Discovery and Optimization of the Novel Immunotoxins Targeting TROP2 for Cancer Therapy.
- 1Engineering Research Center of Cell & Therapeutic Antibody, School of Pharmacy, Shanghai Jiao Tong University, Ministry of Education, Shanghai 200240, China.
- 2Jecho Institute Co., Ltd., Shanghai 200240, China.
- 3Jecho Laboratories, Inc., Frederick, MD 21704, USA.
Abstract
Background: Trophoblast cell surface antigen 2 (TROP2) is widely overexpressed in epithelial cancers and associated with poor prognosis, representing an attractive target for cancer treatment. Recent clinical studies reported favorable outcomes of TROP2-targeting antibody-drug conjugates. However, heterogeneity of human cancers and development of resistance encourage the exploration of alternative cytotoxic payloads. In this regard, bacterial immunotoxin is a viable treatment option owing to the unique and potent mechanism of action. Methods: We first constructed three immunotoxins by fusing deimmunized Pseudomonas Exotoxin A (PE24) to novel TROP2-targeting single-chain variable fragments identified through phage display, which were screened for high binding and cytotoxic activity against tumor cell lines with distinct TROP2 expression. The lead immunotoxin T3PE was engineered by introducing extra disulfide bonds and an albumin-binding domain (ABD) to generate disulfide-stabilized T3PE (dsT3PE and dsT3PE_ABD_CC). Then, both variants were characterized in stability, cell binding, internalization, pharmacokinetic profiles, and in vitro and in vivo antitumor activities. Results: T3PE bound strongly to TROP2 (EC₅₀ = 0.3824 μg/mL) and exerted potent cytotoxicity against NCI-N87 cells (EC₅₀ = 0.09074 μg/mL), but it displayed poor serum stability and was prone to aggregation. Introduction of disulfide bonds stabilized the immunotoxins while preserving the potent cytotoxic activity, and fusion of ABD extended the plasma half-life 6-fold in mice. Additionally, five doses of either dsT3PE or dsT3PE_ABD_CC at 3 mg/kg could significantly reduce tumor progression in the NCI-N87 mouse xenograft model. Conclusions: Together, these results demonstrated the therapeutic potential of these novel anti-TROP2 immunotoxins against TROP2-overexpressing tumors.
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BibTeX
@article{li2026discovery,
title = {{Discovery and Optimization of the Novel Immunotoxins Targeting TROP2 for Cancer Therapy.}},
author = {Junyan Li and Tanja Poredoš and Shuyi Xu and Lei Wang and Haiyang Yin and Yali Yue and Junjun Liu and Tong Wu and Yanlin Bian and Yueqing Xie and Jianwei Zhu},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/ph19101586},
url = {https://europepmc.org/article/MED/42943283},
note = {CC BY},
}
RIS
TY - JOUR
TI - Discovery and Optimization of the Novel Immunotoxins Targeting TROP2 for Cancer Therapy.
AU - Junyan Li
AU - Tanja Poredoš
AU - Shuyi Xu
AU - Lei Wang
AU - Haiyang Yin
AU - Yali Yue
AU - Junjun Liu
AU - Tong Wu
AU - Yanlin Bian
AU - Yueqing Xie
AU - Jianwei Zhu
PY - 2026
DA - 2026/10/07
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101586
UR - https://europepmc.org/article/MED/42943283
AB - Background: Trophoblast cell surface antigen 2 (TROP2) is widely overexpressed in epithelial cancers and associated with poor prognosis, representing an attractive target for cancer treatment. Recent clinical studies reported favorable outcomes of TROP2-targeting antibody-drug conjugates. However, heterogeneity of human cancers and development of resistance encourage the exploration of alternative cytotoxic payloads. In this regard, bacterial immunotoxin is a viable treatment option owing to the unique and potent mechanism of action. Methods: We first constructed three immunotoxins by fusing deimmunized Pseudomonas Exotoxin A (PE24) to novel TROP2-targeting single-chain variable fragments identified through phage display, which were screened for high binding and cytotoxic activity against tumor cell lines with distinct TROP2 expression. The lead immunotoxin T3PE was engineered by introducing extra disulfide bonds and an albumin-binding domain (ABD) to generate disulfide-stabilized T3PE (dsT3PE and dsT3PE_ABD_CC). Then, both variants were characterized in stability, cell binding, internalization, pharmacokinetic profiles, and in vitro and in vivo antitumor activities. Results: T3PE bound strongly to TROP2 (EC₅₀ = 0.3824 μg/mL) and exerted potent cytotoxicity against NCI-N87 cells (EC₅₀ = 0.09074 μg/mL), but it displayed poor serum stability and was prone to aggregation. Introduction of disulfide bonds stabilized the immunotoxins while preserving the potent cytotoxic activity, and fusion of ABD extended the plasma half-life 6-fold in mice. Additionally, five doses of either dsT3PE or dsT3PE_ABD_CC at 3 mg/kg could significantly reduce tumor progression in the NCI-N87 mouse xenograft model. Conclusions: Together, these results demonstrated the therapeutic potential of these novel anti-TROP2 immunotoxins against TROP2-overexpressing tumors.
SN - 1424-8247
ER -