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已发表论文
一种用于肿瘤免疫治疗的新型抗 Siglec-15 抗体的开发
Authors Liu Q, Li L, Nian S, Sun X, Guo X, Li C, Yang Z, Ye Y, Yuan Q
Received 26 May 2025
Accepted for publication 19 November 2025
Published 11 December 2025 Volume 2025:14 Pages 1419—1435
DOI https://doi.org/10.2147/ITT.S536009
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Michael Shurin
Qin Liu,1,* Lin Li,1,* Siji Nian,1 Xiaoke Sun,2 Xiyuan Guo,1 Chengwen Li,1 Zhihui Yang,3 Yingchun Ye,1 Qing Yuan1,4
1Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Key Laboratory of Medical Electrophysiology of the Ministry of Education, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Institute of Nuclear Medicine, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Qing Yuan, Southwest Medical University, No. 1, Xianglin Road, Luzhou, Sichuan, 646000, People’s Republic of China, Email qingyuan@swmu.edu.cn Yingchun Ye, Southwest Medical University, No. 1, Xianglin Road, Luzhou, Sichuan, 646000, People’s Republic of China, Email yeyingchun@swmu.edu.cn
Purpose: As a novel candidate in cancer immunotherapy, siglec-15-targeting antibodies hold promise for providing alternative therapeutic strategies to tumors unresponsive to programmed death ligand 1 (PD-L1) antibody therapy. To date, pharmacological development targeting siglec-15 has not yet achieved significant breakthroughs or clinical approval. Therefore, this study aims to develop a novel anti-siglec-15 antibody designed to restore tumor immune normalization.
Methods: In this study, we constructed a phage immune library derived from lymphoid tissues of lung cancer patients using phage display technology and screened the fully human antibodies against siglec-15 antigen from this library. The antibody affinity was detected by Bio-Layer Interferometry, the binding rate of antibody to positively expressing siglec-15 tumor cells was examined by flow cytometry, and the activity of antibody-mediated killer cells against tumor cells was reflected by Antibody-Dependent Cellular Cytotoxicity (ADCC) action. The blockage of proliferation inhibition caused by siglec-15 antigen by antibodies was investigated by t-lymphocyte proliferation assays, and CD8+ T cells were collected from malignant pleural effusion specimens derived from lung cancer patients to determinewhether antibodies could alleviate the immunosuppression present in the tumor microenvironment (TME). The anti-tumor efficacy of the antibody was investigated in vivo by constructing a zebrafish tumor model and a humanized mouse tumor model.
Results: The antibody demonstrated nanomolar affinity and specificity, enhanced antibody-dependent cellular cytotoxicity (ADCC) against tumor cells, reversed T-cell suppression, and reduced CD8+ T-cell exhaustion in vitro analyses. In vivo models confirmed tumor growth inhibition via increased lymphocyte infiltration and activation.
Conclusion: Antibody immune libraries from lymphoid tissues of lung cancer patients can screen specific antibodies against siglec-15 target antigens and exert certain biological functions in vitro and in vivo.
Plain Language Summary: Following PD-1/PD-L1 blockade, siglec-15 has emerged as a compelling therapeutic target for tumor immune normalization, with its specific antibodies potentially addressing clinical resistance to PD-1 inhibitors. Utilizing phage display technology, we developed a lung cancer patient-derived immune library and isolated a novel anti-siglec-15 antibody exhibiting nanomolar affinity and precise antigen specificity, as rigorously validated through Bio-Layer Interferometry (BLI) and ELISA. Functional characterization demonstrated the antibody’s dual mechanism: enhancing lymphocyte-mediated ADCC against tumor cells while reversing siglec-15-induced suppression of T-cell proliferation. Notably, in vitro analyses of malignant pleural effusions, the antibody significantly reduced CD8+ T-cell exhaustion. We found that anti-siglec-15 recombinant antibodies inhibited tumor growth by increasing lymphocyte infiltration and activation in tumor tissues by constructing a zebrafish tumor model and a PBMC humanized mouse tumor model. These findings provide a theoretical framework for the development of anti-siglec-15 targeting antibody drugs and tumor immunonormalization therapy.
