A multifunctional T-cell engager containing CD80 enhances prostate cancer treatment
Abstract Background T-cell engagers (TCEs), the most extensively studied class of bispecific antibodies, redirect effector T cells to tumor cells to induce immune synapse formation, T-cell activation, and subsequent tumor cell killing. However, their therapeutic efficacy in solid tumors is limited b...
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| Format: | Article |
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Springer
2025-07-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04121-0 |
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| author | Disen Nie Yao Jiang Hui Li Keying Zhang Zhengxuan Li Tong Lu Yu Li Donghui Han Changhong Shi Nianzeng Xing Fa Yang Weihong Wen Weijun Qin |
| author_facet | Disen Nie Yao Jiang Hui Li Keying Zhang Zhengxuan Li Tong Lu Yu Li Donghui Han Changhong Shi Nianzeng Xing Fa Yang Weihong Wen Weijun Qin |
| author_sort | Disen Nie |
| collection | DOAJ |
| description | Abstract Background T-cell engagers (TCEs), the most extensively studied class of bispecific antibodies, redirect effector T cells to tumor cells to induce immune synapse formation, T-cell activation, and subsequent tumor cell killing. However, their therapeutic efficacy in solid tumors is limited by immunosuppressive mechanisms within the tumor microenvironment (TME). To address this challenge, we engineered an enhanced PSMA/CD3 bispecific antibody by incorporating the extracellular domain of CD80, which provides a co-stimulatory signal to counteract T-cell inhibition in prostate cancer. This trifunctional antibody is designated as TriTE-N13. Methods We engineered the fully humanized fusion antibody TriTE-N13 using gene editing and eukaryotic expression systems. In vitro, we evaluated its ability to activate and proliferate T cells, as well as its cytotoxicity against PSMA+ tumor cells in both 2D co-culture and 3D spheroid models. Additionally, we assessed the in vivo antitumor efficacy and safety of TriTE-N13 using human immune-reconstituted mouse models bearing prostate cancer xenografts. Results In vitro, TriTE-N13 demonstrated robust activation of human T cells and high-affinity binding to both human PSMA and CD3 antigens. Furthermore, TriTE-N13 effectively mediated T-cell-dependent cytotoxicity against PSMA-positive prostate cancer cells. In vivo studies revealed that TriTE-N13 achieved significantly greater tumor volume reduction compared to conventional bispecific TCEs, particularly in established large tumors. Conclusions Our findings indicate that incorporating CD80 as a co-stimulatory signal substantially enhances the antitumor efficacy of TCEs against solid tumors. These results position TriTE-N13 as a promising immunotherapeutic candidate for advanced prostate cancer treatment. |
| format | Article |
| id | doaj-art-8a8bc215be3b4c20a9a2d832b30de2a3 |
| institution | DOAJ |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-8a8bc215be3b4c20a9a2d832b30de2a32025-08-20T03:05:29ZengSpringerCancer Immunology, Immunotherapy1432-08512025-07-0174811210.1007/s00262-025-04121-0A multifunctional T-cell engager containing CD80 enhances prostate cancer treatmentDisen Nie0Yao Jiang1Hui Li2Keying Zhang3Zhengxuan Li4Tong Lu5Yu Li6Donghui Han7Changhong Shi8Nianzeng Xing9Fa Yang10Weihong Wen11Weijun Qin12Department of Urology, Xijing Hospital, Fourth Military Medical UniversityDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityLaboratory Animal Center, Fourth Military Medical UniversityDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityLaboratory Animal Center, Fourth Military Medical UniversityDepartment of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityInstitute of Medical Research, Northwestern Polytechnical UniversityDepartment of Urology, Xijing Hospital, Fourth Military Medical UniversityAbstract Background T-cell engagers (TCEs), the most extensively studied class of bispecific antibodies, redirect effector T cells to tumor cells to induce immune synapse formation, T-cell activation, and subsequent tumor cell killing. However, their therapeutic efficacy in solid tumors is limited by immunosuppressive mechanisms within the tumor microenvironment (TME). To address this challenge, we engineered an enhanced PSMA/CD3 bispecific antibody by incorporating the extracellular domain of CD80, which provides a co-stimulatory signal to counteract T-cell inhibition in prostate cancer. This trifunctional antibody is designated as TriTE-N13. Methods We engineered the fully humanized fusion antibody TriTE-N13 using gene editing and eukaryotic expression systems. In vitro, we evaluated its ability to activate and proliferate T cells, as well as its cytotoxicity against PSMA+ tumor cells in both 2D co-culture and 3D spheroid models. Additionally, we assessed the in vivo antitumor efficacy and safety of TriTE-N13 using human immune-reconstituted mouse models bearing prostate cancer xenografts. Results In vitro, TriTE-N13 demonstrated robust activation of human T cells and high-affinity binding to both human PSMA and CD3 antigens. Furthermore, TriTE-N13 effectively mediated T-cell-dependent cytotoxicity against PSMA-positive prostate cancer cells. In vivo studies revealed that TriTE-N13 achieved significantly greater tumor volume reduction compared to conventional bispecific TCEs, particularly in established large tumors. Conclusions Our findings indicate that incorporating CD80 as a co-stimulatory signal substantially enhances the antitumor efficacy of TCEs against solid tumors. These results position TriTE-N13 as a promising immunotherapeutic candidate for advanced prostate cancer treatment.https://doi.org/10.1007/s00262-025-04121-0T-cell engagerCD80Prostate cancerTri-specific antibodiesPSMA/CD3 antigens |
| spellingShingle | Disen Nie Yao Jiang Hui Li Keying Zhang Zhengxuan Li Tong Lu Yu Li Donghui Han Changhong Shi Nianzeng Xing Fa Yang Weihong Wen Weijun Qin A multifunctional T-cell engager containing CD80 enhances prostate cancer treatment Cancer Immunology, Immunotherapy T-cell engager CD80 Prostate cancer Tri-specific antibodies PSMA/CD3 antigens |
| title | A multifunctional T-cell engager containing CD80 enhances prostate cancer treatment |
| title_full | A multifunctional T-cell engager containing CD80 enhances prostate cancer treatment |
| title_fullStr | A multifunctional T-cell engager containing CD80 enhances prostate cancer treatment |
| title_full_unstemmed | A multifunctional T-cell engager containing CD80 enhances prostate cancer treatment |
| title_short | A multifunctional T-cell engager containing CD80 enhances prostate cancer treatment |
| title_sort | multifunctional t cell engager containing cd80 enhances prostate cancer treatment |
| topic | T-cell engager CD80 Prostate cancer Tri-specific antibodies PSMA/CD3 antigens |
| url | https://doi.org/10.1007/s00262-025-04121-0 |
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