wang Peng Jingwen Liang Shiru Chen Yuchong Zhao Mengdie Cao Yilei Yang Shuya Bai Qiaodan Zhou Jiamei Jiang Yilin Gu Ronghua Wang Bin Cheng Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer Journal for ImmunoTherapy of Cancer |
| title | Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer |
| title_full | Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer |
| title_fullStr | Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer |
| title_full_unstemmed | Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer |
| title_short | Anti-CTGF/PD-1 bispecific antibody Y126S restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer |
| title_sort | anti ctgf pd 1 bispecific antibody y126s restrains desmoplastic and immunosuppressive microenvironment in pancreatic cancer |
| url | https://jitc.bmj.com/content/13/6/e012144.full |
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