Keywords: phage display technology, lymphocyte infiltration, T-cell suppression, malignant pleural effusion, tumor microenvironment
1Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Key Laboratory of Medical Electrophysiology of the Ministry of Education, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Institute of Nuclear Medicine, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Qing Yuan, Southwest Medical University, No. 1, Xianglin Road, Luzhou, Sichuan, 646000, People’s Republic of China, Email qingyuan@swmu.edu.cn Yingchun Ye, Southwest Medical University, No. 1, Xianglin Road, Luzhou, Sichuan, 646000, People’s Republic of China, Email yeyingchun@swmu.edu.cn
Purpose: As a novel candidate in cancer immunotherapy, siglec-15-targeting antibodies hold promise for providing alternative therapeutic strategies to tumors unresponsive to programmed death ligand 1 (PD-L1) antibody therapy. To date, pharmacological development targeting siglec-15 has not yet achieved significant breakthroughs or clinical approval. Therefore, this study aims to develop a novel anti-siglec-15 antibody designed to restore tumor immune normalization.
Methods: In this study, we constructed a phage immune library derived from lymphoid tissues of lung cancer patients using phage display technology and screened the fully human antibodies against siglec-15 antigen from this library. The antibody affinity was detected by Bio-Layer Interferometry, the binding rate of antibody to positively expressing siglec-15 tumor cells was examined by flow cytometry, and the activity of antibody-mediated killer cells against tumor cells was reflected by Antibody-Dependent Cellular Cytotoxicity (ADCC) action. The blockage of proliferation inhibition caused by siglec-15 antigen by antibodies was investigated by t-lymphocyte proliferation assays, and CD8+ T cells were collected from malignant pleural effusion specimens derived from lung cancer patients to determinewhether antibodies could alleviate the immunosuppression present in the tumor microenvironment (TME). The anti-tumor efficacy of the antibody was investigated in vivo by constructing a zebrafish tumor model and a humanized mouse tumor model.
Results: The antibody demonstrated nanomolar affinity and specificity, enhanced antibody-dependent cellular cytotoxicity (ADCC) against tumor cells, reversed T-cell suppression, and reduced CD8+ T-cell exhaustion in vitro analyses. In vivo models confirmed tumor growth inhibition via increased lymphocyte infiltration and activation.
Conclusion: Antibody immune libraries from lymphoid tissues of lung cancer patients can screen specific antibodies against siglec-15 target antigens and exert certain biological functions in vitro and in vivo.
Plain Language Summary: Following PD-1/PD-L1 blockade, siglec-15 has emerged as a compelling therapeutic target for tumor immune normalization, with its specific antibodies potentially addressing clinical resistance to PD-1 inhibitors. Utilizing phage display technology, we developed a lung cancer patient-derived immune library and isolated a novel anti-siglec-15 antibody exhibiting nanomolar affinity and precise antigen specificity, as rigorously validated through Bio-Layer Interferometry (BLI) and ELISA. Functional characterization demonstrated the antibody’s dual mechanism: enhancing lymphocyte-mediated ADCC against tumor cells while reversing siglec-15-induced suppression of T-cell proliferation. Notably, in vitro analyses of malignant pleural effusions, the antibody significantly reduced CD8+ T-cell exhaustion. We found that anti-siglec-15 recombinant antibodies inhibited tumor growth by increasing lymphocyte infiltration and activation in tumor tissues by constructing a zebrafish tumor model and a PBMC humanized mouse tumor model. These findings provide a theoretical framework for the development of anti-siglec-15 targeting antibody drugs and tumor immunonormalization therapy.
Keywords: phage display technology, lymphocyte infiltration, T-cell suppression, malignant pleural effusion, tumor microenvironment